strychnine and Seizures

　During the preclinical research period of drug development, animal testing is widely used to help screen out a drug's dangerous side effects. However, it remains difficult to predict side effects within the central nervous system. Here, we introduce a machine learning-based in vitro system designed to detect seizure-inducing side effects before clinical trial. We recorded local field potentials from the CA1 alveus in acute mouse neocortico-hippocampal slices that were bath-perfused with each of 14 different drugs, and at 5 different concentrations of each drug. For each of these experimental conditions, we collected seizure-like neuronal activity and merged their waveforms as one graphic image, which was further converted into a feature vector using Caffe, an open framework for deep learning. In the space of the first two principal components, the support vector machine completely separated the vectors (i.e., doses of individual drugs) that induced seizure-like events, and identified diphenhydramine, enoxacin, strychnine and theophylline as "seizure-inducing" drugs, which have indeed been reported to induce seizures in clinical situations. Thus, this artificial intelligence-based classification may provide a new platform to pre-clinically detect seizure-inducing side effects of drugs.

Topics: Animals; Diphenhydramine; Drug Discovery; Drug Evaluation, Preclinical; Drug-Related Side Effects and Adverse Reactions; Enoxacin; Forecasting; Humans; Machine Learning; Mice; Seizures; Strychnine; Theophylline

Poisons are widespread in plants and animals and humankind has often tried to turn them to its own advantage. Owing to their poisonous properties, some species of Strychnos genus have been employed mainly in hunting and fishing, as an adjunct to weapons used not only in the search of food and clothes, but also for preventing depredation by wild animals. They have been employed for martial and criminal purposes and also as a means of determining guilt or innocence. By their nature, poisons such as strychnine and curare affect the functioning of the victim's body; this also means that they have been, and are, an important source of pharmacological tools and medicines all over the world. With such potentially dangerous substances, care in medication is essential to avoid complications by overdose. All these points are approached in the present review.

Topics: Alkaloids; Curare; Humans; Neuromuscular Agents; Receptors, Glycine; Seizures; Strychnos

Generalized convulsive seizures can be triggered by sensory stimuli in animals treated with subthreshold levels of convulsant drugs. The sensory responses of the brain-stem reticular formation (RF) are extensively enhanced before seizure initiation with bicuculline, strychnine, pentylenetetrazol, physostigmine, and several other convulsants. The responses of RF neurons are more greatly enhanced than other nonprimary neurons in the hippocampus, amygdala, and cortex. The action of systemically administered convulsants involves direct effects on reticular neurons, because RF response enhancement is also seen with iontophoresis. RF neuronal response enhancement does not appear to involve actions of convulsants on specific neurotransmitters, because agents that act on different transmitters enhance the responses of the same RF neuron when given sequentially. Anticonvulsant drugs reverse the effects of convulsants on reticular neurons. The convulsant-induced response enhancement in the RF may involve blockade of inhibitory postsynaptic potentials and/or threshold reduction, effects observed in vitro. RF neurons may be most susceptible to convulsant action because these agents block habituation and other mechanisms that normally restrict RF neuronal responsiveness. The massive synchronization of reticular neuronal firing by sensory stimuli may induce seizures by intense output over widespread RF projection pathways analogous to the afterdischarge seizures seen with electrical stimulation of the RF.

Topics: Animals; Anticonvulsants; Bemegride; Bicuculline; Convulsants; Neurons; Reticular Formation; Seizures; Strychnine

Topics: Amino Acids; Animals; Brain; Central Nervous System; Convulsants; GABA Antagonists; gamma-Aminobutyric Acid; Glycine; Neural Inhibition; Neurotransmitter Agents; Receptors, Cell Surface; Receptors, Glycine; Seizures; Spinal Cord; Strychnine

From binding studies using 3H-GABA and 3H-strychnine in dissected human brain material, inhibitory amino acid neurotransmitter receptors have a widespread distribution in the human CNS. Generally GABA receptors are predominant in the forebrain and upper brainstem whereas glycine receptors are more localized in the lower brainstem and spinal cord. Some areas (eg. the substantia nigra) have appreciable quantities of both receptors. Although glycine receptors are altered in some pathological conditions (eg. in Parkinson's disease, in the substantia nigra) the neuropharmacology of the glycine system is still poorly understood. On the other hand the GABA system has been intensively studied. Dysfunction of GABA receptors occurs in various neurological states, as epilepsy, Parkinson's disease and Huntington's chorea. Furthermore GABA agonists are active in animal models for dyskinesia, epilepsy and depression, amongst others. Clinical studies with progabide confirm these findings in animal models, and suggest that low-medium affinity GABA agonists are more appropriate clinical agents than are high or very high affinity GABA agonists. From these and many other findings there appears to be a very large potential for creating new pharmacological agents for different neuropsychiatric disorders based on agonist activity at inhibitory amino-acid receptors. From the example of progabide these compounds can be made not only specific for the receptor involved, but also to have a lower incidence of neurotoxic effects than presently available drugs.

Topics: Central Nervous System; Epilepsy; Humans; Huntington Disease; Mental Disorders; Nervous System Diseases; Neurotransmitter Agents; Parkinson Disease; Receptors, Cell Surface; Receptors, GABA-A; Receptors, Glycine; Seizures; Strychnine

Topics: Acoustic Stimulation; Adrenal Insufficiency; Age Factors; Animals; Body Constitution; Cats; Disease Susceptibility; Dogs; Epilepsy; Female; Genetic Variation; Humans; Hyperthyroidism; Mice; Neurotransmitter Agents; Pancreatic Diseases; Pregnancy; Seizures; Sex Factors; Strychnine

Topics: Animals; Anticonvulsants; Brain; Cell Membrane Permeability; Cerebral Cortex; Electric Stimulation; Ethyl Chloride; Metals; Mice; Mice, Inbred DBA; Ouabain; Pentylenetetrazole; Rabbits; Rats; Seizures; Sodium-Potassium-Exchanging ATPase; Strychnine; Synaptic Transmission; Tetanus Toxin

Recently, electrophysiological studies on sleep and wakefulness in birds have yielded useful results. Furthermore, recent evidence obtained in behavioral and electroencephalographical investigations of epileptic birds, induced neuropharmacologically or genetically, have led to recognition of the fact that epileptic seizures are present in aves, and that these seizures reveal many similarities between mammalian and avian epilepsy. While the investigation of birds is of obvrious value for demonstrating the neuropharmacological interrelationship with the brain, comparison of the correlation between abnormal behavior and the electroencephalogram in birds and higher vertebrates requires further research. In the present paper, normal and abnormal electroencephalographic activity associated with behavior of birds is reviewed. It was concluded that birds provide a useful preparation for studying experimental epilepsy.

Topics: Animals; Behavior, Animal; Bird Diseases; Birds; Brain; Chickens; Coturnix; Electric Stimulation; Electroencephalography; Epilepsy; Female; Male; Movement; Pentylenetetrazole; Poultry Diseases; Seizures; Sleep; Strychnine; Turkeys; Vocalization, Animal; Wakefulness

Topics: Animals; Benzodiazepines; Cerebellum; Chlordiazepoxide; Cyclic AMP; Diazepam; gamma-Aminobutyric Acid; Ganglia, Autonomic; Glycine; Humans; Isoniazid; Medulla Oblongata; Pentylenetetrazole; Phenobarbital; Phenytoin; Picrotoxin; Receptors, Drug; Seizures; Sensory Receptor Cells; Spinal Cord; Strychnine; Substantia Nigra

Topics: Aminobutyrates; Animals; Choline; Epilepsy; Humans; Hydroxybutyrates; Hypertension; Hypoxia; Mental Disorders; Mice; Nervous System Diseases; Oxygen; Psychopharmacology; Seizures; Sound; Strychnine

Topics: Animals; Anticonvulsants; Biological Assay; Brain Injuries; Diagnosis; Electroconvulsive Therapy; Electroshock; Humans; Methionine Sulfoximine; Methods; Pentylenetetrazole; Phenobarbital; Phenytoin; Picrotoxin; Seizures; Strychnine; Thiosemicarbazones; Trimethadione; Urea

Topics: Ammonia; Animals; Biochemical Phenomena; Biochemistry; Cell Membrane; Epilepsy; Fatty Acids; Humans; Methionine; Nervous System; Neurons; Picrotoxin; Potassium; Seizures; Sodium; Strychnine

Different parts of Malvaviscus arboreus Dill. Ex Cav. (M. arboreus) are traditionally used in the West Region of Cameroon to treat many diseases, including epilepsy.. To determine which part of M. arboreus offers the best anticonvulsant effect, and to assess the acute and sub-acute toxicity of the part of interest.. the anticonvulsant effect of the aqueous lyophilisate of the decoction of flowers, leaves, stems and roots of M. arboreus at various doses was evaluated and compared on the model of acute epileptic seizures induced by pentylenetetrazole (PTZ) (70 mg/kg), injected 1 h after oral administration of the various extracts. Out of these plant parts, the leaves were then selected to prepare the hydroethanolic extract and its anticonvulsant effect against PTZ at the doses of 122.5, 245 and 490 mg/kg, as well as its acute toxicity were compared with those of the aqueous lyophilisate of the leaves. The anticonvulsant effect of the aqueous lyophilisate of M. arboreus leaves was further evaluated on models of acute epileptic seizures induced by picrotoxin (PIC) (7.5 mg/kg), strychnine (STR) (2.5 mg/kg) and pilocarpine (350 mg/kg). The 28 days sub-acute toxicity, as well as the quantitative phytochemistry and the in vitro antioxidant potential (FRAP, DPPH, ABTS+) of the aqueous lyophilisate of the leaves of M. arboreus were also evaluated.. M. arboreus leaves showed the best anticonvulsant effect and the aqueous lyophilisate was the best extract. The latter significantly protected the animals against convulsions induced by PTZ (71.43%) (p < 0.01), PIC (57.14%) (p < 0.05) and STR (42%) and had no effect on pilocarpine-induced seizures. Furthermore, it showed no acute or sub-acute toxicity, and revealed a high content of flavonoids, saponins, tannins and alkaloids, and antioxidant activity in vitro.. The aqueous lyophilisate of the leaves of M. arboreus offers the best anticonvulsant effect on the extraction solvent used, and it would act mainly via a potentiation of the inhibitory systems of the brain (GABA, Glycine). In addition, its richness in bioactive compounds gives it an antioxidant potential, and it is not toxic in acute and sub-acute toxicity. All this justifies at least in part its empirical uses, and makes M. arboreus a candidate for the alternative treatment of epilepsy.

Topics: Anethum graveolens; Animals; Anticonvulsants; Antioxidants; Epilepsy; Pentylenetetrazole; Picrotoxin; Pilocarpine; Plant Extracts; Seizures; Strychnine; Water

Strychnine poisoning induces seizures that result in loss of control of airway muscles, leading to asphyxiation and subsequent death. Current treatment options are limited, requiring hands-on medical care and isolation to low-stimulus environments. Anticonvulsants and muscle relaxants have shown limited success in cases of severe toxicity. Furthermore, nonfatal strychnine poisoning is likely to result in long-term muscular and cognitive damage. Due to its potency, accessibility, and lack of effective antidotes, strychnine poses a unique threat for mass casualty incidents. As a first step toward developing an anti-strychnine immunotherapy to reduce or prevent strychnine-induced seizures, a strychnine vaccine was synthesized using subunit keyhole limpet hemocyanin. Mice were vaccinated with the strychnine immunoconjugate and then given a 0.75 mg/kg IP challenge of strychnine and observed for seizures for 30 min. Vaccination reduced strychnine-induced events, and serum strychnine levels were increased while brain strychnine levels were decreased in vaccinated animals compared to the control. These data demonstrate that strychnine-specific antibodies can block the seizure-inducing effects of strychnine and could be used to develop a therapeutic for strychnine poisoning.

Topics: Animals; Anticonvulsants; Brain; Immunoconjugates; Mice; Seizures; Strychnine

Epilepsy is one of the most prevalent neurological illnesses defined by periodic seizures with or without loss of consciousness caused by aberrant neural activity. There are many allopathic medications available for the treatment of epilepsy such as phenytoin (PHY), but the side effects are a major concern. Therefore, the present study involved the evaluation of the pharmacological significance of. STR (3.5 mg/kg, i.p.) was injected into male rats 30 minutes after the pre-treatment of a standard drug (PHY: 20 mg/kg) and the two doses of EAV (EAV-200 and EAV-400 mg/kg, p.o.) to the respective groups to cause the convulsions. The anti-convulsant effect of EAV-200 and EAV-400 against STR-induced convulsion in rats was investigated in terms of convulsion onset, duration of convulsions, number of convulsions, and convulsion score. Furthermore, the mitochondrial function and integrity in the brain's prefrontal cortex (PFC) were also estimated.. EAV-400 significantly increased the onset of convulsion from 61.67 ± 3.051 to 119.2 ± 2.738 and reduced the STR-induced duration of convulsions from 144.8 ± 3.582 to 69.17 ± 3.736, number of convulsions from 4.000 ± 0.1592 to 1.533 ± 0.1542, and convulsion score from 5.000 ± 0.3651 to 2.833 ± 0.3073 in rats. EAV-400 significantly attenuated the STR-induced decrease in the mitochondrial function and integrity of the rat PFC. In rats, EAV-400 significantly accelerated the onset of convulsions while decreasing the STR-induced duration, frequency, and score.. Based on investigational findings, EAV-400 could be inferred to be a possible anti-epileptic option for the treatment of epilepsy of this plan in preclinical research.

Topics: Amaranthus; Animals; Anticonvulsants; Epilepsy; Male; Rats; Seizures; Strychnine

Seizure-like burst activities are induced by blockade of GABAA and/or glycine receptors in various spinal ventral roots of brainstem-spinal cord preparation from neonatal rodents. We found that this is not applicable to the phrenic nerve and that a new inhibitory descending pathway may suppress seizure-like activity in the phrenic nerve. Experiments were performed in brainstem-spinal cord preparation from newborn rats (age: 0-1 day). Left phrenic nerve and right C4 activities were recorded simultaneously. When GABAA and glycine receptors were blocked by 10 μM bicuculline and 10 μM strychnine (Bic+Str), seizure-like burst activities appeared in the fourth cervical ventral root (C4) but not the phrenic nerve. After making a transverse section at C1, the inspiratory burst activity disappeared from both C4 and the phrenic nerve, whereas seizure-like activity appeared in both nerves. We hypothesized that inhibitory descending pathways other than those via GABAA and/or glycine receptors (from the medulla to the spinal cord) work to avoid disturbance of regular respiratory-related diaphragm contraction by seizure-like activity. We found that cannabinoid receptor antagonist, AM251 was effective for the induction of seizure-like activity by Bic+Str in the phrenic nerve in brainstem-spinal cord preparation. Cannabinoid receptors may be involved in this descending inhibitory system.

Topics: Animals; Animals, Newborn; Bicuculline; Phrenic Nerve; Rats; Receptors, Cannabinoid; Receptors, Glycine; Seizures; Spinal Cord; Strychnine

Newbouldia laevis is a popular medicinal plant whose leaves and roots are used in Nigeria as ethnomedicinal prescriptions for pain, inflammation, convulsion, and epilepsy. These claims have not been scientifically verified prior to this study.. To determine pharmacognostic profiles of the leaves and roots and evaluate the analgesic, anti-inflammatory, and anticonvulsant activities of methanol leaf and root extracts in Wistar rats.. The pharmacognostic profiles of the leaves and roots were determined using standard procedures to serve as fingerprints for the plant. The methanol leaf and root extracts of Newbouldia laevis were tested for acute toxicity using the OECD's up and down method at the maximum dose of 2000 mg/kg (orally) in Wistar rats. Analgesic studies were carried out in acetic acid-induced writhing in rats and tail immersion. The anti-inflammatory activity of the extracts was evaluated using carrageenan-induced rat paw-oedema and formalin-induced inflammation in rats' mode. The anticonvulsant activity was determined using strychnine-induced, pentylenetetrazol-induced, and maximal electroshock-induced rat convulsion models. For each of these studies, the extracts doses of 100, 200 and 400 mg/kg were administered to the rats following the oral route.. Our study revealed some pharmacognostic profiles of Newbouldia laevis leaves and roots that are vital for its identification from closely related species often used for adulteration in traditional medicine. The study further showed that the leaf and root extracts of the plant possessed dose-dependent analgesics, anti-inflammatory and anti-convulsant activities in rats, thus, justifying its use for the treatment of these diseases in Nigerian traditional medicine. There is a need to further study its mechanisms of action towards drug discovery.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Anticonvulsants; Edema; Inflammation; Methanol; Pentylenetetrazole; Plant Extracts; Plant Leaves; Rats; Rats, Wistar; Seizures; Strychnine

Poppy seed tea is used for its opioid effects and contains multiple opium alkaloids, including morphine, codeine, papaverine, and thebaine. Animal studies indicate thebaine has strychnine-like properties, but there is limited literature describing human thebaine poisoning. We describe a cluster of acute thebaine poisoning in people ingesting tea made using poppy seeds with high thebaine content that entered the Australian food supply chain.. This is an observational study of patients poisoned after drinking poppy seed tea. Cases were identified by three prospective toxicovigilance systems: the Emerging Drug Network of Australia collaboration, the New South Wales Prescription, Recreational and Illicit Substance Evaluation program, and the Emerging Drugs Network of Australia Victoria study. We report characteristics of clinical toxicity in cases with reported ingestion of poppy seed tea and analytical confirmation of thebaine exposure.. Forty cases presenting with multi-system toxicity following poppy seed tea ingestion were identified across seven Australian states/territories from November 2022 to January 2023. Blood testing in 23 cases confirmed high thebaine concentrations. All 23 were male (median age 35, range 16-71 years). All patients experienced muscle spasms. Rigidity was described in nine, convulsions in six, while rhabdomyolysis, acute kidney injury, and metabolic acidosis occurred in five patients. There were two cardiac arrests. The thebaine median admission blood concentration was 1.6 mg/L, with a range of 0.1-5.6 mg/L, and was the dominant opium alkaloid in all samples. Convulsions, acute kidney injury, metabolic acidosis, and cardiac arrest were associated with increasing median thebaine concentrations. Four patients were managed in the Intensive Care Unit, with two receiving continuous kidney replacement therapy (one also received intermittent haemodialysis) for kidney injury. There was one death.. Thebaine toxicity, like strychnine poisoning, resulted in neuromuscular excitation characterized by muscle spasm, rigidity, and convulsions. Severe toxicity, including acute kidney injury, metabolic acidosis, and cardiac arrest, appears dose-dependent.

Topics: Acidosis; Acute Kidney Injury; Adolescent; Adult; Aged; Animals; Codeine; Female; Heart Arrest; Humans; Male; Middle Aged; Morphine; Opium; Papaver; Prospective Studies; Seeds; Seizures; Strychnine; Tea; Thebaine; Victoria; Young Adult

The prevalence of epilepsy in the world population together with a high percentage of patients resistant to existing antiepileptic drugs (AEDs) stimulates the constant search for new approaches to the treatment of the disease. Previously a significant anticonvulsant potential of cardiac glycoside digoxin has been verified by enhancing a weak activity of AEDs in low doses under screening models of seizures induced by pentylenetetrazole and maximal electroshock. The aim of the present study is to investigate the influence of digoxin at a sub-cardiotonic dose on the anticonvulsant activity of valproate, levetiracetam, and topiramate in models of primary generalized seizures with different neurochemical mechanisms. A total of 264 random-bred male albino mice have been used. AEDs were administered 30 min before seizure induction once intragastrically at conditionally effective (ED50) and sub-effective (½ ED50) doses: sodium valproate and topiramate - at doses of 300 and 150 mg/kg; levetiracetam - at doses of 100 and 50 mg/kg. Digoxin was administered once subcutaneously at a dose of 0.8 mg/kg body weight (1/10 LD50) 10-15 min before seizure induction. Picrotoxin (aqueous solution 2.5 mg/kg, subcutaneously), thiosemicarbazide (aqueous solution 25 mg/kg, intraperitoneally), strychnine (aqueous solution 1.2 mg/kg, subcutaneously), camphor (oil solution 1000 mg/kg, intraperitoneally) have been used as convulsive agents for seizure induction. It was found that under the conditions of primary generalized seizures induced by picrotoxin, thiosemicarbazide, strychnine, and camphor, digoxin not only shows its own strong anticonvulsant activity but also significantly enhances the anticonvulsant potential of classical AEDs sodium valproate, levetiracetam, and topiramate. The obtained results substantiate the expediency of further in-depth study of digoxin as an anticonvulsant drug, in particular, the in-depth study of neurochemical mechanisms of its action.

Topics: Animals; Anticonvulsants; Camphor; Cardiotonic Agents; Digoxin; Levetiracetam; Male; Mice; Picrotoxin; Seizures; Strychnine; Topiramate; Valproic Acid

The anticonvulsant spectrum of the original promising anticonvulsant N-[(2,4-dichlorophenyl) methyl]-2-(2,4-dioxo-1H-quinazolin-3-yl) acetamide was studied. The compound had a pronounced anticonvulsant effect, significantly reducing the mortality of mice in models of seizures induced by pentylenetetrazole, picrotoxin, strychnine, and caffeine. In the thiosemicarbazideinduced seizure model, the test compound did not reduce mortality. The obtained results indicated that the mechanism of anticonvulsant action involved GABA-ergic (effective in models of pentylenetetrazole and picrotoxin-induced seizures), glycinergic (efficiency in the strychnine model of paroxysms), and adenosinergic (effectiveness in the model of caffeine induced seizures). Molecular docking of a promising anticonvulsant to anticonvulsant biotargets follow the mechanisms of chemo-induced seizures, namely GABA, glycine, and adenosine receptors type A2A, GABAAT, and BCAT enzymes. The conformity between in vivo and in silico studies results was revealed.

Topics: Acetamides; Action Spectrum; Animals; Anticonvulsants; Caffeine; gamma-Aminobutyric Acid; Mice; Molecular Docking Simulation; Pentylenetetrazole; Picrotoxin; Seizures; Strychnine

Herbal medicines have gained tremendous surge of interest in recent years. M. nigra leaves are a rich source of phenolics which are well-known for their antioxidant property. Morus nigra popularly known as black mulberry is considered to be the most significant species of genus Morus. This study was designed to evaluate its activity on seizure model in different doses. Five groups were made comprising of n=10 animals in each group respectively. Group I was on distilled water, Group II was administered with reference drug diazepam and Group III, IV and V were on 125mg/kg, 250mg/kg and 500mg/kg dose of Morus nigra for 15 days prior to experiment. On day 16th all animals were administered with strychnine after 30 minutes of respective treatments and three parameters were recorded i.e. duration, frequency and onset of seizures. M. nigra treatment showed significant seizure protection as noted by delayed latency of seizures (P<0.05), decrease in frequency and jerk's duration (P<0.05) in comparison to control and reference standard. Most significant (P<0.05) anticonvulsant effects were observed with 500mg/kg dose. Anticonvulsant activity of M. nigra could be due to potentiation of both Gabaergic and glycinergic activities. Antiepileptic potential of extract could also be amplified due to its antioxidant activity. This could serve as a non-pharmacological treatment for seizure management.

Topics: Animals; Anticonvulsants; Brain; Disease Models, Animal; Fruit; Male; Mice; Morus; Plant Extracts; Seizures; Strychnine; Time Factors

The decoction from the stem bark of Psychotria camptopus (Rubiaceae) is used in the Cameroonian pharmacopoeia to treat neurological pathologies including epilepsy.. The present work was undertaken to study the anticonvulsant properties of the aqueous (AE) and methanol (ME) extracts from the stem bark of P. camptopus in acute models of epileptic seizures in Wistar rats.. AE and ME were obtained by decoction and maceration of the stem bark powder in water and methanol, respectively. They were tested orally at the doses of 40, 80 and 120 mg/kg, on the latency of onset and duration of epileptic seizures induced by pentylene tetrazole (PTZ, 70 mg/kg, i.p.). The kinetic effect of both extracts at 120 mg/kg was evaluated. Their effects on diazepam (50 mg/kg) induced sleep and strychnine (STR, 2.5 mg/kg, i.p.) induced seizures were determined. ME was further tested on picrotoxin (PIC, 7.5 mg/kg, i.p.) and thiosemicarbazide (TSC, 50 mg/kg, i.p.) induced seizure models. The phytochemical composition of ME was assessed using LC-MS method, as well as its acute toxicity.. AE and ME significantly (p < 0.001) reduced the duration of seizures in both PTZ and STR models. Their maximal effect was observed at 1 h after administration, though their effect at 120 mg/kg was maintained (p < 0.05) up to 24 h post-treatment. Both extracts significantly (p < 0.01) reduced sleep duration. ME significantly (p < 0.001) increased the latency of rat death on PIC-induced convulsions. In TSC rats, ME significantly (p < 0.001) delayed the latency to the first convulsion, and decreased the duration and frequency of convulsions. ME showed no acute toxicity while its phytochemical screening revealed the presence of two flavonoids (Rutin and Butin), two triterpenoid saponins (Psycotrianoside B and Bauerenone) and four alkaloids (10-Hydroxy-antirhine, 10-hydroxy-iso-deppeaninol, Emetine and Hodkinsine). In conclusion, AE and ME from the stem bark of P. camptopus have comparable anticonvulsant properties. The effect of ME is likely due to the presence of flavonoids and alkaloid and the activation of GABA pathway. These results further justify and support the use of P. camptopus in traditional medicine for the treatment of epilepsy.

Topics: Animals; Anticonvulsants; Behavior, Animal; Diazepam; Disease Models, Animal; Epilepsy; Methanol; Mice; Pentylenetetrazole; Phytochemicals; Picrotoxin; Plant Bark; Plant Extracts; Plant Stems; Psychotria; Rats, Wistar; Seizures; Semicarbazides; Sleep; Sleep Latency; Strychnine; Water

Topics: Animals; Anti-Anxiety Agents; Anticonvulsants; Antidepressive Agents; Behavior, Animal; Exploratory Behavior; Flavones; Hypnotics and Sedatives; Male; Mice, Inbred BALB C; Rotarod Performance Test; Seizures; Strychnine; Swimming

The inhibitory glycine receptor (GlyR) is a key mediator of synaptic signalling in spinal cord, brain stem, and higher centres of the central nervous system. We examined the glycinergic activity of sarcophine (SN), a marine terpenoid known for its various biological activities, and its trans-diol derivative (7S, 8R)-dihydroxy-deepoxysarcophine (DSN). SN was isolated from the Red Sea soft coral Sacrophyton glaucum, DSN was semisynthesized by hydrolysis of the epoxide ring. In cytotoxicity tests against HEK293 cells, SN and DSN had LD

Topics: 4-Butyrolactone; Animals; Anthozoa; Binding Sites; Binding, Competitive; Brain; Disease Models, Animal; Excitatory Amino Acid Antagonists; HEK293 Cells; Humans; Male; Mice; Protein Binding; Receptors, Glycine; Seizures; Strychnine

An imbalance between inhibitory (GABA) and excitatory (Glutamate) neurotransmission contribute to the development of epilepsy. Earlier studies reported that dysregulation of GABA and glutamatergic activities resulted in status epilepticus (SE) and ultimately support the development of temporal lobe epilepsy (TLE), a type of resistant epilepsy. In the earlier work, 2-propanone-1,3,5,5-trimethyl-2-cyclohexen-1-ylidine demonstrated anticonvulsant activity against pentylenetetrazole (PTZ)-induced seizures. Apart from the PTZ-induced TLE, the dysregulation muscaranic receptors and glycine receptors are also widely reported phenomena in the development of temporal lobe epilepsy. Keeping the role of these two receptors in epilepsy, the present work investigated the effect of 2-propanone-1,3,5,5-trimethyl-2-cyclohexen-1-ylidine in pilocarpine-induced and strychnine-induced seizure models. Our results demonstrated that 2-propanone-1,3,5,5-trimethyl-2-cyclohexen-1-ylidine significantly delayed the onset of seizure with maximum protection from SE in pilocarpine-induced seizure model. However, the test compound did not revealed any effect on strychnine-induced seizures in mice. Based on these observations, we suggest that 2-propanone-1,3,5,5-trimethyl-2-cyclohexen-1-ylidine could be a potential candidate in reduction of SE and treatment of temporal lobe epilepsy (TLE) in future.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Epilepsy; Male; Mice; Pentylenetetrazole; Pilocarpine; Seizures; Strychnine

The inspiratory motor activities are greater in the intercostal muscles positioned at more rostral thoracic segments. This rostro-caudal gradient of the thoracic inspiratory motor activity is thought to be generated by the spinal interneurons. To clarify the involvement of the inhibitory thoracic interneurons in this rostro-caudal gradient, we examined the effects of 10 μM strychnine, an antagonist of glycine and GABA

Topics: Animals; Animals, Newborn; Brain Stem; gamma-Aminobutyric Acid; Glycine; Inhalation; Interneurons; Movement; Neural Inhibition; Neurotransmitter Agents; Rats, Wistar; Receptors, GABA-A; Receptors, Glycine; Respiratory Muscles; Seizures; Spinal Nerve Roots; Strychnine; Thoracic Vertebrae; Tissue Culture Techniques; Voltage-Sensitive Dye Imaging

The aim of the study was to evaluate the anticonvulsant and neuroprotective activity of Cocculus laurifolius D.C leaves in albino wistar rats against strychnine induced convulsions. Initially the extract was investigated for acute oral toxicity testing in order to examine any signs of toxicity and mortality. For anticonvulsant activity, the ethanolic extract was evaluated at doses 200 and 400 mg/kg, p.o. against strychnine induced convulsions model, at 1, 7, 15 and 30th day of treatment. Meanwhile, the neuroprotective effect of the extract was investigated via histopathological assessment. Cocculus laurifolius (200 and 400 mg/kg, p.o.) exhibited anticonvulsant activity as indicated by significant delay in the onset of convulsions and time to death after strychnine induced convulsions. Similarly, significant reduction in the duration of convulsions and percentage of mortality was observed by ethanolic extract (200 and 400 mg/kg p.o.) at 1, 7, 15 and 30th day of test sessions. Furthermore, Cocculus laurifolius leaves (200 and 400 mg/kg p.o.) also exhibited neuroprotective effect with considerable preserved neuronal structures and significant decrease in neuronal apoptosis, in comparison with control. The results obtained from the present study indicate that ethanolic extract of Cocculus laurifolius leaves possess potential anticonvulsant and neuroprotective effect against strychnine induced convulsions. Therefore, it can be concluded that Cocculus laurifolius leaves may be a valuable in management of epilepsy, however further studies are required on large number of animals to confirm these findings.

Topics: Animals; Anticonvulsants; Apoptosis; Brain; Cocculus; Disease Models, Animal; Female; Male; Neurons; Neuroprotective Agents; Plant Extracts; Plant Leaves; Rats; Rats, Wistar; Seizures; Strychnine

Novel non-imidazole histamine H3 receptor (H3R) antagonists (2-8) were developed and assessed for in-vitro antagonist binding affinities at the human histamine H1-H4R. These novel H3R antagonists (2-8) were examined in-vivo for anticonvulsant effects in three different convulsion models in male adult rats. Compound 6 significantly and dose-dependently exhibited decreased duration of tonic hind limb extension (THLE) in the maximal electroshock (MES)- and fully protected animals against pentylenetetrazole (PTZ)-induced convulsion, following acute systemic administration (5, 10, and 20 mg/kg, i.p.). Contrary, all compounds 2-8 showed moderate protection in the strychnine (STR)-induced convulsion model following acute pretreatment (10 mg/kg, i.p.). Moreover, the acute systemic administration of H3R antagonist 6 (10 mg/kg, i.p.) significantly prolonged latency time for MES convulsions. Furthermore, the anticonvulsant effect observed with compound 6 in MES-model was entirely abrogated when rats were co-injected with the brain penetrant H1R antagonist pyrilamine (PYR) but not the brain penetrant H2R antagonist zolantidine (ZOL). However, PYR and ZOL failed to abolish the full protection provided by the H3R antagonist 6 in PTZ- and STR-models. No mutagenic or antiproliferative effects or potential metabolic interactions were shown for compound 6 when assessing its antiproliferative activities and metabolic profiling applying in-vitro methods. These findings demonstrate the potential of non-imidazole H3R antagonists as novel antiepileptic drugs (AEDs) either for single use or in addition to currently available epilepsy medications.

Topics: Animals; Anticonvulsants; Benzothiazoles; Disease Models, Animal; Dose-Response Relationship, Drug; Histamine H3 Antagonists; Humans; Male; Phenoxypropanolamines; Piperidines; Pyrilamine; Rats; Rats, Wistar; Reaction Time; Seizures; Strychnine

The critical role of α1-glycine receptor (α1-GLYRs) in pathological conditions such as epilepsy is well known. In the present study, structure-activity relations for a series of phenylalanine derivatives carrying selected hydrogen bond acceptors were investigated on the functional properties of human α1-GLYR expressed in Xenopus oocytes. The results indicate that one particular substitution position appeared to be of special importance for control of ligand activity. Among tested ligands (1-8), the biphenyl derivative (2) provided the most promising antagonistic effect on α1-GLYRs, while its phenylbenzyl analogue (5) exhibited the highest potentiation effect. Moreover, ligand 5 with most promising potentiating effect showed in-vivo moderate protection when tested in strychnine (STR)-induced seizure model in male adult rats, whereas ligand 2 with highest antagonistic effect failed to provide appreciable anti(pro)convulsant effect. Furthermore, ligands 2 and 5 with the most promising effects on human α1-GLYRs were examined for their toxicity and potential neuroprotective effect against neurotoxin 6-hydroxydopamine (6-OHDA). The results show that ligands 2 and 5 possessed neither significant antiproliferative effects, nor necrotic and mitochondrial toxicity (up to concentration of 50μM). Moreover, ligand 2 showed weak neuroprotective effect at the 50μM against 100μM toxic dose of 6-OHDA. Our results indicate that modulatory effects of ligands 2 and 5 on human α1-GLYRs as well as on STR-induced convulsion can provide further insights for the design of therapeutic agents in treatment of epilepsy and other pathological conditions requiring enhanced activity of inhibitory glycine receptors.

Topics: Animals; Anticonvulsants; Convulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Glycine; HEK293 Cells; Humans; Ligands; Male; Membrane Potentials; Microinjections; Neuroblastoma; Oocytes; Oxidopamine; Patch-Clamp Techniques; Phenylalanine; Rats; Rats, Wistar; Receptors, Glycine; Seizures; Strychnine; Transduction, Genetic; Xenopus laevis

Epilepsy is the most commonly encountered neurological disorder affecting around 70 million people worldwide, out of which approximately 80% belongs to developing countries. Several shortcomings appeared with the use of conventional antiepileptic agents like, inadequate seizure control, side effects and cost which limit their use. Thus extensive studies are necessary to investigate the pharmacological effects of plants, which would facilitate discovery of novel drugs from herbal source permitting their use to benefit mankind. Hence current study was focused to evaluate the anti-epileptic potential of Nelumbo nucifera fruit in order to ascertain its therapeutic potential. Anti-epileptic activity was assessed using strychnine induced seizure model in 35 male Wister rats divided in five groups i.e. control, reference and 3 test groups. Each group was composed of 7 animals and was given 2% gum tragacanth (control), diazepam 1 mg/kg PO (reference) and N. nucifera fruit 50, 100 and 200 mg/kg PO (test) OD for 15 days. N. nucifera fruit extract at 200 mg/kg exhibited extremely noteworthy delay in the inception of convulsions as compared to control however duration of convulsions was increased significantly but intensity of convulsions was reduced resulting in better survival rate i.e. 42.85% which was comparable to diazepam. Therefore it can be concluded that N. nucifera fruit may be valuable in managing epilepsy but further studies are required on large number of animals to confirm these findings.

Topics: Animals; Anticonvulsants; Fruit; Male; Nelumbo; Plant Extracts; Rats; Rats, Wistar; Seizures; Strychnine; Treatment Outcome

The synthesis, pharmacological evaluation and molecular modelling study of novel naphthalen-2-yl acetate and 1,6-dithia-4,9-diazaspiro [4.4]nonane-3,8-dione derivatives as potential anticonvulsant agents are described. The newly synthesized compounds were characterized by both analytical and spectral data. Alkylation of 1H-imidazole or substituted piperazine with 1-(2-naphthyl)-2-bromoethanone (2) gave naphthalen-2-yl 2-(1H-imidazol-1-yl) acetate (3) and naphthalen-2-yl 2-(substituted piperazin-1-yl) acetate (4-8). Moreover, condensation of naphthalen-2-yl 2-bromoacetate or 2-bromo-1-(naphthalen-2-yl) ethanone with hydrazine hydrate and acetylacetone resulted in the formation of the cyclic pyrazole products 9 and 13. Sonication of naphthalen-2-yl acetate (1) with 2-chloropyridine, 2-chloropyrimidine and 2-(chloromethyl) oxirane gave naphthalen-2-yl 2-(pyridin-2-yl) acetate (10), naphthalen-2-yl 2-(pyrimidin-2-yl) acetate (11) and naphthalen-2-yl-3-(oxiran-2-yl) propanoate (12) respectively. Cyclocondensation reaction of 2-iminothiazolidin-4-one (14) with thioglycolic acid, thiolactic acid and thiomalic acid gave 1,6-dithia-4,9-diazaspiro [4.4]nonane-3,8-dione derivatives (15-17). The compounds were testedin vivofor the anticonvulsant activity by delaying strychnine-induced seizures. The diazaspirononane (17) and 1-(2-naphthyl)-2-bromoethanone (2) showed a high significant delay in the onset of convulsion and prolongation of survival time compared to phenobarbital. The molecular modelling study of anticonvulsant activity of synthesized compounds showed a CNS depressant activity via modulation of benzodiazepine allosteric site in GABA-A receptors.

Topics: Acetates; Allosteric Regulation; Animals; Anticonvulsants; Humans; Male; Mice; Molecular Docking Simulation; Naphthalenes; Receptors, GABA-A; Seizures; Spiro Compounds; Strychnine

Various biological factors have been implicated in convulsive seizures, involving side effects of drugs. For the preclinical safety assessment of drug development, it is difficult to predict seizure-inducing side effects. Here, we introduced a machine learning-based in vitro system designed to detect seizure-inducing side effects. We recorded local field potentials from the CA1 alveus in acute mouse neocortico-hippocampal slices, while 14 drugs were bath-perfused at 5 different concentrations each. For each experimental condition, we collected seizure-like neuronal activity and merged their waveforms as one graphic image, which was further converted into a feature vector using Caffe, an open framework for deep learning. In the space of the first two principal components, the support vector machine completely separated the vectors (i.e., doses of individual drugs) that induced seizure-like events and identified diphenhydramine, enoxacin, strychnine and theophylline as "seizure-inducing" drugs, which indeed were reported to induce seizures in clinical situations. Thus, this artificial intelligence-based classification may provide a new platform to detect the seizure-inducing side effects of preclinical drugs.

Topics: Animals; CA1 Region, Hippocampal; Diphenhydramine; Enoxacin; In Vitro Techniques; Male; Mice; Mice, Inbred ICR; Seizures; Strychnine; Support Vector Machine; Theophylline

The ketogenic diet (KD) is a cheap and effective alternative therapy for most epilepsy. There are paucity of experimental data in Nigeria on the usefulness of KD in epilepsy models. This is likely to be responsible for the poor clinical acceptability of the diet in the country. This study therefore aimed at providing experimental data on usefulness of KD on seizure models.  The study used 64 Wistar rats that were divided into two dietary groups [normal diet (ND) and ketogenic diet (KD)]. Animal in each group were fed for 35days. Medium chain triglyceride ketogenic diet (MCT-KD) was used and it consisted of 15% carbohydrate in normal rat chow long with 5ml sunflower oil (25% (v/w). The normal diet was the usual rat chow. Seizures were induced with one of Pentelyntetrazole (PTZ), 4-Aminopyridine (AP) and Strychnine (STR). Fasting glucose, ketosis level and serum chemistry were determined and seizure parameters recorded. Serum ketosis was significantly higher in MCT-KD-fed rats (12.7 ±2.6) than ND-fed (5.17±0.86) rats. Fasting blood glucose was higher in ND-fed rats (5.3±0.9mMol/l) than in MCT-KD fed rats (5.1±0.5mMol/l) with p=0.9. Seizure latency was significantly prolonged in ND-fed compared with MCT-KD fed rats after PTZ-induced seizures (61±9sec vs 570±34sec) and AP-induced seizures (49±11sec vs 483±41sec). The difference after Str-induced seizure (51±7 vs 62±8 sec) was not significan. The differences in seizure duration between ND-fed and MCT-KD fed rats with PTZ (4296±77sec vs 366±46sec) and with AP (5238±102sec vs 480±67sec) were significant (p<0.05), but not with STR (3841±94sec vs 3510±89sec) respectively. The mean serum Na+ was significantly higher in MCT-KD fed (141.7±2.1mMol/l) than ND-fed rats (137±2.3mMol/l). There was no significant difference in mean values of other serum electrolytes between the MCT-KD fed and ND-fed animals. MCT-KD caused increase resistance to PTZ-and AP-induced seizures, but has no effect on STR-induced seizures. This antiseizure property is probably mediated through GABAergic receptors (PTZ effect) and blockade of membrane bound KATP channels (AP effect) with some enhancement by serum ketosis.

Topics: 4-Aminopyridine; Animal Nutritional Physiological Phenomena; Animals; Biomarkers; Blood Glucose; Diet, Carbohydrate-Restricted; Diet, Ketogenic; Disease Models, Animal; Ketosis; Male; Pentylenetetrazole; Plant Oils; Rats, Wistar; Reaction Time; Seizures; Sodium; Strychnine; Sunflower Oil; Time Factors

Theanine, an additive, holds several effects on the central nervous system without toxicity and affects CNS drugs. Theanine bilaterally alters β wave of the EEG with or without caffeine and pentobarbital-induced locomotor activity. Theanine also enhances hypnosis of pentobarbital sodium (PB) and antidepression of midazolam, suggesting there are complicated interactions between theanine and CNS drugs. On the other side, theanine induces glycine release. Glycine potentiates the strychnine toxicity via NMDA receptor activation. Moreover, PB facilitates GABAA receptor activation by GABA, and it is commonly prescribed for strychnine poison. However, what the role that theanine plays in the anticonvulsion of PB against strychnine poison is still unknown.. Theanine, pentobarbital sodium or strychnine was injected intraperitoneally. EEG was monitored by BIOPAC 16 EEG amplifiers. LD50 of strychnine and hypnotic ED50 of pentobarbital sodium with or without theanine for mice were tested according to Bliss' case.. (1) Theanine enhanced the strychnine toxicity. Both theanine and strychnine 1.0 mg/kg increased the power of the β wave. Theanine aggravated that of strychnine 1.0 mg/kg. Theanine attenuated the LD50 of strychnine. (2) Theanine enhanced the anticonvulsion of PB. Theanine increased the power of α, β wave and decreased hypnotic ED50 of PB; PB attenuated strychnine-induced EEG excitation and mortality with or without theanine, and theanine enhanced the effects of PB. Further, theanine enhanced the anticonvulsion of PB dose-dependently against the strychnine toxicity but not the lethal toxicity of strychnine.. These results indicated theanine interacted with PB and strychnine. Theanine enhanced both the strychnine toxicity and anticonvulsion of PB against strychnine poison.

Topics: Animals; Dose-Response Relationship, Drug; Drug Interactions; Electroencephalography; Female; Glutamates; Hypnotics and Sedatives; Lethal Dose 50; Male; Mice, Inbred ICR; Pentobarbital; Seizures; Strychnine

Many anti-epileptic drugs (AEDs) that mainly target ion channels or post-synaptic receptors are in clinical use, but a proportion of patients are resistant to these traditional AEDs and experience repeated severe break-out seizures. Given its involvement in the etiology of epilepsy, the neurotransmitter glycine may serve as a novel target for epilepsy treatment. Increasing evidence suggests that inhibitors of glycine transporter 1 (GlyT1) exhibit anti-seizure properties in mouse models and show potential as anti-convulsions drugs. In the present study, we investigated the effect of a highly selective GlyT1 inhibitor (named M22) on glycine transport kinetics using a radioactive substrate uptake assay and investigated the anti-seizure effects of M22 on the maximal electroshock seizure threshold (MEST) test and the timed intravenous (i.v.) pentylenetetrazole (PTZ) intravenous test. Our results demonstrate that M22 was capable of elevating the seizure threshold in the MEST test but did not alter the seizure threshold in the PTZ i.v. test. Strychnine, an inhibitor of glycine receptor activity, reversed the threshold elevation at a subconvulsive dosage (0.1 mg/kg subcutaneously) in the MEST test and did not affect M22 plasma levels in mice, suggesting that the anti-seizure effect in this model may be mediated by increased glycine receptor activity. Moreover, M22 administration did not influence motor function and coordination in mice. In combination with the previously reported excellent pharmacokinetic features of M22, our present results suggested that M22 has the potential to serve as a new anti-convulsive drug or as a lead compound for the development of AEDs.

Topics: Animals; Anticonvulsants; Benzamides; Dose-Response Relationship, Drug; Electroshock; Glycine Plasma Membrane Transport Proteins; Injections, Intravenous; Kinetics; Mice; Mice, Inbred C57BL; Molecular Structure; Pentylenetetrazole; Piperidines; Seizures; Strychnine

Various morphological parts of pomegranate (Punica granatum L.) have extensively been used in the folk medicine to treat an array of human ailments. The aim of the present study is to demonstrate the anticonvulsant potential of the ethanolic extract of P. granatum L. seed in chemoconvulsant-induced seizures in mice.. The anticonvulsant activity of the ethanolic extract was investigated in strychnine (STR)-induced and pentylenetetrazole (PTZ)-induced seizure models in mice. Diazepam was used as reference anticonvulsant drug. Ethanolic extract (150, 300, and 600 mg/kg per os, p.o.), diazepam (1 mg/kg intraperitoneally, i.p.), and distilled water (10 ml/kg, i.p.) were administered before induction of seizures by PTZ (60 mg/kg, i.p.) or STR (2.5 mg/kg, i.p.). The latent time before the onset of convulsions, the duration of convulsions, the percentage of seizure protection, and mortality rate were recorded.. The seed ethanolic extract did not show any toxicity and did not protect the animals against seizures but demonstrated a significant increase in seizure latency at 300 and 600 mg/kg in both STR and PTZ seizure models (P < 0.001). It also showed a significant reduction in seizure duration at 300 mg/kg (P < 0.05) and 600 mg/kg (P < 0.001) in the STR seizure model and 600 mg/kg (P < 0.01) in the PTZ seizure model compared with the control group.. Ethanol extract has dose-dependent anticonvulsant activity against STR- and PTZ-induced seizures. This activity might be due to its saponins, flavonoids, triterpenes, and alkaloids ingredients.

Topics: Animals; Anticonvulsants; Diazepam; Disease Models, Animal; Dose-Response Relationship, Drug; Lythraceae; Male; Mice; Pentylenetetrazole; Phytotherapy; Plant Extracts; Random Allocation; Seeds; Seizures; Strychnine; Treatment Outcome

Eighteen new 5-benzylidene-3-(4-arylpiperazin-1-ylmethyl)-2-thioxo-imidazolidin-4-ones were designed as hybrid structures from previously reported anticonvulsant compounds, synthesized and tested for anticonvulsant activity. Initial anticonvulsant screening was performed using the strychnine (2 mg/kg IP) potent generalized-induced seizure and pentylenetetrazole (PTZ) (60 mg/kg IP) acute clonic-induced convulsion screens in mice. All the molecules were found to be effective in at least one seizure model, compounds 10, 13, 15, 17, and 18 were active against both types of seizures induced. Compound 13 turned out to be the most active candidate within the strychnine model, having an average survival time of 6 min close to that of the positive control phenytoin, while compound 8 showed 100% protection from the induced PTZ seizures, resembling the protection of the positive control phenobarbital. Initial SAR studies for anticonvulsant activity are discussed.

Topics: Animals; Anticonvulsants; Brain; Disease Models, Animal; Drug Design; Male; Mice; Molecular Structure; Pentylenetetrazole; Phenobarbital; Piperazines; Seizures; Structure-Activity Relationship; Strychnine

Stereoisomers of the monoterpene epoxycarvone (EC), namely (+)-cis-EC, (-)-cis-EC, (+)-trans-EC, and (-)-trans-EC, were comparatively evaluated for anticonvulsant activity in specific methodologies. In the pentylenetetrazole (PTZ)-induced anticonvulsant test, all of the stereoisomers (at 300 mg/kg) increased the latency to seizure onset, and afforded 100% protection against the death of the animals. In the maximal electroshock-induced seizures (MES) test, prevention of tonic seizures was also verified for all of the isomers tested. However, the isomeric forms (+) and (-)-trans-EC showed 25% and 12.5% inhibition of convulsions, respectively. In the pilocarpine-induced seizures test, all stereoisomers demonstrated an anticonvulsant profile, yet the stereoisomers (+) and (-)-trans-EC (at 300 mg/kg) showed a more pronounced effect. A strychnine-induced anticonvulsant test was performed, and none of the stereoisomers significantly increased the latency to onset of convulsions; the stereoisomers probably do not act in this pathway. However, the stereoisomers (+)-cis-EC and (+)-trans-EC greatly increased the latency to death of the animals, thus presenting some protection. The four EC stereoisomers show promise for anticonvulsant activity, an effect emphasized in the isomers (+)-cis-EC, (+)-trans-EC, and (-)-trans-EC for certain parameters of the tested methodologies. These results serve as support for further research and development of antiepileptic drugs from monoterpenes.

Topics: Animals; Anticonvulsants; Cyclohexane Monoterpenes; Electroshock; Male; Mice; Molecular Structure; Monoterpenes; Pentylenetetrazole; Seizures; Stereoisomerism; Strychnine

Four new pentacyclic benzodiazepine derivatives (PBDTs 13-16) were synthesized by conventional thermal heating and microwave-assisted intramolecular cyclocondensation. Their anticonvulsant, sedative and anxiolytic activities were evaluated by drug-induced convulsion models, a pentobarbital-induced hypnotic model and an elevated plus maze in mice. PBDT 13, a triazolopyrrolo[2,1-c][1,4]benzodiazepin-8-one fused with a thiadiazolone ring, exhibited the best anticonvulsant, sedative and anxiolytic effects in our tests. There was no significant difference in potency between PBDT 13 and diazepam, and we proposed that the action mechanism of PBDT 13 could be similar to that of diazepam via benzodiazepine receptors.

Topics: Animals; Anti-Anxiety Agents; Anticonvulsants; Benzodiazepinones; Exploratory Behavior; Heterocyclic Compounds, 4 or More Rings; Hypnotics and Sedatives; Male; Mice; Mice, Inbred ICR; Molecular Structure; Pentobarbital; Picrotoxin; Reflex, Abnormal; Seizures; Strychnine

Agomelatine is a novel antidepressant drug with melatonin receptor agonist and 5-HT(2C) receptor antagonist properties. We analyzed whether agomelatine has antioxidant properties. Antioxidant activity of agomelatine (25, 50, or 75 mg/kg, i.p.) or melatonin (50 mg/kg) was investigated by measuring lipid peroxidation levels, nitrite content, and catalase activities in the prefrontal cortex, striatum, and hippocampus of Swiss mice pentylenetetrazole (PTZ) (85 mg/kg, i.p.), pilocarpine (400 mg/kg, i.p.), picrotoxin (PTX) (7 mg/kg, i.p.), or strychnine (75 mg/kg, i.p.) induced seizure models. In the pilocarpine-induced seizure model, all dosages of agomelatine or melatonin showed a significant decrease in TBARS levels and nitrite content in all brain areas when compared to controls. In the strychnine-induced seizure model, all dosages of agomelatine and melatonin decreased TBARS levels in all brain areas, and agomelatine at low doses (25 or 50 mg/kg) and melatonin decreased nitrite contents, but only agomelatine at 25 or 50 mg/kg showed a significant increase in catalase activity in three brain areas when compared to controls. Neither melatonin nor agomelatine at any dose have shown no antioxidant effects on parameters of oxidative stress produced by PTX- or PTZ-induced seizure models when compared to controls. Our results suggest that agomelatine has antioxidant activity as shown in strychnine- or pilocarpine-induced seizure models.

Topics: Acetamides; Animals; Brain; Catalase; Female; Lipid Peroxidation; Mice; Nitrites; Oxidative Stress; Pentylenetetrazole; Picrotoxin; Pilocarpine; Seizures; Strychnine

This study investigated the hypnotic, anti-convulsant and anxiolytic effects of 1-nitro-2-phenylethane (BPNE) obtained from the oil of Dennettia tripetala G. Baker (Annonaceae) and established its mechanism of action. The essential oil (EO) from the leaf, fruit and seed was obtained by hydrodistillation, followed by isolation of BPNE purified to 99.2% by accelerated gradient chromatography on silica, and identified by NMR and GC-MS. The pure BPNE and EO of the dried seed (93.6%) were comparatively evaluated for hypnotic, anticonvulsant and anxiolytic effects in mice. The acute toxicity of BPNE was determined and the LD50 was 490 mg/kg, intrapritonealy. The hypnotic activities of the EO and BPNE (50-400 mg/kg, i.p.) were assessed by loss of righting reflex, while sodium pentobarbitone (PBS) and diazepam (DZM) were used as positive controls. The anticonvulsant and anxiolytic effects of the EO and BPNE were evaluated in mice. Both BPNE and EO at doses ≥100 mg/kg induced spontaneous hypnosis with loss of righting reflex, significantly decreased sleep latency (SL) and also increased total sleeping time (TST) dose-dependently. They had comparable activity with NAP in TST. The BPNE exhibited higher hypnotic potency than EO at the same dose levels. The EO and BPNE offered comparable dose-related protections against PTZ- and strychnine-induced convulsions. Flumazenil (2 mg/kg) blocked the hypnotic and anticonvulsant (PTZ-convulsions) effects of both EO and BPNE. The essential oil at 5-20 mg/kg dose levels significantly (p<0.05) increased the percentage time spent and number of entries into the open arms. While at the same dose range BPNE significantly (p<0.05) increased the percentage time spent and the number of entries into the open arms respectively. The study concluded that 1-nitro-2-phenylethane exhibited dose dependent significant hypnotic, anticonvulsant and anxiolytic effects and it is the compound largely responsible for the neuropharmacological effects of the oil.

Topics: Animals; Annonaceae; Anti-Anxiety Agents; Anticonvulsants; Anxiety; Avoidance Learning; Benzene Derivatives; Dose-Response Relationship, Drug; Female; Flumazenil; GABA Modulators; Hypnotics and Sedatives; Male; Mice; Oils, Volatile; Phytotherapy; Plant Extracts; Plant Structures; Reflex, Righting; Seizures; Sleep; Sleep Initiation and Maintenance Disorders; Strychnine

Here we report that indazole is characterized as a potential anticonvulsant, inhibiting pentylenetetrazole-, electroshock- and strychnine-induced convulsions in mice (ED50's: 39.9, 43.2 and 82.4 mg/kg, respectively) but not bicuculline- and picrotoxin-induced convulsions. The median toxic dose (TD(50)) of indazole was 52.3 mg/kg by the minimal motor impairment test. Therefore, nontoxic doses produced anticonvulsant activity against pentylenetetrazole- and electroshock-induced seizures. Indazole (50 mg/kg) had no effect on spontaneous activity but induced hypothermia. It also inhibited the metabolism of dopamine and 5-hydroxytryptamine in the brain in vivo and the activities of monoamine oxidase A and B in vitro, with IC(50) values of 20.6 μM and 16.3 μM, respectively. However, these inhibitory effects do not account for the anticonvulsant activity because treatment with typical monoamine oxidase inhibitors such as pargyline or tranylcypromine did not completely reproduce the anticonvulsant activity of indazole. In the animal seizure models tested, the anticonvulsant profile of indazole most resembled that of gabapentin and somewhat resembled those of the AMPA/kainate antagonist NBQX and the sodium channel inhibitor phenytoin, but differed from that of benzodiazepine. The isobolographic analyses showed that the interactive mode of indazole with gabapentin, NBQX or phenytoin is additive. These results suggest that indazole has anticonvulsant activity and multiple mechanisms.

Topics: Animals; Anticonvulsants; Bicuculline; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Electroshock; Indazoles; Male; Mice; Pentylenetetrazole; Phenytoin; Seizures; Strychnine

We used behavioral pharmacology to characterize heterozygous knockin mice with mutations (Q266I or M287L) in the α1 subunit of the glycine receptor (GlyR) (J Pharmacol Exp Ther 340:304-316, 2012). These mutations were designed to reduce (M287L) or eliminate (Q266I) ethanol potentiation of GlyR function. We asked which behavioral effects of ethanol would be reduced more in the Q266I mutant than the M287L and found rotarod ataxia to be the behavior that fulfilled this criterion. Compared with controls, the mutant mice also differed in ethanol consumption, ethanol-stimulated startle response, signs of acute physical dependence, and duration of loss of righting response produced by ethanol, butanol, ketamine, pentobarbital, and flurazepam. Some of these behavioral changes were mimicked in wild-type mice by acute injections of low, subconvulsive doses of strychnine. Both mutants showed increased acoustic startle response and increased sensitivity to strychnine seizures. Thus, in addition to reducing ethanol action on the GlyRs, these mutations reduced glycinergic inhibition, which may also alter sensitivity to GABAergic drugs.

Topics: 1-Butanol; Alcohol Drinking; Alcohol Withdrawal Seizures; Amino Acid Substitution; Animals; Behavior, Animal; Central Nervous System Depressants; Conditioning, Classical; Drug Synergism; Eating; Ethanol; Female; Food Preferences; Gene Knock-In Techniques; Male; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Transgenic; Motor Skills; Mutation; N-Methylaspartate; Nicotine; Pentylenetetrazole; Quinine; Receptors, Glycine; Reflex, Righting; Reflex, Startle; Rotarod Performance Test; Saccharin; Seizures; Sex Characteristics; Strychnine; Taste Perception

Hedranthera barteri (Hook.f.) Pichon (Apocynaceae) is used traditionally in the treatment of convulsion in Southern Nigeria.. The anticonvulsant activity of the methanol extract of H. barteri leaves was investigated.. The anticonvulsant activity of the extract (50,100 and 200 mg/kg, p.o.) was investigated in seizures induced by picrotoxin and strychnine in mice. The total phenol and flavonoid contents were determined using a modified colorimetric method and the aluminium chloride method, respectively. The mineral composition of the plant was analyzed using atomic absorption spectrophotometry.. The extract significantly prolonged the onset and reduced the duration of the seizures induced by picrotoxin (5 mg/kg, i.p.) and strychnine (1 mg/kg, i.p.). The response was, however, not dose-dependent. Phenobarbitone (2 mg/kg) completely protected the animals from seizures while diazepam (1 mg/kg) only prolonged the onset and reduced the duration of the seizures. The total phenol and flavonoid contents were 236.81 ± 0.05 mg gallic acid equivalent/g dry weight and 51.45 ± 0.01 mg quercetin equivalent/g dry weight, respectively. The elemental analysis revealed the presence of calcium 102.87 mg/g, magnesium 63.29 mg/mg, iron 54.16 mg/g, potassium 54 mg/g, sodium 48.95 mg/g, zinc 46.70 mg/g, manganese 41.72 mg/g, and copper 18.29 mg/g.. The results suggest that the methanol extract of H. barteri has anticonvulsant activity and may be exerting its effect by affecting the gabaergic and glycinergic mechanisms. The observed activity may be due to its flavonoid content and the appreciable amount of calcium present in the plant.

Topics: Animals; Anticonvulsants; Apocynaceae; Female; Male; Mice; Plant Extracts; Plant Leaves; Seizures; Strychnine

We screened the major bioactive flavones isolated from Scutellaria baicalensis (baicalin, baicalein and oroxylin A) for their convulsion related activities. In electrogenic response score system and the pentylenetetrazole seizure model, baicalein but not oroxylin A and baicalin exhibited anticonvulsant effects. In vitro studies also revealed that baicalein induced intracellular Cl(-) influx, whereas oroxylin A blocked muscimol- and baicalein-induced intracellular Cl(-) influx. The anticonvulsant effect of baicalein was inhibited by flumazenil, a benzodiazepine(BZD) receptor antagonist. Therefore, anticonvulsive effect of baicalein was mediated by the BZD binding site of GABA(A) receptor. The 5, 7-dihydroxyl group is present in the structure of the three flavones. It is postulated that this group played a key role in inducing convulsion-related activities.

Topics: Animals; Anticonvulsants; Chlorides; Drug Evaluation, Preclinical; Electroshock; Flavones; Hydroxides; Intracellular Space; Male; Motor Activity; Pentylenetetrazole; Rats; Rats, Sprague-Dawley; Scutellaria baicalensis; Seizures; Structure-Activity Relationship; Strychnine

To investigate the anticonvulsant activity of the leaf extract of Justicia extensa T. Anders used traditionally in the treatment of convulsion.. The anticonvulsant activity of the methanolic extract of Justicia extensa (50, 100 and 200 mg/kg, p.o.) was assessed in strychnine-induced (STR) and picrotoxin-induced (PCT) convulsion models in mice. Diazepam (1 mg/kg) and phenobarbitone (2 mg/kg) were used as reference drugs respectively.. The extract showed no toxicity and significantly prolonged (p<0.01-0.05) the onset and reduced the duration of the seizures induced by picrotoxin (5 mg/kg, i.p.) in a dose dependent manner. Phenobarbitone completely inhibited the seizures in this model. Similarly, in the seizures induced by strychnine (1 mg/kg, i.p.), the extract also prolonged the onset and reduced the duration of the seizures though not in a dose dependent manner. Diazepam failed to inhibit the strychnine-induced seizures. The plant extract however showed a significantly higher anticonvulsant activity at 100 and 200 mg/kg in comparison with diazepam.. The results obtained from this work suggest that Justicia extensa has anticonvulsant activity and this supports the use of the plant traditionally in the treatment of convulsion.

Topics: Acanthaceae; Animals; Anticonvulsants; Convulsants; Diazepam; Disease Models, Animal; Female; Male; Medicine, African Traditional; Methanol; Mice; Nigeria; Phenobarbital; Phytotherapy; Picrotoxin; Plant Extracts; Plant Leaves; Seizures; Solvents; Strychnine

The effect of detoxification on Strychnos nux-vomica seeds by traditional processing with aloe and ginger juices (B), by frying in cow ghee (C), and by boiling in cow milk (D) was investigated. The ethanolic extracts of these samples were subjected to spontaneous motor activity (SMA), pentobarbitone-induced hypnosis, PTZ induced convulsions, diazepam-assisted protection, and morphine-induced catalepsy. All samples reduced SMA and inhibited catalepsy. The seeds processed in milk (D) showed the lowest strychnine content in the cotyledons, exhibited marked inhibition of PTZ induced convulsions and maximal potentiation of hypnosis, and were the safest (LD(50)).

Topics: Aloe; Animals; Behavior, Animal; Catalepsy; Central Nervous System Agents; Diazepam; Dietary Fats; Female; Lethal Dose 50; Male; Medicine, Ayurvedic; Mice; Milk; Morphine; Motor Activity; Pentylenetetrazole; Phytotherapy; Plant Extracts; Rats; Seeds; Seizures; Sleep; Strychnine; Strychnos nux-vomica; Zingiber officinale

The objective of this study is to investigate the anticonvulsant, anxiolytic and sedative activities of the aqueous root extract of Securidaca longepedunculata.. The anticonvulsant effect of the aqueous root extract (100, 200 and 400 mg/kg) was evaluated in mice using the strychnine- and picrotoxin-induced seizure models. Its anxiolytic activity was evaluated using the elevated plus maze (EPM) and the Y maze (YM) methods (Hogg, 1996; Yemitan and Adeyemi, 2003) while the hexobarbitone induced sleep and the hole board models were used to evaluate the sedative and exploratory activities in mice respectively. The acute toxicity studies and phytochemical analysis of the extract were also carried out.. The extract (100-400 mg/kg) produced a significant (P<0.01) dose dependent increase in onset of convulsion compared to the control for strychnine- and picrotoxin-induced seizures. It also produced a significant (P<0.01) dose dependent prolongation of the cumulative time spent in the open arms of the elevated plus maze and Y maze compared with the control. The extract (100-400 mg/kg) produced significant (P<0.01) reduction in the time of onset of sleep induced by hexobarbitone. The prolongation of hexobarbitone sleeping time by the extract (200 mg/kg) was comparable to that produced by diazepam (3 mg/kg). At doses of 100-400 mg/kg, the extract produced a dose dependent decrease in exploratory activity of the mice. The reduction in exploratory activity produced by the extract (400 mg/kg) was greater than that of chlorpromazine (1 mg/kg). The results obtained from the experiments indicate that the extract has central nervous system depressant and anxiolytic activities. The LD(50) obtained for the acute toxicity studies using both oral and intraperitoneal routes of administration were 1.74 g/kg and 19.95 mg/kg respectively.. These findings justify the use of Securidaca longepedunculata in traditional medicine for the management of convulsion and psychosis.

Topics: Administration, Oral; Animals; Anti-Anxiety Agents; Anticonvulsants; Behavior, Animal; Disease Models, Animal; Dose-Response Relationship, Drug; Exploratory Behavior; Female; Hexobarbital; Hypnotics and Sedatives; Injections, Intraperitoneal; Lethal Dose 50; Male; Mice; Picrotoxin; Plant Extracts; Plant Roots; Securidaca; Seizures; Sleep; Strychnine; Time Factors

Preparations of Ficus platyphylla have been used in Nigerian traditional medicine for the management of epilepsy for many years and their efficacy is widely acclaimed among the Hausa communities of northern Nigeria. The anticonvulsant properties of the saponin rich fraction (SFG) obtained from the methanol extract of F. platyphylla stem bark were studied on pentylenetetrazole-, strychnine- and maximal electroshock seizures in mice. Effects of SFG were also examined in murine models for neurological disease and on relevant in vitro targets for anticonvulsant drugs. SFG protected mice against pentylenetetrazole- and strychnine-induced seizures; and significantly delayed the onset of myoclonic jerks and tonic seizures. SFG failed to protect mice against maximal electroshock seizures at doses tested. SFG neither abolished the spontaneous discharges induced by 4-aminopyridine in a neonatal rat brain slice model of tonic-clonic epilepsy nor could it modulate chloride currents through GABA(A) receptor channel complex in cultured cortical cells. However, it was able to non-selectively suppress excitatory and inhibitory synaptic traffic, blocked sustained repetitive firing (SRF) and spontaneous action potential firing in these cultured cells. Our results provide scientific evidence that F. platyphylla stem bark may contain psychoactive principles with potential anticonvulsant properties. SFG impaired membrane excitability; a property shared by most anticonvulsants particularly the voltage-gated sodium channel (VGSC) blocking drugs, thus supporting the isolation and development of the saponin components of this plant as anticonvulsant agents.

Topics: 4-Aminopyridine; Animals; Anticonvulsants; Brain; Cells, Cultured; Electroshock; Female; Ficus; Male; Membrane Potentials; Mice; Neurons; Pentylenetetrazole; Phytotherapy; Plant Bark; Plant Extracts; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Saponins; Seizures; Strychnine

A new series of 4,5-diphenyl-2H-1,2,4-triazol-3(4H)-one were synthesized to study the effect of cyclization of the semicarbazone moiety of aryl semicarbazones on the anticonvulsant activity. Structures of the synthesized compounds were confirmed by the use of their spectral data besides elemental analysis. All compounds were evaluated for their anticonvulsant activity in four animal models of seizures, viz. maximal electroshock seizure (MES), subcutaneous pentylenetetrazole (scPTZ), subcutaneous strychnine (scSTY), and subcutaneous picrotoxin (scPIC)-induced seizure threshold tests. The compounds were also evaluated for neurotoxicity. Compounds 4, 9, 14-19 exhibited anticonvulsant activity in all the four animal models of seizure.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Electroshock; Male; Mice; Pentylenetetrazole; Picrotoxin; Rats; Rats, Sprague-Dawley; Seizures; Semicarbazones; Structure-Activity Relationship; Strychnine; Toxicity Tests

Possible central nervous system effects of the gymnosperm lectin from Araucaria angustifolia seeds were studied in seizure and open field tests. Male Swiss mice were administered saline (control), lectin (0.1, 1, and 10 mg/kg), flumazenil (1 mg/kg), or diazepam (1 mg/kg) intraperitoneally. Lectin at the highest dose increased time to death in the pentylenetetrazole- and strychnine-induced seizure models as compared with control, but not in the pilocarpine model. In the open field test, lectin reduced locomotor activity at all doses tested, as did diazepam, when compared with control. These locomotor effects were reversed by flumazenil pretreatment. In conclusion, A. angustifolia lectin had a protective effect in the pentylenetetrazole- and strychnine-induced seizure models, suggestive of activity in the GABAergic and glycinergic systems, respectively, and also caused a reduction in animal movements, which was reversed by flumazenil, pointing to a depressant action mediated by a GABAergic mechanism.

Topics: Analysis of Variance; Animals; Anticonvulsants; Diazepam; Disease Models, Animal; Dose-Response Relationship, Drug; Exploratory Behavior; Flumazenil; Lectins; Locomotion; Male; Mice; Pentylenetetrazole; Phytotherapy; Plant Extracts; Reaction Time; Seeds; Seizures; Strychnine

Root bark of Nauclea latifolia Smith (Rubiaceae) was evaluated for its anticonvulsant, anxiolytic, and sedative activity in mice. Animal models (maximal electroshock-, pentylenetetrazol-, and strychnine-induced convulsions; N-methyl-D-aspartate-induced turning behavior; elevated plus maze; stress-induced hyperthermia; open field; and diazepam-induced sleep) were used. The decoction from the bark of the roots of N. latifolia strongly increased the total sleep time induced by diazepam. It also protected mice against maximal electroshock-, pentylenetetrazol-, and strychnine-induced seizures. In addition, turning behavior induced by N-methyl-D-aspartate was inhibited. N. latifolia antagonized, in a dose-dependent manner, stress-induced hyperthermia and reduced body temperature. In the elevated plus maze, N. latifolia increased the number of entries into, percentage of entries into, and percentage of time in open arms, and reduced rearing, head dipping, and percentage of time in closed arms. In the open field test, N. latifolia increased crossing and reduced rearing and defecation. It could be concluded that the decoction of N. latifolia, used in traditional medicine in Cameroon in the treatment of fever, malaria, insomnia, anxiety and epilepsy seemed to possess, sedative, anticonvulsant, anxiolytic and antipyretic properties in mice.

Topics: Animals; Anti-Anxiety Agents; Anticonvulsants; Anxiety; Cameroon; Convulsants; Diazepam; Dose-Response Relationship, Drug; Electroshock; Excitatory Amino Acid Agonists; Fever; Hypnotics and Sedatives; Male; Mice; Motor Activity; N-Methylaspartate; Pentylenetetrazole; Plant Roots; Rubiaceae; Seizures; Sleep; Stress, Psychological; Strychnine

Brucine is the predominant alkaloid present in the bark of the tree Strychnos nux vomica and is a weaker alkaloid when compared to strychnine. However, its toxicological property is akin to strychnine. We report a rare case of brucine poisoning complicated by acute renal failure and rhabdomyolysis. A 24-year-old male presented with a history of consumption of a decoction made from the bark of the Strychnos nux vomica tree. Soon after, he developed widespread muscle spasms and convulsions, which were promptly treated. On the fifth day of admission, he developed features of rhabdomyolysis and acute renal failure. Investigations revealed elevated creatine phosphokinase levels and elevated blood urea and serum creatinine. The patient was managed with hemodialysis and recovered gradually. There are many reports of strychnine poisoning producing rhabdomyolysis and renal failure. In this case report, attention is drawn to the fact that brucine, although a weaker alkaloid, can also produce life threatening complications like rhabdomyolysis and acute renal failure.

Topics: Acute Kidney Injury; Creatine Kinase; Humans; Male; Plant Extracts; Poisoning; Poisons; Renal Dialysis; Rhabdomyolysis; Seizures; Strychnine; Strychnos nux-vomica; Treatment Outcome; Young Adult

The effects of embryos of the seeds of Nelumbo nucifera on the central nervous system were studied in mice. MeOH extracts of embryos of Nelumbo nucifera seeds significantly inhibited locomotor activity in mice. The MeOH extract was successively partitioned between H(2)O and n-hexane, between H(2)O and CHCl(3), and between H(2)O and n-BuOH. CHCl(3) extracts strongly inhibited locomotor activity in mice, although other extracts had no effect on locomotor activity. The main alkaloid of CHCl(3) extracts, neferine, dose-dependently inhibited locomotor activity in mice. Neferine induced hypothermia in mice and apparently potentiated thiopental-induced sleeping time. An anxiolytic, diazepam, decreased locomotor activity, rectal temperature and enhanced sleep elicited by thiopental, similar to neferine. In addition, neferine and diazepam showed anti-anxiety effects in the elevated plus maze test. Neferine did not affect muscle coordination by the rota-rod test. Neferine did not affect strychnine- nor picrotoxin-induced seizure. In contrast, diazepam had apparent muscle relaxant and anti-convulsant effects. These results suggest that neferine has several central effects and that neferine may participate in the efficacy of the sedative effects of embryos of the seeds of Nelumbo nucifera. The mechanisms of the sedative effects of neferine are not similar to those of diazepam.

Topics: Animals; Anti-Anxiety Agents; Benzylisoquinolines; Body Temperature; Male; Mice; Mice, Inbred ICR; Motor Activity; Nelumbo; Phytotherapy; Picrotoxin; Plant Extracts; Rotarod Performance Test; Seeds; Seizures; Sleep; Strychnine

Cymbopogon winterianus (Poaceae) is used for its analgesic, anxiolytic and anticonvulsant properties in Brazilian folk medicine. This report aimed to perform phythochemical screening and to investigate the possible anticonvulsant effects of the essential oil (EO) from fresh leaves of C. winterianus in different models of epilepsy. The phytochemical analysis of EO showed presence of geraniol (40.06%), citronellal (27.44%) and citronellol (10.45%) as the main compounds. A behavioral screening demonstrated that EO (100, 200 and 400mg/kg; ip) caused depressant activity on CNS. When administered concurrently, EO (200 and 400mg/kg, ip) significantly reduced the number of animals that exhibited PTZ- and PIC-induced seizures in 50% of the experimental animals (p<0.05). Additionally, EO (100, 200 and 400mg/kg, ip) significantly increased (p<0.05) the latencies of clonic seizures induced by STR. Our results demonstrated a possible activity anticonvulsant of the EO.

Topics: Animals; Anticonvulsants; Behavior, Animal; Diazepam; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Male; Mice; Oils, Volatile; Pentylenetetrazole; Phenytoin; Phytotherapy; Picrotoxin; Plant Leaves; Plant Oils; Poaceae; Seizures; Strychnine

Some new substituted coumarinylthiazolines, coumarinylthiazolidin-4-ones, and substituted chromenothiazoles were synthesized and evaluated for anticonvulsant activity. Some selected compounds were assayed against seizures induced by pentylenetetrazole (PTZ) and strychnine in mice. Compounds 3b, 6b, and 7b were the most active of the series against PTZ induced seizures. Compound 7b provided anticonvulsant activity (PD(50)=95mg/kg, ip) at a dose 200mg/kg compared to phenobarbital (PD(50)=16mg/kg, ip) at a dose 30mg/kg (90% protection). No clear correlation was observed between the antiepileptic activity and molecular lipophilicity descriptors of the tested compounds.

Topics: Animals; Anticonvulsants; Coumarins; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Mice; Molecular Structure; Pentylenetetrazole; Seizures; Stereoisomerism; Structure-Activity Relationship; Strychnine

The anticonvulsant effects of hydroalcoholic extracts (HAEs) from the stem bark of Erythrina velutina and Erythrina mulungu on pentylenetetrazole (PTZ) and strychnine-induced seizure tests and the potentiation of pentobarbital-induced sleeping time in mice with the extracts were examined in this study. These medicinal plants belong to the Fabaceae family and are popularly used in Brazil for their effects on the central nervous system. The extracts of Erythrina velutina (intraperitoneally or orally) and Erythrina mulungu (intraperitoneally) were administered in mice at single doses (200 or 400mg/kg). While Erythrina velutina and Erythrina mulungu did not exhibit any protector effect in PTZ-induced seizures, at any dose, an increase in the latency of convulsion and in the death time was observed with both doses and routes of Erythrina velutina and at higher dose of Erythrina mulungu, in strychnine-induced seizure. No alteration was observed with Erythrina velutina and Erythrina mulungu on sleeping latency at both doses as compared to control (362.8+/-59.5). However, the sleeping time was increased in both plants as compared to control (943.8+/-129.6). In conclusion, we showed that the hydroalcoholic extracts of Erythrina velutina and Erythrina mulungu have anticonvulsant effects only in the strychnine-induced seizure model, suggesting their possible action in glycine system and a potentiation of pentobarbital sleeping time, suggesting depressant action in the central nervous system.

Topics: Administration, Oral; Animals; Anticonvulsants; Dose-Response Relationship, Drug; Erythrina; Glycine; Injections, Intraperitoneal; Male; Mice; Pentobarbital; Pentylenetetrazole; Phytotherapy; Plant Extracts; Plants, Medicinal; Seizures; Sleep; Strychnine

Ivermectin is one of the most commonly used drugs in pharmacotherapy of parasitic diseases in domestic and wild animals caused by parasitic nematodes and arthropods. However, ivermectin and other avermectins very often produce side-effects in hosts. The most dominant clinical symptom of ivermectin toxicity in domestic and wild animals is CNS depression. In nematodes, the target site of ivermectin's action is glutamate-gated chloride-channel receptor and GABA receptor. The depressive effect of ivermectin in mammals might include more than one mechanism; therefore, the anticonvulsive effect of ivermectin against convulsions caused by lidocaine and strychnine was evaluated. Ivermectin antagonized lidocaine- and strychnine-induced convulsions in rats, although these have different mechanisms. In the present study, the anticonvulsive ED50 ofivermectin for lidocaine-induced convulsions was 2.44 mg/kg (95% CL 1.67 to 3.57 mg/kg), whereas for convulsions induced by strychnine it was higher at 4.25 mg/kg (95% CL 2.32 to 3.78 mg/kg). At the same time, both anticonvulsive doses are significantly lower then the observed LD50 of ivermectin (18.20 mg/kg). Furthermore, flumazenil (0.1 and 0.2 mg/kg), an antagonist of benzodiazepine receptors, antagonizes just one part of these anticonvulsive effects of ivermectin. Our results show the significant anticonvulsive properties of ivermectin and support the findings that ivermectin in the CNS of mammals produces multiple inhibitory effects, probably through participation in the function of GABA-sensitive and GABA-insensitive chloride channels.

Topics: Anesthetics, Local; Animals; Anticonvulsants; Antiparasitic Agents; Convulsants; Dose-Response Relationship, Drug; Flumazenil; GABA Modulators; Ivermectin; Lethal Dose 50; Lidocaine; Male; Rats; Rats, Wistar; Receptors, Glycine; Seizures; Strychnine

A series of 4-(4-alkoxylphenyl)-3-ethyl-4H-1,2,4-triazole derivatives was synthesized as open-chain analogues of 7-alkoxyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinolines. Their anticonvulsant activities were evaluated by the maximal electroshock test (MES test) and their neurotoxicity was evaluated by the rotarod neurotoxicity test (Tox). MES test showed that 3-ethyl-4-(4-octyloxyphenyl)-4H-1,2,4-triazole 3q was found to be the most potent with ED(50) value of 8.3mg/kg and protective index (PI=TD(50)/ED(50)) value of 5.5, but compound 3r, 3-ethyl-4-(4-octyloxyphenyl)-4H-1,2,4-triazole, exhibited better PI value of 9.3, which was much greater than PI value of the prototype drug phenytoin. For explanation of the possible mechanism of action, the compound 3r was tested in pentylenetetrazole test, isoniazid test, thiosemicarbazide test, 3-mercaptopropionic acid and strychnine test.

Topics: Animals; Anticonvulsants; Mice; Mice, Inbred C57BL; Quinolines; Seizures; Strychnine; Triazoles

In patients of epilepsy a proportion of unexplained sudden deaths had been attributed to neurogenic arrhythmias. Although some evidence has suggested that epileptogenic activation of the cardiac parasympathetic nerves, which is revealed by ictal bradyarrhythmias or cardiac asystole, might be very critical in causing sudden deaths of patients of epilepsy the firing behavior of cardiac parasympathetic neurons (CPNs) during epileptic attack is not known. In the present study fluorescent tracer was injected into the cardiac sac of newborn rats to retrogradely label the parasympathetic neurons in the nucleus ambiguus (NA). The fluorescence-labeled NA neurons were further examined using whole-cell patch-clamp method in medulla slices with respiratory-like rhythm, and those with an inspiratory-related increase of the mixed inhibitory synaptic activity were identified as CPNs. We have demonstrated that blockade of the GABAergic and the glycinergic receptors in medulla slices evoked intermittent seizure-like firing of CPNs under current-clamp configuration, and evoked intermittent excitatory inward currents (IEICs) under voltage-clamp configuration. These results have given new evidence that CPNs might fire in a seizure-like pattern during epileptic attack, which might be responsible for the neurogenic ictal bradyarrhythmias, cardiac asystole, or even the sudden deaths of patients of epilepsy.

Topics: Animals; Animals, Newborn; Arrhythmias, Cardiac; Brain Stem; Cerebrospinal Fluid; Death, Sudden, Cardiac; GABA Antagonists; Glycine Agents; Neurons; Parasympathetic Nervous System; Patch-Clamp Techniques; Picrotoxin; Rats; Rats, Sprague-Dawley; Seizures; Strychnine; Synaptic Transmission

Previous studies on the anticonvulsant activity of N-Cbz-alpha-aminoglutarimides have shown that the derivatives of N-Cbz-alpha-amino-N-alkoxy glutarimide have significant anticonvulsant activity. In addition, their anticonvulsant activities are dependent on the presence of N-alkoxy groups. Based on these results, a series of N-Cbz-alpha-amino-glutarimidooxy carboxylates derivatives (3a-e) were synthesized in moderate yield using a known synthetic procedure. Their anticonvulsant activities were evaluated using the maximal electroshock seizure (MES) test, the pentylene tetrazole induced seizure (PTZ) test, and the strychinine (Str) threshold test with the ultimate aim of developing more active anticonvulsants. None of the compounds (3a-e) tested showed anticonvulsant activity in the MES and PTZ test. However, all the compounds tested exhibited significant anticonvulsant activity in the Str. test. The most active compound in the Str. test was the methyl ester of N-Cbz-alpha-amino-glutarimidooxy acetic acid 3a (ED50 = 42.9 mg/kg).

Topics: Animals; Anticonvulsants; Carboxylic Acids; Male; Mice; Mice, Inbred ICR; Piperidones; Seizures; Structure-Activity Relationship; Strychnine

Preliminary pharmacological studies were performed on the methanol extract of Bixa orellana L. (Bixaceae) leaves to investigate neuropharmacological, anticonvulsant, analgesic, antidiarrhoeal activity and effect on gastrointestinal motility. All studies were conducted in mice using doses of 125, 250 and 500 mg/kg of body weight. In the pentobarbitone-induced hypnosis test, the extract statistically reduced the time for the onset of sleep at 500 mg/kg dose and (dose-dependently) increased the total sleeping time at 250 and 500 mg/kg dose. A statistically significant decrease in locomotor activity was observed at all doses in the open-field and hole-cross tests. In the strychnine-induced anticonvulsant test, the extract increased the average survival time of the test animals (statistically significant at 250 and 500 mg/kg). The extract significantly and dose-dependently reduced the writhing reflex in the acetic acid-induced writhing test. Antidiarrhoeal activity was supported by a statistically significant decrease in the total number of stools (including wet stools) in castor oil-induced diarrhoea model. A statistically significant delay in the passage of charcoal meal was observed at 500 mg/kg in the gastrointestinal motility test. The extract was further evaluated in vitro for antioxidant and antibacterial activity. It revealed radical scavenging properties in the DPPH assay (IC(50)=22.36 microg/ml) and antibacterial activity against selected causative agents of diarrhoea and dysentery, including Shigella dysenteriae.

Topics: Acetic Acid; Animals; Anti-Bacterial Agents; Antidiarrheals; Bixaceae; Dose-Response Relationship, Drug; Female; Free Radical Scavengers; Gastrointestinal Motility; Gastrointestinal Transit; Male; Methanol; Mice; Motor Activity; Pain; Plant Extracts; Plant Leaves; Seizures; Strychnine

The aqueous root extract of Lecaniodiscus cupanioides was used to study the central nervous system depressant activity pattern of the plant. The extract protected mice from strychnine-induced convulsion at 400 mg/kg p.o. and 100 mg/kg i.p. A dose-dependent prolongation of seizure latency was produced at 400 mg/kg, p.o. and 100 mg/kg i.p. for strychnine-induced seizure; and at 400 mg/kg p.o. and 100 mg/kg i.p. for picrotoxin-induced seizure. Moreover, the CNS depressant activity of the extract (200 mg/kg p.o. and 50 mg/kg i.p.) was demonstrated by a significant prolongation of 40 mg/kg, pentobarbitone sleeping time, and significant reduction in exploratory behavior of mice at a dose of 400 mg/kg p.o., with both effects comparable to effects produced by 4 mg/kg chlorpromazine. Acute oral toxicity test, up to 14 days, did not produce any visible signs of toxicity; however, acute (24 h) i.p toxicity test produced a dose-dependent mortality with LD50 of 455.2 mg/kg.

Topics: Administration, Oral; Animals; Central Nervous System; Central Nervous System Depressants; Dose-Response Relationship, Drug; Female; Injections, Intraperitoneal; Lethal Dose 50; Male; Mice; Phytotherapy; Plant Extracts; Plant Roots; Sapindaceae; Seizures; Strychnine

The present study was carried out to determine possible panicogenic effects of strychnine administered in subconvulsive doses to rats. Two experiments were conducted to assess two major features of panic in animal models: panic-related flight (through the observation of wild running [WR]) and defensive fights. In the first one, 20 adult male Wistar rats were injected with six different doses of strychnine ranging from 0.5 to 4.0 mg/kg. After 15 min of free observation, the animals were submitted to high-intensity acoustic stimulation and the incidence of WR was recorded. Higher doses of strychnine (above 2.5 mg/kg) easily evoked seizures, but lower doses raised the incidence of WR in a dose-dependent manner. The most effective dose for WR (1.5 mg/kg) was used in the second experiment, in which we investigated the effects of strychnine on sleep-deprivation-induced fights (SDIFs) that have defensive characteristics. For this purpose, 40 subjects were submitted to 5 days of REM-sleep deprivation by the single-platform method and were then assigned into two groups, i.e., strychnine vs. control. After the injections, the animals were observed in social groupings for SDIF recordings over a period of 60 min. The strychnine-treated groups had more SDIF than the control groups (P<.05, Mann-Whitney U test). We conclude that the high level of neural excitability promoted by partial blockade of the glycinergic system can contribute to the manifestation of panic reactions.

Topics: Acoustic Stimulation; Aggression; Animals; Convulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Panic; Random Allocation; Rats; Rats, Wistar; Seizures; Sleep Deprivation; Strychnine

The present study was performed to evaluate the central nervous system inhibitory effects of the essential oil from SuHeXiang Wan (Storax pill), a prescription usually used for treating epilepsy in traditional Chinese medicine, on fragrance inhalation (aroma therapy). Preinhalation of the fragrance oil markedly delayed the appearance of pentylenetetrazole-induced convulsion, but showed weak activities on picrotoxin- and strychnine-induced convulsions, which implies this drug may inhibit the convulsion by GABAergic neuromodulation. This essential oil inhibited the binding of [(3)H]Ro15-1788, a selective antagonist for the benzodiazepine receptor and also the binding of [(3)H]flunitrazepam, a selective agonist for the receptor, in the presence of gamma-aminobutyric acid (GABA) and NaCl, showing a positive GABA shift, which suggested the strong possibility of the agonistic activity of the essential oil to the GABA/benzodiazepine receptor complex in rat cerebral cortices. Furthermore, inhalation inhibited the activity of GABA transaminase as the inhalation period was lengthened. The GABA level was significantly increased and glutamate content was significantly decreased in mouse brain by preinhalation of the essential oil. The above results suggest that the anticonvulsive effect of this essential oil can also originate from the enhancement of GABA level in the mouse brain, because convulsion depends partially on GABA concentration which can be properly preserved by inhibiting GABA transaminase. Fragrance inhalation progressively prolonged the pentobarbital-induced sleeping time as inhalation time was lengthened and inhibited brain lipid peroxidation, to which the anticonvulsive action is attributed; this also supported the above results, confirming the inhibitory effects of the essential oil of SuHeXiang Wan on the CNS via the GABAergic system.

Topics: 4-Aminobutyrate Transaminase; Administration, Inhalation; Animals; Anticonvulsants; Antioxidants; Brain; Brain Chemistry; Drugs, Chinese Herbal; Glutamic Acid; Lipid Peroxidation; Male; Mice; Mice, Inbred ICR; Oils, Volatile; Pentylenetetrazole; Phytotherapy; Picrotoxin; Receptors, GABA-A; Seizures; Sleep; Strychnine

The decoction of Mimosa pudica leaves given intraperitoneally at dose of 1000-4000 mg/kg protected mice against pentylentetrazol and strychnine-induced seizures. M. pudica had no effect against picrotoxin-induced seizures It also antagonized N-methyl-D-aspartate- induced turning behavior. These properties could explain its use in African traditional medicine.

Topics: Animals; Anticonvulsants; Dose-Response Relationship, Drug; Injections, Intraperitoneal; Male; Medicine, African Traditional; Mice; Mimosa; Pentylenetetrazole; Phytotherapy; Plant Extracts; Plant Leaves; Seizures; Strychnine

The anticonvulsant activity of bis(acetato)tetrakis(imidazole) copper(II), Cu(OAc)2(Im)4, was studied in normal mice using chemical convulsions induced by strychnine, thiosemicarbazide, picrotoxin, and pentelenetetrazol. Intraperitoneal administration of Cu(OAc)2(Im)4, 50 mg/kg body mass, has delayed the onset of strychnine (3 mg/kg)-induced convulsion by 204% (p < or = 0.005) and thiosemicarbazide (20 mg/kg)-induced convulsant by 61% (p < or = 0.005). The changes in the onset of picrotoxin- (6 mg/kg) and pentelenetetrazol (50 mg/kg)-induced convulsions were not significant. The same dosage of the copper compound was effective in delaying the lethal time and reducing the mortality rate of treated animals. The anticonvulsant activity of Cu(OAc)2(Im)4 complex against strychnine was not related to its constituents because the inorganic form of copper such as copper chloride, copper acetate, and the parent imidazole has no anticonvulsant activity. Other copper(II) complexes like copper(II)aspirinate and bis(acetato)bis(2-methyl imidazole) copper(II) were less effective.

Topics: Animals; Anticonvulsants; Female; Mice; Organometallic Compounds; Seizures; Semicarbazides; Strychnine; Time Factors

The present study evaluated the central activity of the essential oil and the ethanolic extract from Artemisia annua L. in animals as a part of a psychopharmacological screening of this plant. The extract was prepared with fresh leaves in ethanol (AEE) and the essential oil (AEO) was obtained by hidrodestilation. The ED(50) and the LD(50) obtained for the essential oil were 470mg/kg (correlation coefficient r=0.97333 and linear regression y=-26.52x+0.158) and 790mg/kg, and for the extract, 450mg/kg (correlation coefficient r=0.99266 and linear regression y=-27.34+0.156) and more than 2g/kg, respectively. The doses increased the latency time to convulsions induced by picrotoxin and pilocarpine but prevented the onset of pentylenotetrazol and strychnine induced seizures. In addition to, the products have caused marked inhibition in the Rota-rod assay. According to the results, the AEO has a high acute toxicity and a possible cholinergic action, and the AEE showed a possible central activity as dopaminergic and cholinergic agents, and did not present a significant acute toxicity. These differences should be due to chemical substances present in each product. These products had no significant effect as an anticonvulsant, while exhibited a strong depressant activity on the CNS.

Topics: Animals; Anticonvulsants; Artemisia; Central Nervous System Agents; Convulsants; Ethanol; Gas Chromatography-Mass Spectrometry; Lethal Dose 50; Male; Mice; Oils, Volatile; Pentylenetetrazole; Picrotoxin; Pilocarpine; Plant Extracts; Plant Leaves; Postural Balance; Rats; Rats, Wistar; Seizures; Solvents; Strychnine

Topics: Acidosis; Adult; Animals; Dogs; Humans; Male; Myoglobinuria; Poisoning; Seizures; Strychnine

A series of p-nitrophenyl substituted semicarbazones (4a-c) and phenoxy/p-bromophenoxy acetyl hydrazones (8a-q) were synthesized and their anticonvulsant activity was screened against maximal electroshock seizure (MES), subcutaneous metrazole (ScMet) and subcutaneous strychnine (ScSty) tests. Compounds 4a-c with -NHCO- were found to be the most active in all these tests. These compounds were also active in the MES test after oral administration in rats. On the other hand, compounds 8a-q with -OCH2- were devoid of anticonvulsant activity. The studies revealed that the hydrogen bonding domain in semicarbazones, adjacent to the lipophilic aryl ring, is essential for the anticonvulsant activity.

Topics: Administration, Oral; Animals; Anticonvulsants; Drug Design; Electroshock; Female; Hydrogen Bonding; Injections, Subcutaneous; Male; Molecular Structure; Pentylenetetrazole; Quantitative Structure-Activity Relationship; Rats; Rats, Sprague-Dawley; Seizures; Semicarbazones; Stereoisomerism; Strychnine

The present study was designed to evaluate the anticonvulsant effects of a high-fat ketogenic diet (KD) in rats. Animals were maintained on one of four experimental diets: (1) calorie-restricted ketogenic (KCR); (2) calorie-restricted normal (NCR); (3) ad libitum ketogenic (KAL); or (4) ad libitum normal (NAL). The calorie-restricted diets were fed in quantities such that they were calorically equivalent. All animals began diet treatment at age P37 and each was subjected to one of five chemically-induced seizure tests: bicuculline (BIC; s.c.), picrotoxin (PIC; s.c.), kainate (KA, i.p. or s.c.) and gamma-butyrolactone (GBL, i.p.), strychnine (s.c.). Bipolar epidural electrodes were implanted under ketamine/xylazine anesthesia to permit recording the spike and wave discharges (SWD) characteristic of electroencephalograms during absence seizures. Ketonemia was assayed by measuring blood levels of beta-hydroxybutyrate (BHB) spectrophotometrically prior to induction of seizures in each experiment. Animals fed ketogenic diets (i.e. either calorie restricted or ad libitum) exhibited greater blood levels of BHB compared to control groups. Seizure results show that treatment with a KD: (1) reduced the incidence of bicuculline-induced convulsions; (2) diminished the number of picrotoxin-induced seizures (KCR group only); (3) increased latency to GBL-induced SWD and reduced both the number and duration of SWD; but (4) conferred no protection from strychnine-induced seizures; and (5) made KA-induced seizures more severe. Together these results indicate a spectrum of anticonvulsant action for the KD in rats that includes threshold seizures induced via GABA receptors (BIC, PIC, GBL) but not those induced at glycine (strychnine) or the KA-subclass of glutamate receptors. Uniquely, the KD is the only treatment described that protects against both convulsive and non-convulsive (absence) seizures in rats.

Topics: 3-Hydroxybutyric Acid; Animals; Anticonvulsants; Bicuculline; Convulsants; Dietary Fats; Disease Models, Animal; Electroencephalography; Male; Picrotoxin; Rats; Rats, Sprague-Dawley; Seizures; Strychnine; Survival Rate; Time Factors

The genetic basis of a number of epilepsy syndromes has been identified but the precise mechanism whereby these mutations produce seizures is unknown. Three mutations of the alpha(4) subunit of the neuronal nicotinic acetylcholine receptor (nAChR) have been identified in autosomal dominant nocturnal frontal lobe epilepsy. In vitro studies of two mutations suggest an alteration of receptor function resulting in decreased ion channel current flow. We investigated the response of alpha(4) nAChR subunit knockout mice to the gamma-aminobutyric acid (GABA) receptor antagonists; pentylenetetrazole (PTZ) and bicuculline (BIC), the glutamate receptor agonist kainic acid (KA), the glycine receptor antagonist strychnine and the K(+) channel blocker 4-aminopyridine (4-AP). Mutant (Mt) mice had a greater sensitivity to PTZ and BIC, with an increase in major motor seizures and seizure-related deaths. Furthermore, Mt mice were more sensitive to KA and strychnine, but the effects were much smaller compared to those seen with the GABA receptor antagonists. Paradoxically, Mt mice appeared to be relatively protected from 4-AP-induced major motor seizures and death. The results show that a functional deletion of the alpha(4) nAChR subunit in vivo is associated with a major increase in sensitivity to GABA receptor blockers.

Topics: 4-Aminopyridine; Animals; Bicuculline; Binding, Competitive; Brain; Convulsants; Dose-Response Relationship, Drug; Drug Interactions; Excitatory Amino Acid Agonists; GABA Antagonists; Genotype; Kainic Acid; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Pentylenetetrazole; Potassium Channel Blockers; Receptors, GABA-A; Receptors, Nicotinic; Seizures; Strychnine

The present study determined the pharmacological profile of barakol, a major constituent of Cassia siamea Lamk., in rodent behavioral and neurochemical tests. Barakol reduced spontaneous locomotor activity, increased the number of sleeping animals and prolonged the thiopental-induced sleeping time, indicating a sedative effect. As for interactions between barakol and convulsants (pentylenetetrazole (PTZ), picrotoxin, bicuculline and strychnine), only a high dose (100 mg/kg, i.p.) of barakol slightly prolonged the latency of clonic convulsion induced by picrotoxin. This suggests that the sedative effect may not be induced via the GABA or glycine systems. There was no evidence of an anxiolytic effect of barakol in the plus-maze test. However, barakol (25-100 mg/kg, i.p.) could suppress methamphetamine (1 mg/kg, i.p.)-induced hyper-locomotor activity in a dose-dependent manner, indicating an effect on the dopaminergic system. In a microdialysis study, the dose of barakol (100 mg/kg) that inhibited spontaneous locomotor activity in mice did not affect the basal levels of extracellular dopamine (DA) or its metabolites in the striatum. However, pretreatment with barakol (100 mg/kg, i.p.) decreased the maximal dopamine release and dopamine turnover induced by methamphetamine (1 mg/kg, i.p.). This finding indicates that the inhibitory effect of barakol on dopamine release may account for the blocking effect of barakol on the striatum-related behavior induced by methamphetamine.

Topics: Animals; Anticonvulsants; Benzopyrans; Bicuculline; Cassia; Diazepam; Dopamine; Dose-Response Relationship, Drug; Male; Maze Learning; Methamphetamine; Pentylenetetrazole; Phenalenes; Phytotherapy; Picrotoxin; Plant Extracts; Rats; Rats, Wistar; Seizures; Sleep; Strychnine; Thiopental

Glycine receptors (GlyRs) are pentameric ligand-gated ion channels that inhibit neurotransmission in the adult brainstem and spinal cord. GlyR function is potentiated by ethanol in vitro, and a mutant GlyR subunit alpha(1)(S267Q) is insensitive to the potentiating effects of ethanol. To test the importance of GlyR for the actions of ethanol in vivo, we constructed transgenic mice with this mutation. Under the control of synapsin I regulatory sequences, transgenic expression of S267Q mutant GlyR alpha(1) subunits in the nervous system was demonstrated using [(3)H]strychnine binding and immunoblotting. These mice showed decreased sensitivity to ethanol in three behavioral tests: ethanol inhibition of strychnine seizures, motor incoordination (rotarod), and loss of righting reflex. There was no change in ethanol sensitivity in tests of acute functional tolerance or body temperature, and there was no change in ethanol metabolism. Transgene effects were pharmacologically specific for ethanol, compared with pentobarbital, flurazepam, and ketamine. These results support the idea that glycine receptors contribute to some behavioral actions of ethanol and that ethanol sensitivity can be changed in vivo by transgenic expression of a single receptor subunit.

Topics: Animals; Behavior, Animal; Body Temperature; Central Nervous System Depressants; DNA Primers; Ethanol; Glycine; Glycine Agents; Immunoblotting; Maze Learning; Mice; Mice, Transgenic; Motor Activity; Mutation; Oocytes; Patch-Clamp Techniques; Phenotype; Postural Balance; Receptors, Glycine; Seizures; Spinal Cord; Strychnine; Xenopus

The bioassay-guided fractionation of dried flowers of Butea monosperma (BM) was carried out to isolate the active principle responsible for its anticonvulsant activity. The petroleum ether extract was fractionated by column chromatography using solvents of varying polarity such as n-hexane, n-hexane:ethyl acetate, ethyl acetate, and methanol. The anticonvulsive principle of B. monosperma was found to be a triterpene (TBM) present in the n-hexane:ethyl acetate (1:1) fraction of the petroleum ether extract. TBM exhibited anticonvulsant activity against seizures induced by maximum electroshock (MES) and its PD(50) was found to be 34.2+/-18.1 mg/kg. TBM also inhibited seizures induced by pentylenetetrazol (PTZ), electrical kindling, and the combination of lithium sulfate and pilocarpine nitrate (Li-Pilo). However, TBM was not effective against seizures induced by strychnine and picrotoxin. TBM exhibited depressant effect on the central nervous system. After repeated use for 7 days, the PD(50) (MES) of TBM increased to 51.5+/-12.1 mg/kg. Similarly, after repeated use of TBM, the duration of sleep induced by pentobarbital was not reduced significantly. Further studies are required to investigate its usefulness in the treatment of epilepsy.

Topics: Animals; Anticonvulsants; Behavior, Animal; Butea; Convulsants; Dyskinesia, Drug-Induced; Electroshock; Flowers; Lithium; Male; Pentylenetetrazole; Picrotoxin; Pilocarpine; Postural Balance; Rats; Rats, Sprague-Dawley; Seizures; Strychnine

Anticonvulsive effect of water-soluble extract of rhizoma Pinelliae was studied. The result showed that the extract of rhizoma Pinelliae could remarkably inhibit the convulsion induced by strychnine and obviously reduce mortality rate in mice. But the extract could be destroyed easily by heat.

Topics: Animals; Anticonvulsants; Drugs, Chinese Herbal; Mice; Pinellia; Seizures; Strychnine; Survival Rate

A series of semicarbazones and hydrazones were prepared and evaluated for anticonvulsant activity. Some compounds provided significant protection against maximal electroshock (MES) and subcutaneous strychnine induced seizures (ScSty). Compound 2a emerged as the most active compound at a dose of 30 mg/kg in ScSty test. The compounds 1a, 1g and 2a-e showed significant potentiation of sedative and hypnotic activity of pentobarbitone sodium. Thus compound 2a could serve as a prototype for future developments.

Topics: Animals; Anticonvulsants; Chemical Phenomena; Chemistry, Physical; Convulsants; Drug Design; Electroshock; Hypnotics and Sedatives; Magnetic Resonance Spectroscopy; Rats; Seizures; Semicarbazones; Spectrophotometry, Infrared; Stereoisomerism; Strychnine

Psychopharmacological studies were conducted on an extract of Andrographis paniculata herbs. The extract exhibited a significant alteration in behaviour pattern and a reduction in spontaneous motility. The extract also produced a prolongation of the pentobarbitone-induced sleeping time and lowered the body temperature in different experimental animal models.

Topics: Acetic Acid; Animals; Behavior, Animal; Magnoliopsida; Mice; Pain; Pain Measurement; Pentylenetetrazole; Plant Extracts; Plants, Medicinal; Psychotropic Drugs; Rats; Seizures; Strychnine

The acute toxicity and the central effects of Mitragyna africanus (M. africanus) stembark methanol extract were studied in rats. The extract did not produce any death in the treated rats even at the highest dose (6400 mg kg(-1)) used. It produced depressant effects on the central nervous system. The stembark extract potentiated amylobarbitone sleeping time in rats dose-dependently, induced sleep in rats and also produced significant local anaesthetic effect on rabbits, the effects being comparable to that of xylocaine. The extract protected rats treated with a convulsive dose of strychnine (2 mg kg(-1)) and increased the period of onset of convulsions and decreased the number of spasms.

Topics: Amobarbital; Animals; Central Nervous System; Convulsants; Dose-Response Relationship, Drug; Drug Synergism; Female; Hypnotics and Sedatives; Male; Phytotherapy; Plant Extracts; Rabbits; Rats; Rats, Wistar; Seizures; Sleep; Strychnine

A novel series of N-substituted 4-ureido-5,7-dichloro-quinolines were synthesized to contain pharmacophores directed at voltage-sensitive sodium channels (VSNaCs) and N-methyl-D-aspartate (NMDA) receptors. These compounds were shown to act in a use-dependent manner as antagonists of VSNaCs and to act as selective competitive antagonists at the strychnine-insensitive glycine recognition site of NMDA receptors. These agents had little or no effect on alpha-adrenergic receptors, other glutamate receptors, or sites other than the glycine site on the NMDA receptor, and did not block voltage-sensitive calcium channels in vitro. In vivo, the compounds were active in preventing or reducing the signs and symptoms of neurohyperexcitability and had anxiolytic properties. Unlike benzodiazepines, N-substituted 4-ureido-5, 7-dichloro-quinolines showed little interaction with the sedative effects of ethanol, but were effective in controlling ethanol withdrawal seizures. The combined actions of these compounds on VSNaCs and NMDA receptors also impart properties to these compounds that are important for preventing and reducing excitotoxic neurodegeneration, but these compounds lack the undesirable side effects of other agents used for these purposes.

Topics: Animals; Anti-Anxiety Agents; Ataxia; Behavior, Animal; Binding Sites; Binding, Competitive; Cells, Cultured; Cerebellum; Dose-Response Relationship, Drug; Ethanol; Glycine; Humans; In Vitro Techniques; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Neurons; Oocytes; Phenylurea Compounds; Protein Binding; Quinolines; Rats; Receptors, Adrenergic, alpha; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; Seizures; Sodium Channel Blockers; Sodium Channels; Sound; Strychnine; Substance Withdrawal Syndrome; Xenopus

Thalamocortical spike-and-wave discharges characterize the nonconvulsive absence seizures that occur spontaneously in genetic absence epilepsy rats from Strasbourg (GAERS), a selected strain of Wistar rats. GABA is crucial in the generation of absence seizures. The susceptibility to convulsions induced by threshold doses of various GABA receptor antagonists and inhibitors of GABA synthesis, kainic acid and strychnine, was compared in GAERS and in nonepileptic rats from a selected control strain (NE). The brain structures involved in the drug-elicited convulsive seizures were mapped by c-Fos immunohistochemistry. Injection of various antagonists of the GABA(A) receptor, bicuculline and picrotoxin, and inverse agonists of the benzodiazepine site (FG 7142 and DMCM) induced myoclonic spike-and-wave discharges followed by clonic or tonic-clonic seizures with high paroxysmal activity on the cortical EEG. The incidence of the convulsions was dose-dependent and was higher in GAERS than in NE rats. Mapping of c-Fos expression showed that the frontoparietal cortex was constantly involved in the convulsive seizures elicited by a threshold convulsant dose, whereas limbic participation was variable. In contrast, GAERS were less susceptible than NE rats to the tonic-clonic convulsions induced by the inhibitors of glutamate decarboxylase, isoniazide and 3-mercaptopropionic acid. The GABA(B) receptor antagonist CGP 56999 and kainic acid induced a similar incidence of seizures in GAERS and NE rats and predominantly activated the hippocampus. No difference in the tonic seizures elicited by strychnine could be evidenced between the strains. These results suggest that an abnormal cortical GABAergic activity may underlie absence seizures in GAERS.

Topics: 3-Mercaptopropionic Acid; Animals; Bicuculline; Carbolines; Convulsants; Electroencephalography; Epilepsy, Absence; Frontal Lobe; GABA Antagonists; GABA-A Receptor Antagonists; gamma-Aminobutyric Acid; Glutamate Decarboxylase; Isoniazid; Kainic Acid; Limbic System; Male; Parietal Lobe; Picrotoxin; Proto-Oncogene Proteins c-fos; Rats; Rats, Mutant Strains; Rats, Wistar; Seizures; Strychnine

This paper describes an analytical method for strychnine determination in biological samples by gas chromatography/mass spectrometry and their application in the investigation of two cases involving strychnine ingestion: A fatal case and a clinical one. The strychnine is isolated from biological samples using a liquid-liquid extraction procedure. The clean-up procedure is performed using an acid solution. Papaverine is used as internal standard in the quantification of strychnine. In the analysed specimens, the limits of quantification were 0.1 microg/ml or 0.1 microg/g. The recovery rate ranged from 75.0% to 98.7% and the coefficients of variation ranged from 4.8% to 10.5%.

Topics: Acids; Fatal Outcome; Female; Gas Chromatography-Mass Spectrometry; Humans; Male; Middle Aged; Papaverine; Poisons; Seizures; Strychnine; Suicide

The influence of progesterone and testosterone on the incidence of seizures after administration of intraperitoneal pentylenetetrazol and subcutaneous strychnine was evaluated in mice. Pentylenetetrazol and strychnine were administered in doses that induced seizures in 40-50% of control mice in dioestrus (48 and 0.9 mg/kg, respectively). The percentage of seizures induced by pentylenetetrazol and strychnine was significantly lower in female mice in prooestrus/oestrus, when progesterone levels are high, than in dioestrus, when progesterone levels are low. Pretreatment of pentylenetetrazol-challenged mice with progesterone (250 microg/kg) increased the incidence of seizures in prooestrus/oestrus, without affecting seizures in dioestrus. The same pretreatment in strychnine-challenged mice also increased the incidence of seizures in prooestrus-dioestrus, but significantly reduced the incidence of seizures in dioestrus. In addition, progesterone pretreatment significantly increased the percentage of deaths induced by strychnine in prooestrus-oestrus, reducing deaths in dioestrus. Orchidectomized male mice had a significantly higher incidence of seizures after administration of pentylenetetrazol and strychnine than control mice. Administration of 11 daily doses of 250 microg/kg of testosterone to castrated mice significantly reduced the incidence of seizures induced by pentylenetetrazol. These results confirm the modulatory influence of reproductive steroids on the excitability of the central nervous system and the possible clinical importance of progesterone and testosterone in the management of partial epilepsy.

Topics: Animals; Convulsants; Diestrus; Female; Gonadal Steroid Hormones; Male; Mice; Orchiectomy; Pentylenetetrazole; Progesterone; Seizures; Strychnine; Testosterone

A rational, chemical, synthetic effort to identify promising low-affinity uncompetitive N-methyl-D-aspartic acid receptor antagonists for use as antiepileptic drugs led to the discovery of AR-R 15035AR, or [RS]-alpha-phenyl-2-pyridine-ethanamine.2HCl. Chiral separation followed by intensive in vivo screening resulted in the selection of the [S] enantiomer, AR-R 15896AR, as the best compound for further preclinical development. AR-R 15896AR prevented tonic seizures in rodents for up to 6 to 8 h in response to maximal electroshock (MES), 4-aminopyridine, bicuculline, or strychnine, as well as characteristic seizures following injections of N-methyl-DL-aspartic or kainic acids. AR-R 15896AR was ineffective in two kindling models of epilepsy, did not produce tolerance to MES, and was devoid of proconvulsant and phencyclidine-like properties in mice and rats, respectively. Therapeutic indices for AR-R 15896AR were comparable to or exceeded those for standard anticonvulsants. Orally administered AR-R 15896AR rapidly entered the rat brain and was eliminated in parallel from the plasma and plasma-free compartment. A dose-response relationship between plasma and brain levels after p.o. or i.v. administration of AR-R 15896AR and protection against MES was highly correlative. The time course for loss of protection against MES mirrored the elimination of the compound from brain and plasma. The total brain concentration (25 microM) of drug at the ED50 value (approximately 3 mg/kg) for protection against MES seizures was consistent with the reported affinity of AR-R 15896AR at the N-methyl-D- aspartic acid binding site (IC50 value = 1.3 microM). The present findings demonstrated the attractiveness of AR-R 15896AR as a candidate for further development to treat epilepsy.

Topics: 4-Aminopyridine; Animals; Anticonvulsants; Bicuculline; Electric Stimulation; Kainic Acid; Male; Mice; N-Methylaspartate; Pentylenetetrazole; Picrotoxin; Pyridines; Rats; Rats, Sprague-Dawley; Seizures; Seizures, Febrile; Strychnine; Time Factors; Weaning

Withdrawal seizure-prone (WSP) and withdrawal seizure-resistant (WSR) mice were selectively bred to have severe (WSP) or mild (WSR) handling-induced convulsions after chronic ethanol inhalation. The purpose of the present experiments was to determine whether seizure susceptibility differences between WSP and WSR mice during ethanol withdrawal were specific to agents acting at gamma-aminobutyric acidA or excitatory amino acid (EAA) receptors. Male WSP and WSR mice were exposed to ethanol vapor or air for 24 or 72 h. During peak withdrawal (i.e., between 6.5 and 8 h after removal from the inhalation chambers), separate groups of animals were administered pentylenetetrazol, (+)bicuculline, N-methyl-D-aspartate, kainic acid, or strychnine via timed tail vein infusion. Withdrawal from ethanol significantly increased sensitivity to pentylenetetrazol and (+)bicuculline versus air-exposed WSP and WSR mice. In contrast, sensitivity to N-methyl-D-aspartate-induced convulsions was significantly decreased in the ethanol-exposed WSR and unchanged in the ethanol-exposed WSP mice. Sensitivity to kainic acid was significantly increased in both ethanol-exposed WSR and WSP mice, although the magnitude of change in sensitivity was greater in the ethanol-withdrawing WSP line. Interestingly, sensitivity to strychnine was decreased similarly in the ethanol-exposed WSP and WSR mice, compared with their respective air-exposed animals. These results suggest that chronic ethanol increased sensitivity to convulsants active at gamma-aminobutyric acidA receptors similarly in WSP and WSR mice, but differentially changed sensitivity to convulsants active at EAA receptors in the lines. This supports a role for EAA systems in determining genetic susceptibility to alcohol withdrawal.

Topics: Administration, Inhalation; Alcoholism; Animals; Central Nervous System Depressants; Convulsants; Drug Administration Schedule; Ethanol; Genetic Predisposition to Disease; Male; Mice; Receptors, GABA-A; Receptors, Glutamate; Seizures; Sensitivity and Specificity; Strychnine; Substance Withdrawal Syndrome

Intracellular activity of the slow adapting neurone (SAN) was recorded together with extracellular action potentials (APs) of SAN, fast adapting neurone and inhibitory fibre in the isolated stretch receptor of the moulting crayfish. Following strychnine application, spontaneous APs and seizure-like AP trains were observed. A delay of the inhibitory fibre APs relative to SAN inhibitory postsynaptic potential, their waveforms and their initiation by intracellular SAN hyperpolarization indicate that their generation was close to the inhibitory nerve terminal. Such antidromic (ectopic) APs assert their postsynaptic action on both receptor neurones via the axon reflex. The findings provide first evidence of antidromic APs generated in the vicinity of inhibitory terminals, their direct and axon reflex-mediated action on target neurones and support a hypothesis that increased terminal excitability contributes to seizure activity.

Topics: Action Potentials; Animals; Astacoidea; Axons; Convulsants; Dendrites; Evoked Potentials; Extracellular Space; Nerve Fibers; Neural Inhibition; Presynaptic Terminals; Seizures; Strychnine; Synaptic Transmission

A series of semicarbazones and thiosemicarbazones were synthesized and evaluated for anti-convulsant activity. Some compounds provided significant protection against Maximal Electroshock (MES) and subcutaneous strychnine induced seizures. Compound 1 was the most active in the series with activity in a dose of 30 mg/kg in the strychnine seizure pattern test and an ED50 of 10 mg/kg in the MES test. Hence it could serve as a prototype molecule for future development. Also compounds with a p-nitrophenyl substitution in place of the amino hydrogen of semicarbazone moiety showed activity in a dose of 30 mg/kg and an ED50 of 83 mg/kg in the MES test.

Topics: Animals; Anticonvulsants; Convulsants; Electroshock; Hypnotics and Sedatives; Magnetic Resonance Spectroscopy; Mice; Postural Balance; Seizures; Semicarbazones; Sleep; Spectrophotometry, Infrared; Structure-Activity Relationship; Strychnine; Time Factors

The anticonvulsant effects of Shitei-To and its components on maximal electroshock seizures and chemical convulsions were examined. Shitei-To significantly prolonged the latency to bicuculline (2.0 mg/kg, s.c.)-induced clonic convulsions. Repeated treatment with Shitei-To also significantly prolonged the latency to strychnine (1.5 mg/kg, i.p.)- and pentylenetetrazol (90 mg/kg, i.p.)-induced clonic convulsions. On the other hand, Shitei-To had no effect on maximal electroshock seizures. Of the components of Shitei-To, Shitei had almost the same effect as Shitei-To against the clonic convulsions induced by the three chemical agents tested. These findings suggest that Shitei-To has anticonvulsant effects.

Topics: Animals; Anticonvulsants; Bicuculline; Convulsants; Drugs, Chinese Herbal; Electroshock; Male; Mice; Mice, Inbred Strains; Pentylenetetrazole; Seizures; Strychnine

Investigations were carried out to evaluate the effect of acute and chronic administration of both black and green tea on three models of experimentally induced convulsions in mice. Tea extract (both black and green) significantly accelerated the onset of convulsion, increased the duration of convulsion and mortality in mice. Since both the extracts failed to alter the GABA level in brain, based on the earlier report that both black and green tea might act on Ca(2+) channels, it can be suggested that the observed proconvulsive effect of tea is not mediated through GABA but through Ca(2+) channels.

Topics: Animals; Brain Chemistry; Caffeine; Convulsants; Electroshock; Female; gamma-Aminobutyric Acid; Male; Mice; Mice, Inbred BALB C; Phosphodiesterase Inhibitors; Seizures; Strychnine; Tea; Tissue Extracts

In this study, we attempted to clarify the mechanisms mediating cyclosporine-evoked convulsions. Cyclosporine (50 mg/kg, i.p.) significantly enhanced the intensity of convulsions induced by bicuculline (GABA receptor antagonist), but not those induced by strychnine (glycine receptor antagonist), N-methyl-D-aspartic acid, quisqualic acid or kainic acid (glutamate receptor agonists). Bicuculline plus cyclosporine-induced convulsions were significantly suppressed by an activation of GABAergic transmission with diazepam, phenobarbital and valproate. The GABA turnover estimated by measuring aminooxyacetic acid-induced GABA accumulation in the mouse brain was significantly inhibited by cyclosporine (50 mg/kg, i.p.). When cultured rat cerebellar granule cells were exposed to 1 microM cyclosporine for 24 hr, the specific [3H]muscimol (10 nM) binding to intact granule cells decreased to 53% of vehicle controls. The present study provides the first evidence suggesting that cyclosporine inhibits GABAergic neural activity and binding properties of the GABAA receptor. These events are closely related to the occurrence of adverse central effects including tremors, convulsions, coma and encephalopathy under cyclosporine therapy.

Topics: Animals; Anticonvulsants; Bicuculline; Binding Sites; Brain; Cells, Cultured; Cerebellum; Cyclosporine; Drug Synergism; Excitatory Amino Acid Agonists; GABA Agonists; GABA Antagonists; gamma-Aminobutyric Acid; Glycine; Male; Mice; Mice, Inbred Strains; Muscimol; Neurons; Rats; Rats, Wistar; Seizures; Strychnine; Tacrolimus

A series of p-nitrophenyl substituted semicarbazones has been synthesised and their anticonvulsant activity was screened against MES, scPTZ and scSTY. 4(4'-Nitrophenyl)-o-nitrobenzaldehyde semicarbazone has been found to be the most active in all these tests. The studies revealed that a primary amino function is not essential for anticonvulsant activity in the semicarbazone series of compounds. Presumably these compounds could further act on glycine receptors.

Topics: Animals; Anticonvulsants; Chemical Phenomena; Chemistry, Physical; Convulsants; Electroshock; Magnetic Resonance Spectroscopy; Mice; Pentylenetetrazole; Postural Balance; Seizures; Semicarbazones; Spectrophotometry, Infrared; Strychnine

Glycine is a small neutral amino acid exhibiting weak anticonvulsant activities in vivo. Recently, studies have demonstrated that N-(benzyloxycarbonyl)glycine (1) antagonized seizures superior to glycine in addition to activity in the maximal electroshock (MES) test, a convulsive model where glycine is inactive. In the present study a series of ester and amide derivatives of 1 as well as esters of N-(3-phenylpropanoyl)glycine (5) have been prepared. The compounds were evaluated in the MES test as well as in several chemically induced seizure models. Among the derivatives investigated, N-(benzyloxycarbonyl)glycine benzylamide (16) was the most potent compound exhibiting an anticonvulsant activity in the MES test comparable to the drug phenytoin. Median effective doses (ED50) of 4.8 and 11.6 mg/kg were determined at 30 min and 3 h after i.p. administration, respectively. Compound 16 also effectively suppressed tonic seizures in different chemically induced models such as the strychnine, 3-mercaptopropionic acid, and pentylenetetrazole tests. Moreover, the compound studied here did not show acute neurotoxicity in the rotorod test up to a dose of 150 mg/kg. It is concluded that N-(benzyloxycarbonyl)glycine amides, especially 16, are potent anticonvulsant agents.

Topics: 3-Mercaptopropionic Acid; Amides; Animals; Anticonvulsants; Dose-Response Relationship, Drug; Electroshock; Esters; Glycine; Male; Mice; Mice, Inbred Strains; Neurotoxins; Pentylenetetrazole; Radioligand Assay; Rats; Rats, Wistar; Receptors, Glycine; Seizures; Spinal Cord; Strychnine

Although most epilepsies are adequately treated by conventional antiepileptic therapy, there remains an unfulfilled need for safer and more effective anticonvulsant agents. Starting from milacemide, a weak anticonvulsant, and trying to elucidate its mechanism of action, we discovered a structurally novel class of potent and preclinically safe anticonvulsants. Here we report the structure-activity relationship (SAR) study within this series of compounds. Different parts of the structural lead 2-[[4-(3-chlorobenzoxy)benzyl]amino]acetamide (6) were thus varied (Figure 1), and many potent anticonvulsants were found. As an outcome of this study, 57 ((S)-2-[[4-(3-fluorobenzoxy)benzyl]amino]propanamide methanesulfonate, PNU-151774E) emerged as a promising candidate for further development for its potent anticonvulsant activity and outstanding therapeutic indexes (TIs) in different animal tests.

Topics: Alanine; Animals; Anticonvulsants; Benzylamines; Bicuculline; Drug Design; Electroshock; Indicators and Reagents; Male; Mice; Mice, Inbred ICR; Models, Molecular; Molecular Structure; Motor Activity; Picrotoxin; Postural Balance; Rats; Rats, Inbred Strains; Seizures; Structure-Activity Relationship; Strychnine

An 18-year-old female who accidentally ingested strychnine developed chemical pancreatitis in addition to the classical clinical picture of strychnine poisoning. Many drugs or chemicals have been reported to be associated with pancreatitis; however, this paper provides us with the first evidence that acute pancreatitis may follow strychnine poisoning. The patient survived despite the development of seizures, lactic acidosis, rhabdomyolysis, and pulmonary infiltrates. Toxicology testing confirmed the presence of strychnine in blood (2.17 mg/L), gastric aspirate, and urine. Attention is drawn to the fact that survival can follow the ingestion of large doses of strychnine providing there is no delay in diagnosis and treatment. The pathophysiologic mechanism of chemical pancreatitis is discussed.

Topics: Acute Disease; Adolescent; Creatine Kinase; Female; Humans; L-Lactate Dehydrogenase; Pancreatitis; Poisons; Seizures; Strychnine

Previous studies have demonstrated that Lister hooded rats will exhibit characteristic bursts of locomotion when exposed to a 20-kHz acoustic stimulus; this ultrasound-induced locomotion has been suggested as a potential model for panic attacks. Although ultrasound presentation rarely induces convulsions, the locomotor bursts exhibited resemble pre-convulsant running. The present studies examined the interactions between strychnine treatment and experimenter-presented ultrasounds on behaviour in male Lister hooded rats. Strychnine was selected because it is a potent and effective convulsion-inducing agent which is not known to induce anxiety in humans. Behaviour in a circular arena (75 cm diameter) was observed live, videotaped and traced electronically. In experiments 1 and 2, moderate (60 s) or relatively brief (15 s) exposure to an ultrasound stimulus (20 kHz, 98 dB, SPL) typically resulted in 5- to 10-s bursts of locomotion in saline-treated subjects; strychnine treatment (0.5, 0.7, 1.0 mg/kg, injected i.p., 10 min prior to testing) significantly increased this ultrasound-induced locomotion in a dose-dependent manner. Experiment 3 demonstrated that the strychnine enhancement of the ultrasound response was not different in naive animals when compared to those subjects which had received occasional strychnine and/or ultrasound treatment previously. Experiment 3 also demonstrated that strychnine treatment can cause at least modest running in subjects exposed to a 2 kHz tone (96 dB SPL). In experiment 4, exposure to the 20 kHz, 98 dB ultrasound stimulus for a much longer period, 9 min, resulted in irregular cycles of bursts of locomotion, followed immediately by periods of relative inactivity in saline-treated animals; approximately 10% of these subjects exhibited tonic-clonic convulsions. No convulsions occurred in strychnine-treated subjects during the period 10-20 min post-injection in the absence of ultrasound exposure; in contrast, the frequency of occurrence of convulsions in strychnine-treated subjects (10-20 min post-injection) exposed to the ultrasound stimulus was greater than 50%; these convulsions typically occurred at the end of a locomotor burst. The results of the present studies suggest that there may be a relationship between ultrasound-induced locomotor bursts and convulsant activity.

Topics: Acoustic Stimulation; Animals; Convulsants; Male; Motor Activity; Rats; Seizures; Strychnine; Time Factors; Ultrasonics

Nitric oxide (NO) formation has been shown in many neuronal tissues subserves a variety of functions. N-Methyl-D-aspartate (NMDA) receptor stimulation which releases nitric oxide and raises cGMP levels, mediates epileptiform activity induced by various agents. Disinhibition of inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and/or activation of NMDA receptor appears to be factors involved in the initiation and generalization of the pentylenetetrazole (PTZ) induced seizures. In the present study, we examined the effects of N(omega)-nitro-L-arginine methylester (L-NAME) which inhibits nitric oxide synthase, on PTZ and strychnine induced seizures in mice. L-NAME (100 mg/kg) significantly prolonged the onset time of tonic generalized extension without affecting myoclonic jerks and tonic-clonic convulsions. L-NAME (200 mg/kg) significantly delayed three characteristic behavioral changes including first myoclonic jerk (FMJ), generalized clonic seizure (GCS) and tonic generalized extension (TGE). The effects of L-NAME were reversed by L-arginine (1000 mg/kg). L-NAME (100 and 200 mg/kg) significantly delayed the onset time of strychnine induced TGE. The effects of both doses of L-NAME were reversed by L-arginine. In conclusion, our results demonstrate that NO synthase inhibition suppresses the onset time of PTZ and strychnine induced seizures. Under the light of our current knowledge NO synthase inhibitors seem far away to be considered as a group of antiepileptic drugs. On the other hand there are some strong evidences about the role of NO in central pathophysiological mechanisms.

Topics: Animals; Convulsants; Drug Evaluation, Preclinical; Enzyme Inhibitors; Male; Mice; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Pentylenetetrazole; Seizures; Strychnine

1. A putative agonist for the strychnine-sensitive glycine receptor picolinic acid was tested for its anticonvulsant activities in mice and muscle-relaxant activities in rats and compared with indole-2-carboxylic acid (I2CA), an antagonist for the strychnine-insensitive glycine receptor. Their effects on segmental reflexes in the cat spinal cord were examined to elucidate their sites of action. 2. Picolinic acid (200 and 400 mg/kg IP) delayed the onsets of strychnine- but not pentylenetetrazole-induced seizures. It delayed the onsets of bicuculline-induced seizures only at the higher dose. I2CA (200 and 400 mg/kg IP) delayed the onsets of these 3 kinds of seizures. Both compounds reduced muscle tone in rat decerebrate rigidity at a dose of 100 mg/kg IV. 3. Picolinate methylester, a picolinate derivative with higher lipophilicity, depressed spinal reflexes in both intact and spinalized cats at cumulative doses of 25 to 200 mg/kg IV. I2CA (50 mg/kg IV) inhibited spinal reflexes only in intact preparations. 4. These results suggest that the anticonvulsant and muscle-relaxant activities of picolinic acid (PA) are due to inhibition of spinal neurons, but that I2CA selectively affects supraspinal structures.

Topics: Animals; Anticonvulsants; Bicuculline; Carboxylic Acids; Cats; Decerebrate State; Female; Glycine Agents; Indoles; Male; Mice; Muscle Relaxation; Muscle, Skeletal; Picolinic Acids; Rats; Rats, Wistar; Reflex; Seizures; Strychnine

The seizure sensitivities to pentylenetetrazol (Ptz, 25-100 mg/kg) and strychnine (S, 2 mg/kg) were tested in two mice lines selected for large (LB) and small (SB) brain weight (brain weight difference being approximately 75 mg). The selection was based on a regression line connecting body and brain weight. SB mice were more sensitive to both drugs-their seizure latencies were shorter and lethality higher than in LBs. The seizures generated by Ptz and S are known to affect different neurotransmitter systems. The interstrain differences in seizure susceptibility are probably determined by SB mice nervous system traits rather than by differences in the particular neurochemical trait. The data on neocortical cytoarchitectonics obtained during our previous brain selection experiment could serve as the indirect evidence favouring such a suggestion.

Topics: Animals; Brain; Cerebral Cortex; Convulsants; Dose-Response Relationship, Drug; Electroencephalography; Female; Genotype; Male; Mice; Mice, Inbred Strains; Organ Size; Pentylenetetrazole; Seizures; Selection, Genetic; Strychnine

While occasional myoclonic jerks are prevalent in cancer patients receiving opioids, severe myoclonic jerks and seizures due to opioids are uncommon. In this retrospective case series, we describe five cancer patients with refractory cancer pain and severe neuroexcitatory toxicity associated with extremely high-dose opioid therapy to characterize better the syndrome, its treatment, and its outcome. Two patients died following seizures, but three patients recovered following prompt treatment with parenteral midazolam infusions and rotation to alternative opioids. Possible mechanisms and treatment options for this potentially lethal clinical syndrome are reviewed. The authors conclude that severe multifocal myoclonus and seizures associated with extremely high-dose opioid therapy are life-threatening, and respond to parenteral midazolam infusion, rotation to alternative opioids, and aggressive supportive care.

Topics: Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Anesthetics, Intravenous; Drug Administration Schedule; Female; Humans; Male; Midazolam; Myoclonus; Seizures; Strychnine

Topics: Adenosine; Animals; Anticonvulsants; Calcitonin Gene-Related Peptide; Convulsants; Drug Synergism; Injections, Intraventricular; Mice; Seizures; Strychnine

Anticonvulsant activity, lethality and neurotoxicity of a valproic acid (VPA) analog, N-(2-propylpentanoyl) urea (VPU) in comparison to its parent compound were investigated in mice. Intraperitoneally administered VPU demonstrated a higher protection than VPA in both the maximal electroshock seizure (MES) and the pentylenetetrazole (PTZ) tests exhibiting a median effective dose (ED50) of 66 and 57 mg/kg, respectively. VPU weakly blocked the effect of bicuculline and was ineffective in strychnine test. Furthermore, VPU was also active orally demonstrating an ED50 approximately 6 times higher than its ED50 by the intraperitoneal route. Based on the relatively high median lethal dose (LD50), 1553 mg/kg, VPU possesses a greater margin of safety (LD50/ED50) than did VPA. Unwanted (side) effects in terms of impairment of motor activity and neurotoxicity were assessed by the rotorod test, locomotor activity test as well as potentiation of barbiturate sleeping time. The median neurotoxic dose (TD50) as measured by rotorod test were 625 mg/kg for intraperitoneally given VPU. This finding results in higher protective index (PI = TD50/ED50) of VPU (PI = 9.5) than that of VPA (PI = 1.1) implying that, in therapeutic dose, VPU may produce less neurological side effects than did VPA. Superiority of VPU in terms of higher potency in parallel with minimal neurological deficit as assessed by rotorod test was evident throughout the observation period of 12 hours. Similar results on locomotor activity as well as potentiation of barbiturate sleeping time were obtained with VPU and VPA. Thus, VPU is preferably expected to exert minor degree of CNS depression. Taken altogether, our findings demonstrate greater anticovulsant activity for VPU than for VPA. In addition, this compound is also orally active and seems to offer a greater safety margin in parallel with lower unwanted effects in relation to its parent compound. As indicated by the animal data obtained, VPU is an attractive anticonvulsant candidate for further investigation.

Topics: Animals; Anticonvulsants; Bicuculline; Central Nervous System; Convulsants; Dose-Response Relationship, Drug; Electroshock; Lethal Dose 50; Male; Mice; Motor Activity; Pentylenetetrazole; Seizures; Sleep; Strychnine; Time Factors; Urea; Valproic Acid

The crude drug, Chotoko (Uncariae Uncis cam Ramlus), the hooks of Uncaria spp. (Rubiaceae), has been claimed to possess sedative and anti-spasmodic actions, and is contained in a Chinese traditional preparation, Choto-san, as a main crude drug. Examinations were made on the anti-convulsion effects of Choto-san and Chotoko against some animal models of epilepsy conducted by the stimulation of drugs or electricity. Oral administration of the Choto-san extract to mice at the doses of 1.0 g/kg and 3.0 g/kg tended to inhibit the glutamate-induced convulsion in a dose-dependent manner, and the effect of the Chotoko extract at a 3.0 g/kg dose was significant, while both the extracts showed no activity against the picrotoxine-induced, strychinine-induced, and electroshock convulsions. The Choto-san preparation without Chotoko was inactive, and the activity of the Chotoko extract was more potent than that of the every crude drug comprising Choto-san, suggesting that Chotoko plays the most important role in the Choto-san prescription and contains some active compounds. Bioassay-guided fractionation of the Chotoko extract led to the location of the active components in the less polar alkaloids-containing fraction, from which three indole alkaloids, geissoschizine methylether (1), hirsuteine (2) and hirsutine (3), and an oxyindole alkaloid, isocorynoxeine (4) were isolated and identified. Oral administration of 1 and 2 to mice at the doses of 50, 100, and 200 mg/kg inhibited the glutamate-induced convulsion in a dose-dependent manner. The effect of 3, the dihydro derivative of 2, was less potent than those of 1 and 2. Compound 4 showed no activity at a 100 mg/kg dose compared with control. The above results support the Chinese herbal description of the anti-spasmodic action of Chotoko, and show that 1 and 2 contained in Chotoko must be mainly contributed to the activity. It is also suggested that Choto-san may be clinically available for treatment of epilepsy.

Topics: Alkaloids; Animals; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Glutamic Acid; Indole Alkaloids; Indoles; Male; Mice; Mice, Inbred Strains; Picrotoxin; Seizures; Strychnine

2,3-Dihydro-6,7-dichloro-pyrido[2,3-b]pyrazine-8-oxide was synthesized and evaluated for in vitro/in vivo antagonistic activity at the strychnine insensitive glycine binding site on the NMDA receptor revealing it to be a useful tool to evaluate the effectiveness of glycine antagonists in vivo.

Topics: Animals; Avoidance Learning; Binding Sites; Cyclic N-Oxides; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glycine; Kynurenic Acid; Mice; Motor Activity; N-Methylaspartate; Neuroprotective Agents; Pyrazines; Rats; Receptors, N-Methyl-D-Aspartate; Seizures; Stereotyped Behavior; Strychnine

The anticonvulsant activity of the novel drug D-23129 (N-(2-amino-4-(4-fluorobenzylamino)phenyl)carbamic acid ethyl ester) was evaluated in animal models of epileptic seizures. D-23129 was active after oral and intraperitoneal administration in rats and mice in a range of anticonvulsant tests at nontoxic doses. The compound was active against electrically induced seizures (MES, ED50 rat p.o. = 2.87 mg/kg), against seizures induced chemically by pentylenetetrazole (s.c. PTZ, ED50 mouse p.o. = 13.5 mg/kg), picrotoxin and N-methyl-D-aspartate (NMDA) and in a genetic animal model, the DBA/2 mouse. It was not active against seizures induced by bicuculline and strychnine. Motor impairment, evaluated with the rotarod test and by observation in the open field, was minimal at doses showing anticonvulsant activity. D-23129 was very effective in elevating the threshold for electrically and chemically induced seizures. Considering the dose increasing the MES threshold by 50% (TID50 mouse i.p. = 1.6 mg/kg; TID50 rat i.p. = 0.72 mg/kg) and the TD50 obtained in the rotarod test, the protective index of D-23129 is better than that of valproate and phenytoin. During 14 days chronic oral treatment with 15 mg/kg, no development of tolerance was observed. D-23129 thus presents an orally active, safe, broad spectrum anticonvulsant agent, which is structurally unrelated to anticonvulsants currently used. We expect that D-23129 will improve the treatment of refractory seizures in humans.

Topics: Administration, Oral; Animals; Anticonvulsants; Behavior, Animal; Bicuculline; Carbamates; Dyskinesia, Drug-Induced; Electroshock; Female; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Mice; Mice, Inbred DBA; N-Methylaspartate; Pentylenetetrazole; Phenylenediamines; Postural Balance; Rats; Rats, Wistar; Seizures; Strychnine

Aminophylline reversed the protective action of both, D-3-(2-carboxypiperazine-4-yl)-1-propenyl-1-phosphonic acid (D-CPP-ene-a competitive NMDA antagonist) and valproate (used as a conventional antiepileptic drug for comparative purposes) against maximal electroshock-induced seizures. The respective ED50 values of aminophylline were 55.7 and 98.4 mg/kg i.p. However, aminophylline (up to 100 mg/kg i.p.) did not influence the protective efficacy of 1-(4-aminophenyl)-4-methyl-7,8-methyl- enedioxy-5H-2,3-benzodiazepine (GYKI 52466-a non-NMDA antagonist). Strychnine affected the protection provided by D-CPP-ene, GYKI 52466, and valproate against maximal electroshock-the ED50 values of strychnine for the reversal of the anticonvulsive effects of D-CPP-ene, GYKI 52466 or valproate were 0.082, 0.35 and 0.28 mg/kg s.c., respectively. An involvement of strychnine sensitive glycinergic receptor-mediated events in the mechanism of the anticonvulsive activity of excitatory amino acid antagonists and valproate may be postulated. The ineffectiveness of aminophylline to reduce the anticonvulsive effects of GYKI 52466 may distinguish a new class of antiepileptic drugs offering an advantage over conventional antiepileptics in patients with epilepsy, requiring aminophylline for pulmonary reasons.

Topics: Aminophylline; Animals; Anti-Anxiety Agents; Anticonvulsants; Benzodiazepines; Convulsants; Electroshock; Excitatory Amino Acid Antagonists; Male; Mice; N-Methylaspartate; Phosphodiesterase Inhibitors; Piperazines; Seizures; Strychnine; Valproic Acid

The gamma 2 subunit of the gamma-aminobutyric acid type-A (GABAA) receptor is associated with the actions of benzodiazepines and related drugs. A phosphorothioate-modified antisense oligodeoxynucleotide directed against the gamma 2 subunit was given by i.c.v. injection (18 micrograms in 2 microliters saline) to male Sprague-Dawley rats every 12 h for 3 days. Controls received the corresponding sense oligodeoxynucleotide. 4-6 h after the last i.c.v. treatment, rats were given methyl-beta-carboline-3-carboxylate (beta-CCM), a benzodiazepine "inverse agonist', by slow i.v. infusion. Compared to naive rats, the beta-CCM threshold dose was not affected by the sense oligodeoxynucleotide, but was increased 87% in antisense oligodeoxynucleotide-treated rats. The treatment had no effect on the seizure threshold for picrotoxin. Both antisense and sense oligodeoxynucleotide treatments slightly increased the threshold for strychnine seizures. The results suggest that antisense oligodeoxynucleotide treatment altered GABAA receptor composition and interfered with the actions of a benzodiazepine receptor ligand in vivo, and may provide a tool for studying regulation of receptor structure and function.

Topics: Analysis of Variance; Animals; Body Weight; Carbolines; Convulsants; Injections, Intraventricular; Male; Oligonucleotides, Antisense; Picrotoxin; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; RNA, Messenger; Seizures; Strychnine

Baccharis serraefolia is a widely used plant to treat diarrhoea in Mexican traditional medicine. Although the methanolic extract of this plant has shown an important dose-dependent spasmolytic activity, its underlying mechanism has not been studied. In the present work, the methanolic extract of B. serraefolia significantly delayed the onset of tonic seizures induced by strychnine and pentylenetetrazol; besides, it diminished the death rate and number of animals that exhibited convulsions. It produced potentiation of the hypnotic effect of pentobarbital. Oral administration produced an inhibition of gastrointestinal transit in mice as effective as that produced by loperamide. As to the effect on smooth muscles, the active extract produced an inhibition of contraction induced electrically, which could not be reversed by naloxone. The calcium concentration-contraction curve showed a rightward displacement when the extract was added to isolated guinea pig ileum depolarized with high K+ and cumulative concentrations of Ca2+. The results suggest that the methanolic extract does not interact with classical opiate receptors and its effects, at least that produced on smooth muscle, may be due to a probable interference with calcium influx and/or calcium release from an intra-cellular store.

Topics: Administration, Oral; Analysis of Variance; Animals; Antidiarrheals; Calcium; Convulsants; Dose-Response Relationship, Drug; Drug Synergism; Electric Stimulation; Gastrointestinal Transit; Guinea Pigs; Hypnotics and Sedatives; Ileum; Loperamide; Male; Medicine, Traditional; Methanol; Mexico; Mice; Mice, Inbred BALB C; Muscle Contraction; Muscle Relaxation; Muscle, Smooth; Pentobarbital; Pentylenetetrazole; Plant Extracts; Plants, Medicinal; Seizures; Strychnine

We compared the anticonvulsant activity and neurotoxicity of 4-amino-N-(2,6-dimethylphenyl)phthalimide (ADD 213063) with those of phenytoin (PHT), carbamazepine (CBZ), phenobarbital (PB), ethosuximide (ESM), valproate (VPA), and felbamate (FBM). Evaluation of anticonvulsant properties performed according to well-established procedures in rats and mice showed that ADD 213063 is most effective in protecting animals against maximal electroshock seizures (MES). This anti-MES activity is achieved with nontoxic doses, with the optimal effect recorded in rats dosed orally with anti-MES ED50 and protective index (PI) values of 25.2 mumol/kg and > 75, respectively. ADD 213063 protects to a lesser extent against seizures induced by subcutaneous (s.c.) picrotoxin and subcutaneous pentylenetetrazol (PTZ) in mice dosed intraperitoneally and orally, respectively. The profile of anticonvulsant action of ADD 213063 closely parallels that of CBZ.

Topics: Animals; Anticonvulsants; Behavior, Animal; Bicuculline; Carbamazepine; Drug Evaluation, Preclinical; Electroshock; Injections, Intraperitoneal; Injections, Subcutaneous; Mice; Mice, Inbred Strains; Nervous System; Pentylenetetrazole; Phenytoin; Phthalimides; Rats; Rats, Sprague-Dawley; Seizures; Strychnine

Early developmental exposure to caffeine in rats results in changes in brain excitability that persist to adulthood. The mechanism of these alterations is unknown. To identify potential neurotransmitter systems involved, we exposed neonatal rats to caffeine and determined seizure thresholds for chemoconvulsants active at different CNS receptors in the adult animal. Rats were unhandled (NH) or received by gavage (0.05 ml/10 g) either vehicle (water) or caffeine (15-20 mg/kg/day) for postnatal days 2-6. At age 70-90 days, each rat was infused intravenously (i.v.) with picrotoxin (PIC), bicuculline (BIC) [convulsants acting at the gamma-aminobutyric acid/benzodiazepine (GABA/BDZ) receptor], pentylenetetrazol [PTZ, possibly acting at both GABA/BDZ and N-methyl-D-aspartate (NMDA) receptors], caffeine (acting at adenosine receptors), strychnine (STR, acting at glycine receptors), or kainic acid (KA, acting at the NMDA receptor). Seizure thresholds were analyzed as a function of neonatal treatment and sex. Thresholds for caffeine, PTZ, PIC, and KA were increased as a function of neonatal caffeine exposure (p = 0.01, 0.02, 0.02, and 0.005, respectively). The thresholds for BIC and STR were not altered. There were also gender differences in seizure susceptibility. Thresholds for seizures produced by BIC, caffeine, PIC, and STR were higher in females (p = 0.005, 0.005, 0.001, and 0.0001, respectively), but were not different for seizures caused by PTZ. These results suggest that early developmental exposure to caffeine affects later seizure susceptibility. Moreover, some of these effects are gender specific.

Topics: Animals; Animals, Newborn; Bicuculline; Brain; Caffeine; Female; Kainic Acid; Male; Pentylenetetrazole; Picrotoxin; Rats; Receptors, Purinergic P1; Seizures; Sex Factors; Strychnine

A series of aryl and hetarylsulfonylhydrazones of aromatic aldehydes were tested for acute toxicity and anticonvulsant activity in mice. Some of these compounds were effective in the MES, pentetrazol and strychnine tests. Thiophene derivatives were the most active terms of the series.

Topics: Animals; Anticonvulsants; Body Temperature; Electroshock; Female; Hydrazones; Hypnotics and Sedatives; Lethal Dose 50; Male; Mice; Motor Activity; Muscle Relaxants, Central; Pentobarbital; Pentylenetetrazole; Seizures; Sleep; Strychnine

Catnip or catmint (Nepeta cataria) is a plant used extensively to treat human diseases and in toys for pets. We investigated the effects of acute and long-term administration of the plant on some behaviors of mice. The plant was fed as 10% of the normal diet for 2 h/d for 1 or 7 d. Acute and long-term dosing increased both rearing and locomotion frequencies observed in an open field. Acute exposure to catnip increased stereotyped behavior and susceptibility to seizures, did not interfere with haloperidol-induced catalepsy, and decreased sleeping time after sodium pentobarbital administration. Long-term exposure induced tolerance to stereotypic behavior, catalepsy and sleeping time, and increased the susceptibility to seizures induced by picrotoxin and strychnine. An amphetamine-like effect of catnip was suggested to explain the acute effects, while dispositional and functional adaptative changes were considered involved with the long-term effects.

Topics: Animals; Behavior, Animal; Catalepsy; Male; Mice; Motor Activity; Pentobarbital; Picrotoxin; Plant Extracts; Plant Leaves; Plants, Medicinal; Seizures; Sleep; Stereotyped Behavior; Strychnine

The nucleus reticularis pontis oralis (RPO) is necessary for the expression of tonic hindlimb extension (THE) in maximal electroshock (MES) seizures of rats. Previous work in this laboratory has demonstrated that both systemic administration and focal RPO microinfusion of D-cycloserine inhibits THE. The purpose of the present study was to characterize specific components of the NMDA receptor/ionophore complex that regulate the anticonvulsant activity mediated by the RPO. Bilateral RPO microinfusion of the competitive NMDA antagonists (-)AP7 and D-CPP as well as the uncompetitive antagonist dizocilpine ((+)MK-801) inhibited THE in a dose-related fashion. Bilateral RPO microinfusion of NMDA did not affect the THE response to MES but did induce convulsions resembling audiogenic seizures in genetically epilepsy prone rats. Bilateral RPO microinfusion of the strychnine-insensitive glycine site partial agonist D-cycloserine and the antagonist 5,7-dichlorokynurenic acid inhibited THE. The strychnine-insensitive glycine partial agonists (+)HA-966 and ACPC, as well as the agonists glycine and D-serine, did not significantly affect the THE response. Strychnine microinfusions in the RPO had no effect on THE. The results support a hypothesis that the RPO is a site of anticonvulsant drug action in MES and indicate that either competitive or uncompetitive NMDA antagonist action regulates the anticonvulsant activity mediated by the RPO. The role of the strychnine-insensitive glycine site in the regulation of the anticonvulsant activity medicated by the RPO is uncertain.

Topics: Animals; Dizocilpine Maleate; Dose-Response Relationship, Drug; Electroshock; Male; N-Methylaspartate; Pons; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures; Strychnine

The convulsant action of strychnine was studied in 310 male albino rats, aged 3 to 25 days. Doses of 0.25-4 mg/kg were administered intraperitoneally and the animals were observed for 30 min. Generalized tonic-clonic seizures involving also tonic hindlimb extension occurred in all age groups. The convulsant effects of strychnine increased from day 3 to day 18, and decreased again from day 25, as indicated by the incidence and latencies of seizures. Lethal effects did not occur before day 12. Hyperactivity was seen as the first sign of strychnine action in rats during the first week of life, automatisms predominating in 18-day-old animals. Electroencephalographic study in 30 rat pups with implanted electrodes demonstrated an extremely poor electro-clinical correlation.

Topics: Aging; Animals; Convulsants; Dose-Response Relationship, Drug; Electrodes, Implanted; Electroencephalography; Hindlimb; Injections, Intraperitoneal; Male; Rats; Rats, Wistar; Seizures; Strychnine

The effects of two non-competitive NMDA antagonists--MK-801 and ketamine--were studied in a model of generalized seizures elicited by s.c. injection of strychnine (2 or 3 mg/kg) in adult rats. The animals were observed in isolation for 30 min after strychnine administration. Pretreatment with MK-801 (0.5 or 2 mg/kg i.p.) suppressed the tonic, but not the clonic phase of generalized seizures following both doses of strychnine. A similar action of ketamine (20 or 40 mg/kg i.p.) was indicated but it did not attain statistical significance. Strychnine-induced lethality was not changed significantly. A comparison with antiepileptic drugs demonstrated that only phenobarbital (10-80 mg/kg i.p.) was clearly effective against strychnine-induced seizures; carbamazepine (25 or 50 mg/kg i.p.) and partly phenytoin (30 or 60 mg/kg i.p.) were able to suppress the incidence of the tonic phase. Primidone (40 or 80 mg/kg i.p.) as well as the benzodiazpines bretazenil (0.1 or 1 mg/kg i.p.) and midazolam (two lower doses of 0.5 and 1 mg/kg i.p.) were without significant effect. The 2 mg/kg dose of midazolam was partly effective. Only phenobarbital, carbamazepine and the highest dose of midazolam prevented strychnine-induced lethality.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Dizocilpine Maleate; Ketamine; Male; Rats; Rats, Wistar; Seizures; Strychnine

Control over stress protects against many of the deleterious effects of stress exposure, but the endogenous mediators responsible for these prophylactic effects have remained elusive. Using behavioral pharmacology, in vitro radioligand binding and neurochemical analyses, we demonstrate that exposure to escapable stress results in brain and behavior changes reminiscent of benzodiazepine administration. The stress control group shows significant protection against picrotoxinin-induced seizures, reductions in [35S]t-butylbicyclophosphorothionate (TBPS) binding and a 3-fold increase of benzodiazepine-like substances in brain in comparison to both yoked-inescapable shock and non-shock controls. These observations suggest that coping behavior leads to the release of endogenous benzodiazepine-like compounds in brain which protect the organism from stress pathology.

Topics: Analysis of Variance; Animals; Brain; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cerebral Cortex; Convulsants; Electroshock; Escape Reaction; Flumazenil; GABA-A Receptor Agonists; Hippocampus; Male; Picrotoxin; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Seizures; Sesterterpenes; Stress, Psychological; Strychnine; Sulfur Radioisotopes; Tritium

1. The effects of some noradrenergic agents on seizures induced by strychnine were investigated in mice. 2. Strychnine (0.5-4 mg/kg, i.p.) dose-dependently produced tonic seizures. 3. DOPS (4-8 mg/kg, i.p.) significantly shortened the latency of seizures elicited by strychnine (2 mg/kg, i.p.). Similarly, DOPS (4 mg/kg, i.p.) effectively increased the incidence and significantly shortened the latency of seizures induced by strychnine (1 mg/kg, i.p.). 4. Imipramine (20-40 mg/kg, i.p.) and pargyline (200 mg/kg, i.p.) significantly shortened the latency of strychnine (2 mg/kg, i.p.)-induced seizures. 5. Phentolamine (5-20 mg/kg, i.p.) effectively antagonised the seizures elicited by strychnine (2 mg/kg, i.p.). Furthermore, phentolamine (10 mg/kg, i.p.) attenuated the seizure-potentiating effect of DOPS (4 mg/kg, i.p.). 6. Propranolol (0.5-2 mg/kg, i.p.) and prazosin (1-2 mg/kg, i.p.) reduced the incidence and significantly delayed the latency of seizures induced by strychnine (2 mg/kg, i.p.). 7. Reserpine (5-10 mg/kg, i.p.) significantly prolonged the latency of strychnine (2 mg/kg, i.p.)-induced seizures. 8. Clonidine (0.25-1 mg/kg, i.p.) dose-dependently and significantly antagonised strychnine (2 mg/kg, i.p.)-induced seizures. 9. Idazoxan (1-4 mg/kg, i.p.) in a dose related manner significantly shortened the latency of seizures induced by strychnine (2 mg/kg, i.p.). Similarly, idazoxan (2 mg/kg, i.p.) profoundly potentiated seizures elicited by strychnine (1 mg/kg, i.p.). Idazoxan (4 mg/kg, i.p.) significantly antagonised the protective effect of clonidine (1 mg/kg, i.p.) against strychnine (2 mg/kg, i.p.)-induced seizures. 10. Disulfiram (3 x 25 - 3 x 100 mg/kg, i.p.) significantly attenuated strychnine (2 mg/kg, i.p.)-induced seizures. DOPS (4 mg/kg, i.p.) significantly potentiated strychnine seizures in disulfiram (3 x 100 mg/kg, i.p.)-pretreated animals. 11. These results indicate that enhancement of noradrenergic neurotransmission potentiates strychnine seizures in mice.

Topics: Adrenergic alpha-Antagonists; Animals; Clonidine; Dioxanes; Disulfiram; Droxidopa; Idazoxan; Imipramine; Male; Mice; Pargyline; Phentolamine; Prazosin; Propranolol; Receptors, Adrenergic; Reserpine; Seizures; Strychnine

Systemic administration of kainic acid in the rat results in the development of a characteristic excitotoxic syndrome, consisting of automatisms (wet dog shakes, WDS), sustained limbic seizures and brain damage. Since kainate increases the release of excitatory amino acid neurotransmitters such as glutamate, this syndrome is thought to be due, at least in part, to excessive activation of glutamate receptors, particularly of the N-methyl-D-aspartate (NMDA) subtype. We examined the effect of D-cycloserine, a partial agonist for the NMDA receptor-associated glycine binding site, in the kainate model of limbic seizures in rats. For comparison, the uncompetitive NMDA antagonist MK-801 (dizocilpine) and the GABAmimetic anticonvulsant diazepam were used. D-Cycloserine exerted a potent, dose-dependent and long-lasting anticonvulsant effect against kainate-induced seizures. At 160 mg/kg, seizures were almost completely suppressed by D-cycloserine over a 3 h observation period. No adverse effects were observed at anticonvulsant doses of D-cycloserine. In contrast to its potent effect on kainate-induced seizures, D-cycloserine did not significantly alter the number of automatisms (WDS) determined after kainate. MK-801, 0.3 mg/kg, also markedly reduced seizure severity in response to kainate, but this anticonvulsant effect was accompanied by marked motor impairment. Similarly, diazepam, 5 mg/kg, significantly attenuated kainate-induced seizures but marked ataxia was observed at this dosage. In contrast to D-cycloserine, both MK-801 and diazepam reduced WDS behaviour caused by kainate. The data demonstrate that pharmacological manipulation of the strychnine-insensitive glycine site is a powerful means of protecting against kainate-induced seizures.

Topics: Animals; Behavior, Animal; Cycloserine; Diazepam; Dizocilpine Maleate; Dose-Response Relationship, Drug; Female; Kainic Acid; Rats; Rats, Wistar; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Seizures; Strychnine

Endothelins (ET-1 and ET-3) are produced in the brain and may act as neuropeptides. The effects of two endothelins (ET-1 and ET-3) were investigated using pentylenetetrazole- (PTZ), strychnine- (STR), picrotoxin- (PIC) and bicuculline-induced (BIC) convulsions. ET-1 did not exert any anticonvulsive effect. ET-3, being more specific for the brain, showed anticonvulsive activity on PTZ and BIC seizures, but not on PIC and STR seizures. Different mechanisms underlie the action of the convulsants. PTZ, BIC and PIC realized their convulsive effects through the GABAergic inhibitory transmitter system; STR exerted an excitatory effect on the spinal cord by blocking the glycine transmitter system. The results suggest that the anticonvulsive effects of ET-3 might be due to an indirect influence on the GABAergic system in the brain.

Topics: Animals; Anticonvulsants; Bicuculline; Endothelins; gamma-Aminobutyric Acid; Injections, Intraventricular; Male; Mice; Pentylenetetrazole; Picrotoxin; Seizures; Strychnine

With hippocampal slice electrophysiology, direct evidence that mineralocorticoid receptors (MR) mediate excitatory effects of corticosteroids on neuronal activity was found. The present experiments extended this hypothesis to a whole animal model. The effects of manipulations of MR binding on convulsions produced by pentylenetetrazol (PTZ), strychnine and kainic acid were examined. Moderate increases in plasma corticosterone levels resulted in enhanced susceptibility to several convulsion types; decreased levels attenuated the susceptibility. The proconvulsant effects of corticosterone were inhibited by the MR antagonist, spironolactone. Convulsions typically affected by these manipulations were PTZ-induced myoclonic jerk and face and forelimb clonus and kainic acid-induced convulsions. Other convulsion types, e.g., PTZ-induced running bouncing clonus and tonic hindlimb extension and strychnine-induced convulsions, were generally unaffected by these manipulations, which suggests that central MR effects are not global. The convulsions that were sensitive to MR manipulations are believed to originate in limbic structures. These results provide the first direct evidence for a role of central MRs in the modulation of central nervous system excitability in a whole animal. Furthermore, they suggest that central MR action may be important in disruptions of excitability, such as epilepsy, drug withdrawal syndromes and arousal states in healthy animals.

Topics: Animals; Corticosterone; Disease Susceptibility; Kainic Acid; Male; Mice; Mice, Inbred Strains; Pentylenetetrazole; Receptors, Mineralocorticoid; Seizures; Strychnine

This study evaluated a possible mechanism by which glycine potentiates the activity of diazepam (DZP) and valproic acid (VAL) against the clonic seizures induced by pentylenetetrazol (PTZ) in rats. Neither 7-chlorokynurenic acid (7-CLKYNA) nor strychnine in doses of 10, 50, or 100 nmol ICV significantly altered the clonic seizure response to PTZ. However, 7-CLKYNA (100 nmol, ICV), but not strychnine (100 nmol, ICV), antagonized the anticonvulsant activity induced by coadministration of DZP (1.0 mg/kg, IP) and glycine (40 mmol/kg, PO). Neither 7-CLKYNA (100 nmol, ICV) nor strychnine (100 nmol, ICV) significantly altered the anticonvulsant activity induced by coadministration of VAL and glycine. 7-CLKYNA (100 nmol, ICV) had no effect on the anticonvulsant activity of DZP or VAL in the absence of glycine. These results provide evidence that the glycine potentiation of the anticonvulsant activity of DZP in clonic seizures induced by PTZ may be mediated by the strychnine-insensitive glycine receptor.

Topics: Animals; Diazepam; Drug Synergism; Glycine; Injections, Intraventricular; Kynurenic Acid; Male; Pentylenetetrazole; Rats; Rats, Sprague-Dawley; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Seizures; Strychnine

Pretreatment of mice with 30 mg xylazine/kg ip protected against convulsions induced by amphetamine, but it intensified pentylenetetrazole- and strychnine-induced seizures. Xylazine pretreatment also protected rats against electroshock-induced convulsions. These findings support a noradrenergic mechanism being involved in the proconvulsant and/or anticonvulsant effects of xylazine.

Topics: Amphetamine; Animals; Anticonvulsants; Convulsants; Electroshock; Female; Male; Mice; Pentylenetetrazole; Rats; Rats, Wistar; Seizures; Strychnine; Xylazine

We investigated the effects of chemical convulsants in the leopard frog. Systemic kainic acid (5-20 mg/kg) caused limbic-like seizures, with staring, catatonia, fasciculations, and severe motor seizures, which were almost always lethal. Intracerebral electroencephalographic (EEG) recordings showed spike or spike-and-wave patterns at 6-8 Hz that decreased in frequency and increased in amplitude, maximal at an electrode in the midline olfactory/telencephalic (OLF-M) region. With time, an interictal pattern of 100-200 microV periodic spikes developed, followed by diffuse suppression of all brain activity. Seizures induced by pentylenetetrazole (150-450 mg/kg) and bicuculline (5-10 mg/kg) were characterized by the abrupt onset of motor activity, which continued intermittently for several hours, followed by recovery. EEG recordings in animals treated with pentylenetetrazole showed rhythmic spike-and-wave bursts at 1.5-3 Hz that were maximal at OLF-M. Recordings from frogs treated with bicuculline showed repetitive 3-6 Hz spike-and-wave discharges maximal at OLF-M that were nearly constant in amplitude and at times became continuous. Strychnine (1-5 mg/kg) caused reversible seizures characterized by tonic extensions of the extremities, that seemed to originate in the spinal cord. Frogs with recurrent seizures from systemic cis-diamminedichloroplatinum II showed 4-8 Hz rhythmic spike-and-wave activity that gradually slowed in frequency and increased in amplitude. Thus, the frog's reactivity to convulsive agents is similar to that of mammals.

Topics: Animals; Behavior, Animal; Bicuculline; Brain; Cisplatin; Convulsants; Electroencephalography; Kainic Acid; Pentylenetetrazole; Rana pipiens; Seizures; Strychnine

Topics: Administration, Inhalation; Animals; Anticonvulsants; Lavandula; Male; Mice; Nicotine; Oils, Volatile; Pentylenetetrazole; Plant Extracts; Plant Oils; Seizures; Strychnine

Selected examples from three series of isomeric (alkylthio)-1,2,4-triazoles were prepared and examined for anticonvulsant activity versus strychnine-, maximal-electroshock-, pentylenetetrazole-, and 3-mercaptopropionic-acid-induced seizures in mice. A number of 5-aryl-3-(alkylthio)-4H-1,2,4-triazoles were selective antagonists of strychnine-induced convulsions. The isomeric 3-aryl-5-(alkylthio)- and 5-aryl-3-(alkylthio)-1H-1,2,4-triazoles were essentially inactive as anticonvulsants. The most potent antagonist of strychnine-induced convulsions was 5-(2-fluorophenyl)-4-methyl-3-(methylthio)-4H-1,2,4-triazole (3s), while the most selective antagonist was 5-(3-fluorophenyl)-4-methyl-3-(methylsulfonyl)-4H-1,2,4-triazole (3aa). The anticonvulsant profiles of these 4H-1,2,4-triazoles suggested that they were acting functionally like glycine receptor agonists. Since it has recently been postulated that compounds possessing glycine-agonist-like properties might be useful in the treatment of spasticity, we examined 5-phenyl-4-methyl-3-(methylsulfonyl)-4H-1,2,4-triazole (3c) in an in vivo model of spasticity. In this regard, 3c reduced the occurrence of hyperreflexia in rats that had received spinal transections 5-10 weeks previously. While triazole 3c appeared to possess glycine-agonist-like properties in vivo, it did not displace [3H]strychnine binding from rat brain stem/spinal cord membranes in vitro. On the other hand, 3c enhanced muscimol-stimulated 36Cl influx in a rat cerebellar membrane preparation, indicating a possible interaction of these triazoles with the GABAA receptor.

Topics: Animals; Anticonvulsants; Cerebellum; Cerebral Cortex; Chlorides; Electroshock; Flumazenil; Male; Mice; Molecular Structure; Muscle Spasticity; Paralysis; Rats; Rats, Sprague-Dawley; Seizures; Structure-Activity Relationship; Strychnine; Triazoles

The effects of muscimol, aminooxyacetic acid (AOAA), diamino-n-butyric acid (DABA), baclofen, bicuculline, picrotoxin, strychnine, diazepam, phenobarbitone and phenytoin on cimetidine-induced seizures were studied in mice. Cimetidine (400-1000 mg/kg, i.p.) induced dose-dependent tonic convulsion. Muscimol, AOAA and DABA effectively protected mice against cimetidine-induced seizures. Bicuculline and picrotoxin significantly potentiated the seizures induced by cimetidine and effectively antagonized the protective effects of muscimol, AOAA and DABA against the seizures. Diazepam and phenobarbitone significantly protected the mice against cimetidine-induced seizures while phenytoin and strychnine did not significantly alter the seizures. These results indicate that the attenuation of central gamma-aminobutyric acid neurotransmission may underlie cimetidine-induced seizures in mice.

Topics: Aminobutyrates; Aminooxyacetic Acid; Animals; Baclofen; Bicuculline; Cimetidine; Diazepam; Female; Mice; Muscimol; Phenobarbital; Phenytoin; Picrotoxin; Receptors, GABA; Seizures; Strychnine

D-Cycloserine has been shown to exert anticonvulsant activity in maximal electroshock seizures. The purpose of the present study was to evaluate the spectrum of D-cycloserine anticonvulsant activity using other experimental models of epilepsy. D-Cycloserine induced a dose-related decrease in the incidence of tonic convulsions induced by 120 mg/kg of pentylenetetrazol. The ED50 of D-cycloserine for the inhibition of the tonic convulsions was 109 mg/kg. The anticonvulsant activity was specific for the D-isomer at L-cycloserine (400 mg/kg) had no effect on the tonic convulsions. D-Cycloserine had no effect on the pentylenetetrazol-induced clonic convulsions induced by either 70 or 120 mg/kg pentylenetetrazol, electrically induced nonkindled hippocampal seizures or kindled amygdala seizures. D-Cycloserine had no effect on strychnine-induced tonic convulsions. These results indicate that D-cycloserine is inactive against clonic convulsions and may be active only against tonic convulsions mediated by brainstem sites.

Topics: Animals; Anticonvulsants; Cycloserine; Electric Stimulation; Electroencephalography; Hippocampus; Kindling, Neurologic; Male; Pentylenetetrazole; Rats; Rats, Sprague-Dawley; Seizures; Strychnine; Time Factors

The toxicity of LJC 10,627 to the central nervous system of rats was evaluated by examining the effects of the compound on gamma-aminobutyric acidA, benzodiazepine, and glycine receptor binding in rat synaptic membranes and on the induction of behavioral convulsions by intraventricular administration to rats. The concentrations of this compound needed to inhibit specific [3H]muscimol binding, specific [3H]diazepam binding, and specific [3H]strychnine binding were greater than those of imipenem, as demonstrated by the 50% inhibitory concentrations (IC50S of LJC 10,627, greater than 10 mM for each; IC50S of imipenem, 0.6, 1.9, and 0.2 mM, respectively). These results reflect the fact that LJC 10,627 does not evoke severe convulsions or cause death, even when it is administered intraventricularly at a high dose (300 micrograms per rat), and suggest that the low neurotoxic potential of LJC 10,627 may be attributed to the chemical structure of this compound, which has a methyl radical at the 1 beta site and a triazolium radical at the side chain of the second site.

Topics: Animals; Behavior, Animal; Binding, Competitive; Central Nervous System Diseases; Diazepam; GABA-A Receptor Antagonists; In Vitro Techniques; Male; Muscimol; Rats; Rats, Sprague-Dawley; Receptors, Glycine; Receptors, Neurotransmitter; Seizures; Strychnine; Synaptic Membranes; Thienamycins

The effects of blockade of the alpha-amino-3-hydroxy-5-methyl-isoxazole-4-proprionate (AMPA) and kainate subtypes of NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline) and compared to the effects of N-methyl-D-aspartate (NMDA) receptor blockade with D-CPPene (D-(E)-4-(3-phosphonoprop-2-enyl)-piperazine-2-carboxylic acid), a competitive NMDA antagonist. Both compounds exerted peak blocking activity 30 min after intraperitoneal administration. Using this pretreatment interval, a dose-response relationship for blocking handling-induced, strychnine-potentiated convulsions was generated for each compound. D-CPPene blocked seizures with an ED50 of 0.72 (0.59-0.87) mg/kg and NBQX blocked seizures with an ED50 of 68.0 (36.72-125.94) mg/kg. These results indicate that both NMDA and non-NMDA subtypes of excitatory amino acid receptors are activated in handling-induced, strychnine-potentiated convulsions.

Topics: Animals; Anticonvulsants; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Handling, Psychological; Male; Mice; Piperazines; Receptors, Amino Acid; Receptors, AMPA; Receptors, Kainic Acid; Receptors, N-Methyl-D-Aspartate; Seizures; Strychnine

Hypoxic and convulsive resistances have daily rhythms, the pattern of which depends on the year season. Latent period of occurrence of epileptic seizures and time of life at the "height" of 11,000 m above the sea level undergo similar changes in autumn and spring. In winter minimal similarity between daily dynamics of each of these resistances and analogous ones in other seasons is observed, but rhythms of tolerance to hypoxia are maximally synchronized with the rhythms of convulsive resistance. In autumn hypoxic and convulsive resistances are minimal. Maximums of these indices are observed in different seasons: for tolerance to hypoxia it is summer, for convulsive resistance--spring.

Topics: Animals; Atmosphere Exposure Chambers; Circadian Rhythm; Disease Susceptibility; Hypoxia; Male; Rats; Reaction Time; Seasons; Seizures; Strychnine; Time Factors

1. Strychnine-sensitive glycine receptors are primarily localized in the brainstem and spinal cord where they are the major mediators of postsynaptic inhibition. A compound which acts functionally like a glycine receptor agonist would be potentially useful as a pharmacological tool and as a therapeutic agent for treating disorders of glycinergic transmission. 2. MDL 27,531 (4-methyl-3-methylsulphonyl-5-phenyl-4H-1,2,4-triazole) blocked strychnine-induced tonic extensor seizures in mice following either intraperitoneal (ED50 = 12.8 mg kg-1; 30 min) or oral (ED50 = 7.3 mg kg-1; 30 min) administration. Time course studies revealed a maximal effect at 30-60 min, though significant activity was still seen after 24 h. 3. MDL 27,531 was selective in antagonizing strychnine seizures and little or no activity was seen against seizures produced by other chemical convulsants (bicuculline; quinolinic acid; mercaptopropionic acid); by electrical stimuli (maximal electroshock); or by sensory stimuli (audiogenic seizure susceptible mice). MDL 27,531 blocked pentylenetetrazol-induced seizures with an ED50 = 55 mg kg-1. This profile differed from those of the anticonvulsants diazepam, valproic acid, and diphenylhydantoin. 4. The antagonism of strychnine seizures by MDL 27,531 occurred at doses that did not produce signs of sedation (suppression of spontaneous motor activity), motor ataxia (disruption of rotarod performance), muscle relaxation (inhibition of morphine-induced Straub tail), or CNS depression (potentiation of hexobarbitone sleep time). MDL 27,531 had less side effect potential (as derived from ratios obtained from the above measures) relative to those of the known muscle relaxants diazepam and baclofen. 5. Although MDL 27,531 behaved functionally like a selective agonist at the strychnine-sensitive glycine receptor, the compound did not alter the in vitro binding of [3H]-strychnine to mice brainstem/spinal cord membranes at concentrations of up to 100 microM. In further in vitro binding assays, MDL 27,531 at concentrations of up to 100 microM, did not displace the binding of [3H]-muscimol, [3H]-flunitrazepam, or["S]-t-butylbicyclophosphorthionate to rat cortical membranes. These ligands bind to the 7y-aminobutyric acid (GABA), benzodiazepine, and picrotoxin-convulsant binding sites, respectively.6. MDL 27,531 (10-100mgkg-', i.p.) enhanced binding of the benzodiazepine antagonist [3H]-Ro15-1788 to mouse cerebral cortex in vivo without directly affecting GABA l

Topics: Administration, Oral; Animals; Electric Stimulation; Hypnotics and Sedatives; Injections, Intraperitoneal; Male; Mice; Receptors, Glycine; Receptors, Neurotransmitter; Seizures; Strychnine; Triazoles

Ralitoline, a thiazolidinone derivative chemically distinct from known antiepileptic drugs, possesses remarkable anticonvulsant properties as demonstrated in various animal models of epilepsy. The efficacy of this compound seems to be comparable or even better than that of conventional antiepileptics. In the present study, the activity of ralitoline was investigated in four seizure models in rodents in order to characterize the anticonvulsant profile of action further. In the maximal electroshock seizure test (mice), this compound showed marked anticonvulsant effects (ED50 2.8 mg/kg i.p.). The efficacy of clinically established anti-epileptics was significantly increased when ralitoline was given as co-medication. In the strychnine seizure test (mice), ralitoline (5 and 10 mg/kg) prolonged the latency of tonic seizures as well as the survival time. On the other hand, in the subcutaneous pentylenetetrazol seizure threshold test (mice), this drug revealed limited protective actions at higher doses and increased the effectiveness of ethosuximide. In unrestrained rats with chronically implanted electrodes, ralitoline (5 mg/kg) significantly reduced the duration of electrically-evoked hippocampal discharges and raised the focal stimulation threshold (10 mg/kg). In the rotorod ataxia test (mice), a TD50 value of 14.5 mg/kg i.p. was determined for ralitoline (protective index TD50/MES-ED50 5.2). With regard to the possible mode of action, whole-cell voltage-clamp experiments on cultured neonatal rat cardiomyocytes showed that ralitoline may act specifically on voltage-sensitive sodium channels. The compound inhibited the fast sodium inward current in a frequency- and voltage-dependent manner. In conclusion, the findings confirm the potent anticonvulsant effects of ralitoline, especially against generalized tonic-clonic and complex partial seizures. Moreover, in combination with antiepileptics, an additive synergism can be found at lower concentrations. Regarding the mode of action, this drug was capable of depressing the fast sodium inward current in cultured heart ventricular cells, suggesting that the local anesthetic properties may be important for the anticonvulsant activity of ralitoline.

Topics: Animals; Anticonvulsants; Brain; Cells, Cultured; Electric Stimulation; Male; Mice; Models, Biological; Motor Activity; Pentylenetetrazole; Phenobarbital; Rats; Rats, Wistar; Seizures; Sodium Channels; Strychnine; Thiazoles

Topics: Administration, Oral; Animals; Dose-Response Relationship, Drug; Injections, Intraperitoneal; Injections, Intravenous; Lethal Dose 50; Male; Mice; Seizures; Strychnine

Seizures elicited by posture change and intraperitoneal administration of convulsants were studied ontogenetically in the Mongolian gerbil (Meriones unguiculatus). In posture change, the first signs of seizure appeared after age 6 weeks with maximal frequency at 8-9 weeks. Adults developed complex, but stereotyped, seizures. Facial twitch was followed by the generalized convulsion, further progressing to trembling of the limbs and then kicking of the hindlimb (full seizure) after 55 days of age. Pentylenetetrazole induced a seizure similar to the full event in gerbils as young as 37 days of age. The seizure pattern elicited by strychnine or glutamate was different from that of pentylenetetrazole.

Topics: Animals; Behavior, Animal; Brain; Electroencephalography; Epilepsy; Gerbillinae; Neurotransmitter Agents; Pentylenetetrazole; Posture; Receptors, GABA-A; Seizures; Strychnine

Modulation of the NMDA receptor by the strychnine-insensitive glycine site was studied both in vitro and in vivo. In vitro the glycinergic stimulation of [3H]MK801 binding was measured in three different rat forebrain membrane preparations. An increased association rate of [3H]MK801 in the presence of glycine was observed. The binding of the radioligand was also enhanced by D-serine, whereas L-serine was less potent. The concentration-effect curves were shifted to the right by the glycine antagonist 7-chlorokynurenic acid (7CKA). In vivo modulation of the N-methyl-D-aspartate (NMDA) receptor was studied using NMDA induced convulsions in 7 day old rats. The NMDA effect was blocked by (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten,5,10-imine maleate (MK801) and D-(-)-2-amino-5-phosphono-pentanoic acid (AP5). The effect of a submaximal dose of NMDA was dose-dependently potentiated by 1-10 mg/kg D-serine, whereas higher doses of L-serine were needed to obtain a similar effect. 7CKA did not affect NMDA-induced convulsions but reduced the D-serine potentiation of NMDA responses. This study illustrates the ability of the strychnine-insensitive glycine site to modulate the NMDA receptor function both in vitro and in vivo.

Topics: 2-Amino-5-phosphonovalerate; Animals; Animals, Newborn; Dizocilpine Maleate; Glycine; Kynurenic Acid; Male; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures; Serine; Stereoisomerism; Strychnine

The N-methyl-D-aspartate (NMDA)-preferring glutamate receptor subtype possesses, in addition to the recognition site for glutamate, a binding site for glycine. We report here on the pharmacological properties of 3-(4,6-dichloro-2-carboxyindol-3-yl)-propionic acid (MDL 29,951) and 4-carboxymethylamino-5,7-dichloroquinoline-2-carboxylic acid (MDL 100,748), two novel glycine antagonists of NMDA receptor activation in vitro and in vivo. We have measured in parallel the effects of two previously described glycine antagonists, 7-chlorokynurenic acid and 5,7-dichlorokynurenic acid. All were potent inhibitors of [3H]glycine binding. Ki values (microM) were 0.36 (7-chlorokynurenic acid), 0.08 (5,7-dichlorokynurenic acid), 0.07 (MDL 100,748) and 0.14 (MDL 29,951). MDL 100,748 and MDL 29,951 were approximately 2000-fold selective for the glycine binding site relative to the glutamate recognition sites. All four compounds completely inhibited the use-dependent binding of [3H]N-[1-(2-thienyl) cyclohexyl]-piperidine and were noncompetitive, glycine-reversible inhibitors of both NMDA-induced biochemical and electrophysiological responses in brain slice preparations. A competitive interaction with the glycine binding site was also evident in that MDL 29,951 and MDL 100,748 produced parallel rightward shifts in the glycine requirement for demonstration of NMDA-stimulated elevations in cytosolic calcium in cultured neuronal preparations. The glycine antagonists were potent anticonvulsants after their i.c.v. administration to audiogenic seizure-susceptible DBA/2J mice. Because the compounds chosen encompass a variety of chemical structures, the results indicate that glycine is required for NMDA receptor activation and that bioavailable glycine antagonists may form the basis of a novel therapy for epilepsy.

Topics: Acoustic Stimulation; Animals; Anticonvulsants; Binding Sites; Brain; Calcium; Glycine; Indoles; Male; Mice; Mice, Inbred DBA; Propionates; Quinolines; Rats; Receptors, N-Methyl-D-Aspartate; Seizures; Strychnine

Topics: Adult; Humans; Male; Seizures; Strychnine

A series of substituted 3-(2-carboxyindol-3-yl)propionic acids was synthesized and tested as antagonists for the strychnine-insensitive glycine binding site of the NMDA receptor. Chlorine, and other small electron-withdrawing substituents in the 4- and 6-positions of the indole ring, greatly enhanced binding and selectivity for the glycine site over the glutamate site of the NMDA receptor; one of the most potent compounds is 3-(4,6-dichloro-2-carboxyindol-3-yl)propionic acid (IC50 = 170 nM; greater than 2100-fold selective for glycine). The importance of a heteroatom NH and the enhancing effect of the propionic acid side chain were demonstrated and are consistent with previous results which suggest the presence of a pocket on the receptor which can accept an acidic side chain. Substitution of a sulfur at C3 led to the most potent compound 3-[(carboxymethyl)thio]-2-carboxy-4,6-dichloroindole (IC50 = 100 nM).

Topics: Animals; Binding Sites; Cerebral Cortex; Glycine; Hippocampus; Indoles; Mice; Mice, Inbred DBA; Propionates; Rats; Receptors, N-Methyl-D-Aspartate; Seizures; Structure-Activity Relationship; Strychnine; Substrate Specificity

Spinal seizures in mice induced by handling following pretreatment with a subconvulsive dose of strychnine could be blocked by competitive N-methyl-D-aspartate (NMDA) receptor antagonists (D-, L-, DL-CPPene (CPPene = (E)-4-(3-phophonoprop-2-enyl)-piperazine-2-carboxylic acid), D-AP5 (D-2-amino-5-phophonovalerate)) and compounds acting at receptor-coupled modulatory sites (R-HA 966, ifenprodil). NMDA cation channel antagonists (MK-801, phencyclidine) however, resulted in ataxia, tremor and loss of righting. There are differences between NMDA antagonists acting via the receptor and the cation channel in this model of spinal seizure.

Topics: Animals; Calcium Channel Blockers; Male; Mice; Mice, Inbred Strains; N-Methylaspartate; Receptors, N-Methyl-D-Aspartate; Seizures; Strychnine

One half hour following the ingestion of a possibly tainted antibiotic capsule, a 14 year-old female experienced acute onset of stiffness and weakness in her lower extremities. She subsequently survived despite the development of convulsions, severe lactic acidosis (pH 6.86), hyperthermia (Temp 40.5 degrees C) and rhabdomyolysis. Toxicology testing confirmed the presence of strychnine in blood, gastric aspirate, and urine. Her course, history and outcome are presented and the pharmacokinetics, the mechanism of action, signs and symptoms and treatment of strychnine poisoning are reviewed.

Topics: Adolescent; Anti-Bacterial Agents; Diazepam; Drug Contamination; Female; Humans; Poisoning; Seizures; Strychnine

We have investigated the pharmacological basis of CNS excitation that occurs in association with general anaesthesia in mice. Propofol produced sustained clonic movements during anaesthesia. Methohexitone produced intermittent non-rhythmic jerking during anaesthesia. Ethanol and pentobarbitone produced anaesthesia without associated clonic movements. Doses of all anaesthetic drugs were equipotent. Surface EEG recordings showed paroxysmal discharges consistent with interictal manifestations of cortical seizures with methohexitone or propofol, but not with ethanol or pentobarbitone. Strychnine, a glycine antagonist without effects on the cerebral cortex, and bicuculline, a GABAA antagonist with effects on the cerebral cortex, were used in doses that were equipotent-0.5 log units less than the ED10 for clonic convulsions. Strychnine potentiated both excitatory behaviour and EEG paroxysmal discharges when given with methohexitone or propofol, but not with ethanol or pentobarbitone. Bicuculline did not affect either behaviour or EEG with any of the anaesthetic drugs. Our data show that methohexitone and propofol produced CNS excitation, while pentobarbitone and ethanol did not. We propose that the pharmacological basis of this excitation may be glycine antagonism occurring in subcortical structures.

Topics: Anesthesia, General; Animals; Bicuculline; Central Nervous System; Electroencephalography; Ethanol; Glycine; Male; Methohexital; Mice; Mice, Inbred Strains; Pentobarbital; Propofol; Seizures; Strychnine

We have examined the influence of strychnine-insensitive glycine (gly2) receptor agonists and antagonists on the expression of generalized seizure activity (generalized seizure threshold (GST), afterdischarge duration and motor seizure response) in fully amygdala kindled rats. Intra-amygdaloid administration of the selective gly2 receptor antagonist, 7-chlorokynurenic acid (7-C1KYN) (10-50 nmol) dose-dependently raised GSTs in a glycine-reversible manner. The same doses had no significant effect on other parameters of seizure expression. (+/-)-3-Amino-1-hydroxy-2-pyrrolidone (HA-966), a proposed low-efficacy partial agonist at the gly2 receptor17, showed similar but weaker anticonvulsant activity in this model. The active, R-(+)-enantiomer of HA-966 showed greater anticonvulsant efficacy than the racemic mixture, but was still clearly less active than 7-C1KYN. The gly2 receptor agonists glycine (10-50 nmol), D-serine (50 nmol) and D-alanine (50 nmol) failed to influence any of the parameters of the seizure response, suggesting that gly2 receptors in the basolateral amygdala are fully saturated in vivo. The behavioural impairment induced by high doses of 7-C1KYN did not appear to be associated with gly2 receptor blockade. These results support the concept that potent and selective gly2 receptor antagonists may provide a useful, novel class of anticonvulsant agents.

Topics: Alanine; Amygdala; Animals; Glycine; Kindling, Neurologic; Kynurenic Acid; Male; Pyrrolidinones; Rats; Rats, Inbred Strains; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Seizures; Serine; Strychnine

Experiments examining seizure sensitivity were conducted on adult male offspring exposed to diazepam at 1.0 or 2.5 mg/kg per day in utero over gestational days 14-20. Threshold dosages to facial clonus, myoclonic jerk, clonic seizure, and extensor tonus were determined via i.v. infusion of bicuculline, methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), picrotoxin, pentylenetetrazol, caffeine and strychnine. Relative to uninjected and vehicle-exposed adult male offspring, prenatal diazepam administration reduced the threshold for bicuculline- and DMCM-induced facial clonus and myoclonic jerk by 40-50%. The threshold dosages to facial clonus, myoclonic jerk and clonic seizure from picrotoxin infusion were similarly reduced in animals exposed to diazepam in utero. In contrast, seizure thresholds to pentylenetetrazol, caffeine and strychnine were not affected by early developmental exposure to diazepam. In parallel biochemical studies, an increased sensitivity to the antagonistic effects of bicuculline methiodide on gamma-aminobutyrate (GABA)-stimulated chloride influx was observed in cortical synaptoneurosomes from adult male progeny of diazepam-treated dams. The results are interpreted to reflect a long-lasting alteration in the function of the GABA/benzodiazepine receptor complex by prenatal diazepam exposure that is manifest at the behavioral and neurochemical level in a pharmacologic specific manner.

Topics: Animals; Bicuculline; Caffeine; Carbolines; Cerebral Cortex; Chlorides; Convulsants; Diazepam; Female; GABA-A Receptor Antagonists; Male; Picrotoxin; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Receptors, GABA-A; Seizures; Strychnine; Synaptosomes

The convulsive effects of methyl beta-carboline-3-carboxylate (beta-CCM), a benzodiazepine receptor ligand, are different in two inbred strains of mice: BALB/cBy mice are more sensitive to beta-CCM than C57BL/6J mice. In the present article, we report the effects of [3H]flunitrazepam binding in these two strains, which suggest a possible explanation of the differences in their sensitivity to beta-CCM by the involvement of brain benzodiazepine receptors.

Topics: Animals; Brain; Carbolines; Clonazepam; Convulsants; Flunitrazepam; Kinetics; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Receptors, GABA-A; Seizures; Species Specificity; Strychnine

We have investigated in mice the effects of several drugs which may be administered as part of an anaesthetic technique on the convulsive threshold to laudanosine and to strychnine, which is reported to have a similar mechanism of action. I.v. administered propofol, thiopentone and midazolam increased the dose of convulsant necessary to produce seizure when administered 2 min before the convulsive stimulus. In contrast, methohexitone and etomidate exhibited a proconvulsant effect, although with the latter this was significant only in laudanosine-treated mice. Pethidine was proconvulsant in both laudanosine- and strychnine-treated mice, but morphine was proconvulsant only in strychnine-treated mice. The effects of morphine, but not pethidine, were antagonized by naloxone 1 mg kg-1. Laudanosine, but not strychnine caused arousal from anaesthesia in subconvulsive doses. This and other evidence suggests that the mechanism of the CNS excitation produced by strychnine and laudanosine are not the same.

Topics: Analgesics; Anesthetics; Animals; Arousal; Brain; Drug Interactions; Female; Isoquinolines; Mice; Morphine; Naloxone; Seizures; Strychnine

Appearances of pentetrazole-, picrotoxin- and strychnine-induced convulsive seizures in taurine-deficient mice produced by treatment with guanidinoethyl sulfonate (GES), a taurine transport antagonist, were investigated. Mice were fed a taurine-free diet and water containing 1% GES from 2 weeks of pregnancy to weaning. The same feeding condition was applied to male offsprings from 3 weeks of age. At 5 weeks of age, convulsants were administered to some mice and the others were sacrificed for determination of brain amino acids concentrations. The incidences of both seizure and death for strychnine and death for picrotoxin were enhanced by treatment with GES, whereas the latency of pentetrazole-induced tonic extensor was prolonged. Significant decrease of brain taurine, asparaginic acid and GABA concentrations were observed in mice treated with GES. These results suggest that convulsive seizures caused by disinhibition of taurine and GABA system are enhanced by deficiency of brain taurine level.

Topics: Amino Acids; Animals; Brain Chemistry; Female; gamma-Aminobutyric Acid; Male; Mice; Mice, Inbred ICR; Pentylenetetrazole; Picrotoxin; Seizures; Strychnine; Taurine

The repeated administration of subconvulsant doses of pentylenetetrazol (PTZ) produced a progressive sensitization to the effects of this compound (i.e., chemical kindling) in the rat. A very similar time-course for PTZ-induced kindling was observed using two different treatment schedules: 1) one injection every day (30 mg/kg, IP), and 2) one injection (30 mg/kg, IP) every second day. When these treatment schedules were used for eight consecutive weeks, more than 80% of the rats displayed convulsions by the end of treatment. In contrast, only 20% of the rats were sensitized if PTZ was administered twice daily at the dose of 15 mg/kg, IP. The increased sensitivity to the convulsant effect of PTZ was still present one year after completion of the chronic treatment. Moreover, rats kindled with PTZ showed an enhanced susceptibility to convulsions induced by different inhibitors of central GABAergic function, such as the chloride channel blocker picrotoxin, the benzodiazepine receptor ligands FG 7142 and Ro 15-4513, and the inhibitor of GABA synthesis isoniazid. In contrast, the sensitivity to the convulsant action of the glycine receptor antagonist strychnine was unchanged by repeated PTZ administration. It is suggested that kindling produced by PTZ may be associated with a persistent reduction in the inhibitory function of the GABAergic system in the brain.

Topics: Animals; Azides; Benzodiazepines; Carbolines; GABA Antagonists; Isoniazid; Kindling, Neurologic; Male; Pentylenetetrazole; Picrotoxin; Rats; Rats, Inbred Strains; Seizures; Strychnine

Topics: Animals; Anticonvulsants; Male; Mice; Norepinephrine; Seizures; Strychnine

Topics: Animals; Anticonvulsants; Electroshock; Mice; Pentylenetetrazole; Postural Balance; Seizures; Stereoisomerism; Strychnine; Tranylcypromine

The side-effect profile of quinolone antibiotics in man includes CNS disturbances such as dizziness, insomnia and convulsions. Although it has been suggested that the proconvulsive liability of quinolones involves an interaction with GABA receptors in the central nervous system, no animal model has been described to evaluate or confirm the mechanism of this effect. The proconvulsive activity of the quinolone antibiotics, nalidixic (NAL) and oxolinic (OXO) acid were tested in male mice following oral doses of 10-100 mg/kg utilizing the convulsive stimuli pentylenetetrazole (PTZ), picrotoxin, strychnine or electroshock. While NAL and OXO did not alter the threshold for convulsions induced by PTZ, strychnine or picrotoxin, both agents lowered the threshold for electroshock-induced seizures. Furthermore, the proconvulsive actions of NAL and OXO were completely blocked by the excitatory amino acid receptor antagonists, MK-801 and 2-amino-4-phosphonobutyric acid (AP-4). These data indicate that the mechanism of convulsive liability of quinolone antibiotics does not involve GABA receptor interactions as previously thought, but appears to involve activation of excitatory amino acid (EAA) receptors, possibly located in the optic region of the central nervous system.

Topics: Animals; Anti-Infective Agents; Convulsants; Dose-Response Relationship, Drug; Male; Mice; Mice, Inbred Strains; Nalidixic Acid; Oxolinic Acid; Pentylenetetrazole; Picrotoxin; Seizures; Strychnine

Topics: Animals; Anticonvulsants; Brazil; Male; Medicine, Traditional; Mice; Phenobarbital; Picrotoxin; Plant Extracts; Rats; Rats, Inbred Strains; Seizures; Strychnine

This study determined the effects of discrete microinjections of GABA agonists in the cholinergic nuclei of the pontomesencephalic tegmentum on spontaneous behavior and seizures induced by intravenous pentylenetetrazol, bicuculline or strychnine, in the rat. Injections of both the GABAA agonist piperidine-4-sulfonic acid and the GABAB agonist (-)baclofen in the laterodorsal tegmental nucleus produced a dose-dependent suppression of behavioral arousal and a reduction in the threshold of myoclonic and clonic but not tonic seizures induced by bicuculline and pentylenetetrazol. There were no significant effects on any type of strychnine seizure. Injections in the surrounding brainstem structures, including the pedunculopontine tegmental nucleus, had little effect on spontaneous behavior and did not significantly alter the thresholds of pentylenetetrazol-induced seizures. We have previously demonstrated that injections of GABA agonists in the central medial intralaminar nucleus of the thalamus have similar effects on behavior and seizures. Since the central medial nucleus receives important direct cholinergic projections from the laterodorsal tegmental nucleus, these two nuclei form a discrete ascending system which regulates seizure threshold.

Topics: Alcian Blue; Animals; Baclofen; Bicuculline; Female; Histocytochemistry; In Vitro Techniques; Microinjections; Pentylenetetrazole; Piperidines; Rats; Rats, Inbred Strains; Seizures; Strychnine; Tegmentum Mesencephali; Thalamic Nuclei

1. In order to determine whether the strychnine-insensitive glycine modulatory site on the N-methyl-D-aspartate (NMDA) receptor/ion channel complex is fully activated in vivo, the ability of the selective glycine receptor agonist, D-serine, to modulate seizure susceptibility in the mouse has been examined. 2. D-Serine (10-200 micrograms per mouse, i.c.v.) dose-dependently increased the potency of NMDLA in inducing seizures in Swiss Webster mice by approximately 3 fold. L-Serine was without significant effect. 3. The potency of pentylenetetrazol in inducing seizures was also enhanced by D-, but not L-serine, although the magnitude of the shift (1.6 fold) was considerably less than for NMDLA. 4. Similar doses of D-serine were also able to block the anticonvulsant effect of the non-selective glycine receptor antagonist, kynurenic acid, against seizures induced by NMDLA, but were without effect on the anticonvulsant effect of the competitive NMDA receptor antagonist, 3-((+)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP). 5. D-Serine completely antagonized the protective effect of the selective glycine receptor antagonist, 7-chlorokynurenic acid, against sound-induced seizures in DBA/2 mice, but was less effective in this model against the less selective antagonist, kynurenic acid. 6 The results indicate that in vivo, NMDA receptors are not maximally potentiated by endogenous glycine and suggest an important involvement of the glycine modulatory site on the NMDA receptor/ion channel complex in the pathophysiology of epilepsy.

Topics: Acoustic Stimulation; Animals; Aspartic Acid; Diazepam; Injections, Intraventricular; Ion Channels; Kynurenic Acid; Male; Mice; Mice, Inbred DBA; N-Methylaspartate; Pentylenetetrazole; Piperazines; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Seizures; Serine; Strychnine

Mice injected with pilocarpine (100-400 mg/kg plus 1 mg/kg methylscopolamine), picrotoxin (0.75-6 mg/kg) or strychnine (0.75-6 mg/kg) exhibited clonic or clonic/tonic convulsions. Pretreatment with the D-1 agonist CY 208-243 (0.375-1.5 mg/kg) dose-dependently potentiated the convulsions elicited by 100 mg/kg pilocarpine, but had neither a convulsant nor anticonvulsant effect in mice receiving picrotoxin (3 or 6 mg/kg) or strychnine (0.75 or 1.5 mg/kg). This facilitatory effect of CY 208-243 was abolished by the D-1 antagonist SCH 23390 (0.2 mg/kg). SCH 23390 by itself (0.05-0.8 mg/kg) dose-dependently protected mice against pilocarpine (400 mg/kg) seizures. Stimulating D-2 receptors with LY 171555 (0.167-4.5 mg/kg) dose-dependently protected mice against seizure activity induced by pilocarpine, but neither protected nor sensitised mice given picrotoxin or strychnine. The neuroleptics haloperidol (1-4 mg/kg), sulpiride (10-50 mg/kg), metoclopramide (1.25-6.25 mg/kg), thioridazine (0.5-2 mg/kg) and clozapine (0.5-2 mg/kg) had no effect on the seizure threshold to 100 mg/kg pilocarpine by themselves, although 10 mg/kg thioridazine and clozapine caused 100% convulsions, possibly through a toxic action. When administered in conjunction with a minimally effective quantity of CY 208-243 (0.375 mg/kg), however, all five neuroleptics interacted synergistically with the D-1 agonist to promote convulsions to pilocarpine (100 mg/kg). No such interaction occurred between submaximally protective doses of the D-1 blocker SCH 23390 (0.05 and 0.2 mg/kg) and a wide range of doses of the D-2 stimulant LY 171555 (0.167-4.5 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antipsychotic Agents; Apomorphine; Benzazepines; Dopamine; Dopamine Agents; Dose-Response Relationship, Drug; Drug Synergism; Ergolines; Female; Indoles; Male; Mice; Phenanthridines; Picrotoxin; Pilocarpine; Quinpirole; Seizures; Strychnine

Intracerebroventricular (ICV) injection of N-methyl-D-aspartate (NMDA) was shown to induce generalized seizures in mice. The competitive NMDA antagonists DL-2-amino-5-phosphonovaleroate (DL-AP7) and 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate (CPP), the NMDA "channel blocker" antagonist (+)-5-methyl-10,11-dihydro 5H-dibenzo-[a,d] cycloheptan-5,10-imine maleate (MK-801) and the strychnine-insensitive glycine antagonists kynurenic acid (KYNA) and 7-chloro-kynurenic acid (7-Cl-KYNA), when co-administered (ICV) with NMDA, antagonized NMDA-induced generalized seizures. Administration (ICV) of DL-AP7, CPP and MK-801 resulted in impared learning performance in a passive avoidance task in mice, with ED50 close to the anticonvulsant dose. The glycine antagonists KYNA and 7-Cl-KYNA at high doses significantly failed to affect performance in the same model of learning. The results indicate that compounds acting at the strychnine-insensitive glycine site may have a larger "therapeutic window" as anticonvulsants than antagonists of the NMDA receptor and channel.

Topics: 2-Amino-5-phosphonovalerate; Animals; Dizocilpine Maleate; Injections, Intraventricular; Kynurenic Acid; Learning; Male; Mice; N-Methylaspartate; Piperazines; Receptors, Glycine; Receptors, Neurotransmitter; Seizures; Strychnine

Bilateral inferior olive lesions, produced by systemic administration of the neurotoxin 3-acetylpyridine (3AP) produce a proconvulsant state specific for strychnine-induced seizures and myoclonus. We have proposed that these phenomena are mediated through increased excitation of cerebellar Purkinje cells, through activation of glutamate receptors, in response to climbing fiber deafferentation. An increase in quisqualic acid (QA)-displaceable [3H]AMPA [(RS)-alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid] binding in cerebella from inferior olive-lesioned rats was observed, but no difference in [3H]AMPA binding displaced by glutamate, kainic acid (KA) or glutamate diethylester (GDEE) was seen. The excitatory amino acid antagonists GDEE and MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10 imine] were tested as anticonvulsants for strychnine-induced seizures in 3AP inferior olive-lesioned and control rats. Neither drug effected seizures in control rats, however, both GDEE and MK-801 produced a leftward shift in the strychnine-seizure dose-response curve in 3AP inferior olive-lesioned rats. GDEE also inhibited strychnine-induced myoclonus in the lesioned group, while MK-801 had no effect on myoclonus. The decreased threshold for strychnine-induced seizures and myoclonus in the 3AP-inferior olive-lesioned rats may be due to an increase in glutamate receptors as suggested by the [3H]AMPA binding data.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Anticonvulsants; Dizocilpine Maleate; Epilepsies, Myoclonic; Glutamates; Ibotenic Acid; Male; Olivary Nucleus; Pyridines; Quisqualic Acid; Rats; Rats, Inbred Strains; Seizures; Strychnine; Tritium

The anticonvulsant effects of two doses of clonazepam (CZP, Rivotril Roche, 0.1 and 1 mg/kg i.p.) were studied on model motor seizures induced by strychnine, bicuculline, 3-mercaptopropionic acid and metrazol in male laboratory rats (Wistar strain). In the first part the effects of different doses of the convulsants were investigated and for interaction with CZP doses were chosen after which more than 70% of the animals displayed generalized tonic-clonic convulsions (a grand mal seizure). Strychnine induced this type of seizure only: two doses (2 and 3 mg/kg s.c.) were used. CZP reduced the incidence of convulsions only after the larger dose, but plain solvent (propylene glycol, ethanol, water) was equally effective. The other substances first induced a seizure of minimal (mainly clonic) convulsions and only later a grand mal seizure. CZP was highly effective against bicuculline (3 mg/kg s.c.) and metrazol (100 mg/kg s.c.), but was less so against 3-mercaptopropionic acid. The effect on grand mal seizures was more pronounced in every case than on minimal seizures. The decisive role in the anticonvulsant effect of CZP is played by the mechanisms by which the convulsants induce epileptic manifestations. CZP is most effective against substances acting on the supramolecular complex GABA receptor (benzodiazepine receptor) chloride ionophore (bicuculline and probably metrazol).

Topics: 3-Mercaptopropionic Acid; Animals; Anticonvulsants; Bicuculline; Clonazepam; Dose-Response Relationship, Drug; Male; Pentylenetetrazole; Rats; Rats, Inbred Strains; Seizures; Strychnine

Electrical kindling of the rat amygdala was performed following daily intra-amygdaloid injections of the strychnine-insensitive glycine receptor antagonist 7-chlorokynurenic acid (7-CIKYN) (10 nmol), 7-CIKYN (10 nmol) plus glycine (40 nmol), or vehicle alone. Control (vehicle-treated) animals showed their first fully kindled (Stage 5) seizure after 9.5 +/- 0.8 daily stimulations. Animals pretreated with 7-CIKYN (10 nmol) showed a significant retardation of development of both the electroencephalographic and motor (17.7 +/- 2.9 daily stimulations) components of the seizure response. This inhibitory influence of 7-CIKYN was blocked when glycine (40 nmol) was co-injected daily with the antagonist. The mean initial afterdischarge threshold (ADT) was unaffected by pretreatment with 7-CIKYN (10 nmol). These results provide the first demonstration of an antiepileptogenic action of a strychnine-insensitive glycine receptor antagonist. They further support a key involvement of NMDA receptors in generative mechanisms of epilepsy.

Topics: Amygdala; Animals; Anticonvulsants; Electric Stimulation; Kindling, Neurologic; Kynurenic Acid; Limbic System; Male; Rats; Rats, Inbred Strains; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Seizures; Strychnine

A series of 4(3H)-quinazolinones structurally related to 2-methyl-3-o-tolyl-4(3H)-quinazolinone (methaqualone, 3) were synthesized and evaluated for anticonvulsant activity. Preliminary screening of these compounds revealed that 2-[2-oxo-2-(4-pyridyl)ethyl]-3-aryl-4(3H)-quinazolinones 6l and 8i, 8k, and 8p-r having a single ortho substituent on the 3-aryl group had the most promising anticonvulsant activity. Compounds 6l and 8i possessing 3-o-tolyl and 3-o-chlorophenyl groups, respectively, showed good protection against MES- and scMet-induced seizures, combined with relatively low neurotoxicity after intraperitoneal administration in mice. They also exhibited low toxicity in tests for determining the mean hypnotic dose (HD50) and the median lethal dose (LD50). Although these compounds were markedly more potent as anticonvulsants when administered orally in mice and rats, they were also more neurotoxic. This neurotoxicity was particularly acute in oral tests with rats, which resulted in marginal protective indices. In drug differentiation tests, compound 6l was ineffective against seizures induced by bicuculline, picrotoxin, and strychnine, while 8i showed some protection against picrotoxin-induced seizures.

Topics: Animals; Anticonvulsants; Bicuculline; Chemical Phenomena; Chemistry; Drug Evaluation, Preclinical; Electroshock; Lethal Dose 50; Male; Methaqualone; Mice; Molecular Structure; Pentylenetetrazole; Picrotoxin; Pyridines; Rats; Rats, Inbred Strains; Seizures; Structure-Activity Relationship; Strychnine

Fluoroacetic and fluorocitric acid toxicity is often characterized by seizures, however the mechanism of this activity is unknown. Intrathecal (i.t.) injection of fluorocitrate in mice resulted in seizures after an average latency of 15 s, while intracerebroventricular (i.c.v.) injection produced seizures after 36.5 min, and required higher doses to achieve this effect. This indicates the probable site of fluoroacetate and fluorocitrate neurotoxicity is the spinal cord. To mimic citrate accumulation, characteristic of fluoroacetate and fluorocitrate poisoning, citric acid was injected i.t. and also found to produce seizures. The structurally unrelated compounds EDTA, EGTA, glutamic acid and lactic acid also produced seizures identical to fluorocitrate. The ability of these compounds to chelate Ca2+ correlates well with their ability to cause seizures when administered i.t. and coadministration of calcium greatly attenuated the neurotoxicity of these compounds as well as fluoroacetate and fluorocitrate. In contrast, Ca2+ was unable to inhibit seizures elicited by strychnine, suggesting calcium's ability to inhibit chelators of divalent cations is not due to a general anticonvulsant effect. These results suggest that changes in Ca2+ concentration in the spinal cord may be responsible for some forms of seizure activity.

Topics: Animals; Calcium; Cations, Divalent; Chelating Agents; Citrates; Fluoroacetates; Injections, Intraventricular; Injections, Spinal; Male; Mice; Nervous System Diseases; Seizures; Spinal Cord; Strychnine

5.7-Dinitro-quinoxaline-2.3-dione (MNQX) displaced [3H]glycine binding to cortical membranes but had no effect n [3H]3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid ([3H]CPP) binding. MNQX potently antagonized N-methyl-D-aspartate (NMDA)-evoked release of [3H]GABA from cultured cortical neurones, NMDA evoked spreading depression and NMDA depolarizations in the rat neo-cortex. All of these responses were reversed by addition of glycine to the perfusion media. These results suggested that MNQX is an antagonist at the strychnine-insensitive glycine receptor associated with the NMDA receptor/ionophore complex. Furthermore the compound was found to antagonise audiogenic seizures in DBA-2 mice indicating the potential of glycine antagonists of this type in anticonvulsant therapy.

Topics: Animals; Anticonvulsants; Aspartic Acid; Cerebral Cortex; Cortical Spreading Depression; Female; gamma-Aminobutyric Acid; Glycine; In Vitro Techniques; Male; Mice; Mice, Inbred DBA; N-Methylaspartate; Pregnancy; Pyrrolidinones; Quinoxalines; Rats; Receptors, Glycine; Receptors, Neurotransmitter; Seizures; Strychnine

The gut-stimulating principle in Croton penduliflorus seed oil isolated as white crystals (CP crystals) significantly reduced pentobarbitone-induced sleeping time in mice at doses of 3 and 6 mg/kg intraperitoneally. Indomethacin (4 mg/kg) and atropine (0.044 mg/kg) significantly reversed the action of CP crystals on pentobarbitone sleeping time with indomethacin having a profound reversal effect. CP crystals significantly reduced the mean onset of convulsions and the mean death time in mice treated with a surely convulsive dose of strychnine. CP crystals significantly reduced the intensity of morphine and pethidine analgesia and prolonged the duration of pethidine analgesia. Most actions of CP crystals suggest that it stimulates the CNS and reduces the intensity of opioids (except codeine) while prolonging their duration of analgesic action.

Topics: Analgesia; Animals; Arachidonic Acids; Central Nervous System; Croton Oil; Endorphins; Female; Gastric Emptying; Male; Mice; Palmitic Acids; Pentobarbital; Pentylenetetrazole; Plants, Medicinal; Seeds; Seizures; Sleep; Stearic Acids; Strychnine

A fatal case of strychnine poisoning is presented. The patient vomited then suffered a series of tonic convulsions which were triggered by tactile stimulation. In between paroxysms he was initially alert. Eventually the patient became comatosed due to anoxia and had a cardiac arrest. He presented with a marked metabolic acidosis and rapidly developed renal failure caused by acute rhabdomyolysis. This clinical picture is classical for strychnine poisoning and the complications which the intoxication produces. Attention is drawn to the fact that survival can even follow the ingestion of very large doses of strychnine providing there is no delay in diagnosis and treatment.

Topics: Adult; Humans; Male; Seizures; Strychnine

The effects of the N-methyl-D-aspartate receptor antagonist MK-801 and the dihydropyridine calcium channel antagonist nimodipine were assessed for their anticonvulsant activity alone and in combination against clonic convulsions to pentylenetetrazole (PTZ) and strychnine (STR) in mice. Nimodipine (2-20 mg/kg) and MK-801 (0.1 and 0.5 mg/kg) did not affect the number of mice displaying clonic convulsions to PTZ. However, nimodipine in a dose-dependent manner increased (100%) the latency to clonic convulsions and lethality (mortality from tonic extension convulsions and respiratory failure) following PTZ. In contrast, MK-801 did not increase the latency to PTZ convulsions, but prevented the lethal effects of PTZ. When combined, MK-801 and nimodipine produced a significant reduction in the number of animals (40-60%) displaying PTZ convulsions and a greater increase in the latency to PTZ convulsions than did nimodipine alone. In contrast, MK-801 decreased the onset time, and increased the severity of STR convulsions. A combination of MK-801 and nimodipine which afforded significant protection against PTZ convulsions did not affect STR convulsions. These findings suggest that MK-801 and nimodipine, while possessing significant anticonvulsant activity on their own, produce a potent anticonvulsant synergism against PTZ but not STR.

Topics: Animals; Anticonvulsants; Dibenzocycloheptenes; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Male; Mice; Nimodipine; Pentylenetetrazole; Reaction Time; Seizures; Strychnine

Glycine levels and receptor binding were measured in the medulla and spinal cord of 2-month, 10-month, and 24-month-old Fischer 344 rats. The behavioral response to the administration of the glycine antagonist, strychnine, was also evaluated in 2- and 24-month-old animals to investigate the relevance of these parameters to the susceptibility to seizures. Significant reductions in glycine in both the spinal cord and medulla occurred from 2 to 24 months of age. The glycine precursors, serine and threonine, were decreased only in the spinal cord. [3H]Strychnine binding was also decreased by 38% and 34% in the medulla and spinal cord, respectively, of 24-month-old rats compared to 2-month-olds. [3H]GABA binding was similarly reduced while no age-related changes in [3H]diazepam binding in the spinal cord were detected. Comparison of 2- and 24-month-old animals after systemic injection of 1.75 mg/kg strychnine showed that senescent animals have a higher incidence of seizures and mortality compared to young animals. Decreases in glycinergic neurotransmission may lower strychnine seizure threshold in the aged animal.

Topics: Aging; Animals; Glycine; Medulla Oblongata; Rats; Rats, Inbred F344; Seizures; Spinal Cord; Strychnine

Topics: Animal Welfare; Animals; Animals, Laboratory; Research Design; Seizures; Strychnine

1. A range of compounds structurally related to the centrally acting muscle relaxant mephenesin and to the chemical convulsant strychnine were synthesized and tested for their ability to alter the threshold pressures for the onset of high pressure convulsions in mice. 2. The ability of both groups of compounds to alter the threshold pressure for convulsions was found to be dependent on the nature of a simple molecular skeleton. Thus, compounds that possessed a negatively polarized group located both in the same plane as and some 4.5 A from an aromatic nucleus increased the thresholds whereas compounds with a positively polarized group at the same location reduced the thresholds. 3. These findings support the suggestion that pressure elicits convulsions via a selection action on a receptor protein complex rather than via some general perturbation of the lipid regions of cellular membranes.

Topics: Animals; Atmospheric Pressure; Chemical Phenomena; Chemistry; Male; Mephenesin; Mice; Mice, Inbred C57BL; Seizures; Structure-Activity Relationship; Strychnine

GABAergic-dopaminergic relationships in rats were analysed quantitatively by means of behavioral studies. Acute and long-term haloperidol administration induced significant leftward displacement of the control dose-response curves for picrotoxin but not those for strychnine or 3-mercaptopropionic acid (3-MPA). Apomorphine given acutely increased the sensitivity of the animal to strychnine but not to picrotoxin or 3-MPA. In animals that presented convulsion a stereotyped gnawing and/or licking behavior was observed immediately after the ictus activity as a consequence of the combined acute administration of haloperidol and picrotoxin. Long-term haloperidol treatment increased the gnawing and/or licking behavior immediately before and/or after the ictus activity induced by picrotoxin (1 and 72 h after haloperidol withdrawal) or 3-MPA (72 h after withdrawal). A possible effect of the drugs employed on the DA-nigroamygdaloid and/or the GABA-striatonigral fiber systems is discussed.

Topics: 3-Mercaptopropionic Acid; Animals; Dopamine; gamma-Aminobutyric Acid; Haloperidol; Male; Picrotoxin; Rats; Rats, Inbred Strains; Seizures; Stereotyped Behavior; Strychnine; Time Factors

1. The effects of intraperitoneal administration of glycine were studied on the behavioural effects of raised ambient pressure in mice, compared with the effects of such administration on the actions of chemical convulsants. 2. Glycine did not alter the onset pressures for the occurrence of tremor, myoclonic jerks or clonic convulsions, when the ambient pressure was raised using helium. 3. Glycine showed a protective action against the convulsant effects of strychnine. 4. No protective action of glycine was found against the convulsant actions of pentylenetetrazol or bicuculline. 5. It is suggested that the results provide evidence that the high pressure neurological syndrome and strychnine convulsions have different neurophysiological origins.

Topics: Animals; Atmospheric Pressure; Bicuculline; Dose-Response Relationship, Drug; Glycine; High Pressure Neurological Syndrome; Male; Mice; Mice, Inbred Strains; Pentylenetetrazole; Seizures; Strychnine; Time Factors

The effects of the dihydropyridine calcium channel antagonists, nitrendipine and nimodipine, on convulsions produced by different mechanisms have been studied in rats. Nitrendipine and nimodipine significantly raised the thresholds to pentylenetetrazol for up to six hours after their injection. The calcium channel agonist, BAY K 8644, lowered the convulsion threshold to pentylenetetrazol and antagonised the effects of nitrendipine. In contrast, the severity of seizures produced by N-methyl-dl-aspartate (NMA) was increased by nitrendipine. BAY K 8644 also slightly increased the effects of NMA. Nimodipine and nitrendipine caused small, but significant, increases in the threshold pressures for the convulsions caused by raising the atmospheric pressure with helium gas. The compounds had no effect on strychnine convulsions. The conclusion is that the calcium channel antagonists are anticonvulsant against only certain types of convulsions, such as pentylenetetrazol and high pressure (and ethanol withdrawal, reported previously). Others may be increased, such as NMA seizures, or unaffected, such as strychnine-induced convulsions.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Animals; Anticonvulsants; Aspartic Acid; Atmospheric Pressure; Calcium Channel Blockers; Electrophysiology; Male; N-Methylaspartate; Nimodipine; Nitrendipine; Pentylenetetrazole; Rats; Rats, Inbred Strains; Seizures; Strychnine

Pentobarbital and phenobarbital exhibited anticonvulsant effects against picrotoxin (10 mg/kg, IP) as well as against strychnine (4 mg/kg, IP). Pentobarbital was also effective against bicuculline whereas only hypnotic doses of phenobarbital provided some protection against bicuculline- (8 mg/kg, IP) induced convulsions. Diazepam as well as THIP, but not baclofen, were also effective against all the three chemoconvulsants. Baclofen or subeffective doses of diazepam or THIP, when combined with subeffective dose of pentobarbital exhibited anticonvulsant activity against all the chemoconvulsants studied. On the other hand, a combination of subeffective doses of these agents with subeffective doses of phenobarbital provided protection only against picrotoxin and strychnine. These observations indicate that pentobarbital is quite effective against convulsions caused by agents acting at picrotoxin site, GABAA receptor or glycine receptor whereas phenobarbital is effective only against agents acting at picrotoxin site and glycine receptor, and is very weak anticonvulsant against agents causing blockade of GABAA receptors. Furthermore, activation of GABAA receptors or benzodiazepine receptors also provide protection against agents acting at GABAergic system or glycine receptors. On the contrary, activation of only GABAB receptors is inadequate to provide the protective effect. However, the activation of GABAA as well as GABAB receptors facilitate the anticonvulsant effect of both the barbiturates. Furthermore, pentobarbital, but not phenobarbital, facilitates the anticonvulsant effect of benzodiazepines against chemoconvulsants acting at GABAergic site or glycine receptors.

Topics: Animals; Anticonvulsants; Baclofen; Bicuculline; Convulsants; Diazepam; Drug Interactions; Isoxazoles; Male; Pentobarbital; Phenobarbital; Picrotoxin; Rats; Rats, Inbred Strains; Receptors, GABA-A; Seizures; Strychnine

The effects of alpha 2-adrenoceptor agonists and antagonists were examined on seizure thresholds determined by intravenous infusions of convulsants in rodents. alpha 2-Adrenoceptor antagonists were proconvulsant; dose dependently reducing the threshold for pentylenetetrazol- or bicuculline-induced tonic seizures. Strychnine-induced tonic seizures were unaffected. The alpha 2-adrenoceptor agonists clonidine, BHT-933 and UK 14,304 did not modify pentylenetetazol-induced seizures at low or moderate doses but at high doses clonidine and BHT-933 were proconvulsant. The facilitatory effect of alpha 2-adrenoceptor antagonists on pentylenetetrazol-induced tonic seizures was blocked by clonidine or UK 14,304. The proconvulsant action of alpha 2-adrenoceptor antagonists was contrasted with that of ethyl-beta-carboline-3-carboxylate, a benzodiazepine receptor contragonist, which markedly reduced the threshold for seizure initiation rather than the tonic seizure threshold. The selective facilitatory action of alpha 2-adrenoceptor blockade on tonic seizures suggests that a noradrenergic mechanism is involved in the control of seizure propagation rather than seizure initiation.

Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Animals; Bicuculline; Carbolines; Convulsants; Male; Mice; Pentylenetetrazole; Rats; Rats, Inbred Strains; Seizures; Strychnine

Strychnine poisoning leads to seizures that have traditionally been attributed to competitive antagonism of glycine receptors in the spinal cord. Although glycine is thought to act as an inhibitory neurotransmitter, a strychnine-insensitive glycine (Gly2) receptor has been recently described in cultured mouse neurons that is thought to be allosterically linked to the excitatory amino acid NMDA receptor. The present study demonstrates that intrathecally administered glycine, in contrast to other putative inhibitory transmitters, potentiates rather than inhibits strychnine-induced convulsions in mice. The seizure-potentiating effects of glycine are blocked by aminophosphonovaleric acid, an NMDA antagonist. In addition, in animals pretreated with a subconvulsive dose of strychnine to block strychnine-sensitive glycine receptors (Gly1), glycine enhances, rather than inhibits, NMDA-induced convulsions. Together, these results indicate that the seizure-potentiating effects of glycine involve activation of NMDA receptors. This study provides the first evidence that glycine is capable of modulating the activity of NMDA receptors in the spinal cords of adult animals. In light of the elevated concentrations of glycine found in epileptogenic brain foci, these data also suggest that glycine may be a positive modulator in the production of epileptic seizures.

Topics: 2-Amino-5-phosphonovalerate; Animals; Aspartic Acid; Drug Synergism; Glycine; Injections, Spinal; Mice; N-Methylaspartate; Receptors, Amino Acid; Receptors, Cell Surface; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Seizures; Strychnine; Valine

Buspirone, gepirone and ipsaperone administered intraperitoneally (40 mg/kg) to naive rats were found to be proconvulsive for strychnine-induced seizures. The dose of strychnine required to induce seizures in 50% of test animals (CD50) was 2.18 mg/kg in naive rats, while CD50s for rats treated with the azaspirodecanediones ipsaperone, gepirone and buspirone were 1.65, 0.97 and 0.70 mg/kg respectively. Azaspirodecanediones have high affinity for the 5-HT1A serotonin receptor, however, the specific 5-HT1A agonist, 8-hydroxy-2-(di-n-propyl-amino)-tetralin (8-OH-DPAT) had no effect on strychnine seizure in naive rats (CD50 = 2.0 mg/kg). The strychnine specific proconvulsive effects of inferior olive lesions and buspirone were additive, resulting in a CD50 of 0.1 mg/kg. This observation indicates that the buspirone-induced decrease in strychnine seizure threshold does not require intact inferior olive-climbing fiber pathways. Cerebellar sites for possible azaspirodecanedione action are discussed.

Topics: Animals; Anti-Anxiety Agents; Buspirone; Drug Synergism; Male; Olivary Nucleus; Pyridines; Pyrimidines; Rats; Rats, Inbred Strains; Receptors, Serotonin; Seizures; Strychnine; Syndrome

Using Sprague-Dawley rats, the anti-convulsant potencies of Althesin, ketamine and methohexitone were determined for bicuculline-and strychnine-induced seizures and compared with their effects on hyperbaric seizures. All three anaesthetics protected against both types of chemical convulsants; the degree of protection varied from 34 to 151%, with Althesin being the most effective. However, there was no correlation between their anti-convulsant and anaesthetic potencies, and no relationship between the effects on chemical convulsions and the interactions of the same agents with hyperbaric convulsions. These data suggest that the order of anti-convulsant potencies at equivalent anaesthetic concentration is Althesin much greater than ketamine = methohexitone, and that neither bicuculline-nor strychnine-induced seizures are a good model for hyperbaric convulsions.

Topics: Alfaxalone Alfadolone Mixture; Anesthetics; Animals; Anticonvulsants; Bicuculline; Female; Ketamine; Methohexital; Rats; Rats, Inbred Strains; Seizures; Strychnine

Intrathecal administration of 25 micrograms strychnine induced consistent sensory and motor behavioral events in rats. Sensory events included scratching and biting the lower half of the body, spontaneous vocalizations and skin hyperalgesia, evidenced by vocalization and reflex scratching in response to stimulation with a 5.5 g von Frey fiber. This mild stimulus failed to elicit vocalizations in the preinjection condition. Strychnine induced two types of motor seizures: (1) falling over with tail whipping and (2) convulsions. The effect of equimolar doses of glycine (G) and some related amino acids: beta-alanine (A), taurine (T) and betaine (B) on the strychnine syndrome was tested by administering them (intrathecal route) along with strychnine. T and G but not B significantly decreased most of the sensory events triggered by strychnine. All amino acids significantly decreased the incidence and duration of convulsions; T and B abolished them. A decreased vocalizations and skin hyperalgesia but synergized with strychnine to facilitate scratching and self biting. These results are consistent with findings that G, A and T displace strychnine from its binding sites in the CNS.

Topics: Alanine; Amino Acids; Animals; Betaine; Glycine; Injections, Spinal; Pain; Rats; Rats, Inbred Strains; Seizures; Strychnine; Taurine

The relative ability of the enantiomers of the ethyl and m-nitrophenyl esters of nipecotic acid to block convulsions induced by bicuculline and pentylenetetrazol, as well as to block the uptake of GABA into whole brain mini-slices, was studied in mice. Neither (+)ethyl nipecotate hydrogen tartrate [(+)E.Tartrate], which is hydrolyzed to (-)nipecotic acid, nor (-)ethyl nipecotate hydrogen tartrate [(-)E.Tartrate], which is hydrolyzed to (+)nipecotic acid, provided protection against challenge with bicuculline. Both (+)E.Tartrate and (-)ethyl nipecotate hydrochloride [(-)E.HCl], which are hydrolyzed to (-)nipecotic acid, blocked seizures induced by pentylenetetrazol. However, neither (-)E.Tartrate nor (+)ethyl nipecotate hydrochloride [(+)E.HCl], which are hydrolyzed to (+)nipecotic acid, provided significant protection against challenge with pentylenetetrazol. These results agree with the relative ability of these compounds to inhibit the uptake of GABA, where (-)nipecotic acid was more potent than (+)nipecotic acid and (+)E.Tartrate was more potent than (-)E.Tartrate. The enantiomers of m-nitrophenyl-3-piperidinecarboxylate hydrochloride, (+)MNPC.HCl and (-)MNPC.HCl, were almost equi-effective in preventing seizures induced by bicuculline. This lack of significant difference in anticonvulsant activity is in contrast with the ability to inhibit the uptake of GABA, where (-)MNPC.HCl was significantly more potent than (+)MNPC.HCl. Changing the route of administration from subcutaneous to intraperitoneal injection reduced the onset of time of the peak effect and the anticonvulsant potency of (+/-)MNPC.HCl. Cholinergic effects were observed with the administration of (+)E.Tartrate and (-)E.HCl, but not with (-)E.Tartrate, (+)E.HCl, (+)MNPC.HCl or (-)MNPC.HCl.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anticonvulsants; Bicuculline; Esters; GABA Antagonists; Male; Mice; Nipecotic Acids; Parasympathomimetics; Pentylenetetrazole; Pharmaceutical Preparations; Prodrugs; Proline; Seizures; Strychnine

A number of different depressant and convulsant agents have been shown to alter accumulation of cerebellar cyclic GMP. Since the different hexachlorocyclohexane (HCH) isomers elicit different pharmacological responses in mammals, we examined their effects on the accumulation of cerebellar cyclic GMP. Mice received one of the HCH isomers and were sacrificed for determination of cyclic GMP concentrations one hour later. Gamma-HCH increased cyclic GMP while alpha and delta-HCH decreased it. In addition, alpha and delta-HCH prevented the increase in cyclic GMP due to the gamma isomer. Picrotoxin increased cyclic GMP in a manner similar to that of gamma-HCH while strychnine produced only a small increase. All three HCH isomers inhibited the binding of 3H-TBOB (a ligand for the GABA-A-receptor linked chloride channel) in mouse cerebellum. It is concluded that the different HCH isomers can have different effects on cerebellar cyclic GMP accumulation and that these effects may be mediated through actions at the GABA-A receptor linked chloride channel.

Topics: Animals; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cell Membrane; Cerebellum; Cyclic GMP; Hexachlorocyclohexane; Isomerism; Male; Mice; Picrotoxin; Seizures; Strychnine

The effects of chemically and electrically-evoked seizures on [3H]nitrendipine binding to voltage-dependent calcium channels in mouse brain were determined 30 and 60 min following the initiation of convulsions. While maximal electroconvulsive shock, pentylenetetrazol and strychnine exhibited either no or marginal effects, Ro 5-4864 produced a decrease (14%) in the Bmax of [3H]nitrendipine at 30 min but not 60 min. The convulsant dihydropyridine calcium channel activator, BAY K 8644, produced a significant increase in the Kd (31%) of [3H]nitrendipine at 30 min, and a significant increase in both the Bmax (21%) and Kd (28%) of [3H]nitrendipine 60 min following the initiation of convulsions. While maximal electroconvulsive shock, pentylenetetrazol and strychnine exhibited either no or marginal effects, Ro 5-4864 produced a decrease (14%) in the Bmax of [3H]nitrendipine at 30 min but not 60 min following the initiation of convulsions. These findings indicate that modulation of voltage-dependent calcium channels by certain convulsants may be important in the genesis of seizures or in post-ictal compensatory processes.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Animals; Benzodiazepinones; Brain; Calcium Channels; Convulsants; Electroshock; Kinetics; Male; Mice; Mice, Inbred ICR; Nifedipine; Nitrendipine; Pentylenetetrazole; Receptors, Nicotinic; Seizures; Strychnine

The anticonvulsant effect of compounds that inhibit peptidyl-dipeptidase (PDP) on bicuculline (BIC)- and strychnine (STRYC)-induced seizures was assessed after intracerebroventricular (ICV) or intraperitoneal (IP) administration in Swiss albino mice. STRYC-induced seizures were delayed by ICV injections and high IP doses of captopril, but not by ICV or IP injections of enalapril or by lower doses of captopril (0.1 mg/kg and 1 mg/kg IP). BIC-induced seizures were not suppressed by ICV or IP injections of either compound; on the contrary, captopril and enalapril exhibited proconvulsant effects when given IP or ICV by shortening the time of onset of tonic seizures and death. Results indicate that the anticonvulsant effect of captopril against STRYC-induced seizures is not mediated by central gamma-aminobutyric acid (GABA) receptors or by the inhibition of PDP.

Topics: Animals; Bicuculline; Captopril; Dipeptidases; Enalapril; Enzyme Inhibitors; Female; Injections, Intraperitoneal; Injections, Intraventricular; Male; Mice; Seizures; Strychnine

Cerebellar stimulation has been associated with anticonvulsant activity in several experimental seizure models. We examined the effect of destruction of cerebellar climbing fibers, by systemic administration of 3-acetylpyridine (3AP) or electrothermic lesion of the inferior olive, on seizures produced by various chemical convulsants in rats. We found that inferior olive lesioned rats had lower threshold to seizures induced by strychnine and brucine, both glycine antagonists. The dose response curve for strychnine seizure was shifted 2.5 times to the left in 3AP lesioned rats. No difference in seizure threshold was seen when picrotoxin, bicuculline or pentylenetetrazole PTZ) were used to produce seizures. Abnormal motor behavior (AMB) including myoclonus, backward movement and hyperextension, produced by all of the convulsants tested, was significantly aggravated in 3AP pretreated rats. The inferior olive-climbing fiber projection to the cerebellum appears to modulate seizures induced by inhibition of glycinergic neurotransmission.

Topics: Animals; Bicuculline; Cerebellum; Convulsants; Male; Motor Activity; Neural Pathways; Olivary Nucleus; Pentylenetetrazole; Picrotoxin; Rats; Rats, Inbred Strains; Reaction Time; Seizures; Strychnine

The administration of the GABA-blocking agents picrotoxin and bicuculline to adult (2.5-3 months old) CBA/HZgr mice resulted in the appearance of convulsions, the occurrence and/or lethality of which was greater in males than in females. The latency of picrotoxin-induced convulsions was also shorter in male mice. Strychnine, a drug which induces convulsions by blocking glycine receptors was equally effective in producing convulsions in both male and female adult mice. Unlike adult mice, young (20 days old) or old (2 years old) mice fail to display sex differences following the picrotoxin administration. Accordingly, the observed sex differences in the sensitivity of CBA mice to administration of convulsive agents are specific for the GABA system and present only in sexually mature, but not in immature or old animals.

Topics: Aging; Animals; Bicuculline; Female; GABA Antagonists; Male; Mice; Mice, Inbred CBA; Picrotoxin; Seizures; Sex Factors; Strychnine

Enzymatic production of prostaglandins (PGs) from exogenous arachidonic acid was studied in brain microsomal fractions prepared from mice following pentylenetetrazol (PTZ)-induced convulsions. Prostaglandin E2 (PGE2) and prostaglandin F2 alpha (PGF2 alpha) measured either by radioimmunoassay or after incubation with [1-14C]arachidonic acid (AA) was significantly increased in microsomes from the convulsed animals. Pretreatment of the mice with the anticonvulsant ethosuximide prevented the enhanced PG production. The increased PG synthesis could not be attributed to an increased substrate availability nor to an activated phospholipase nor to a direct effect of the convulsant on the fatty acid cyclooxygenase. Evidence that a modification of the cyclooxygenase had occurred with seizure activity was obtained from kinetic analysis; the apparent Km for the AA was lowered from 30 +/- 3 microM in the controls to 12 +/- 1 microM in the PTZ-treated mice. Further evidence for a modification of the fatty acid cyclooxygenase was obtained from incubations of the microsomes with catalase to reduce peroxide formation. Limiting peroxide levels did not decrease the microsomal cyclooxygenase activity in the PTZ-treated mice to control levels. Seizure activity induced by picrotoxin and strychnine also increased the microsomal capacity of the convulsed animals to synthesize PGs. The increased brain fatty acid cyclooxygenase activity may result from a biochemical modification of the enzyme induced by seizure activity.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Brain; Dinoprost; Dinoprostone; Ethosuximide; Female; Kinetics; Mice; Microsomes; Pentylenetetrazole; Picrotoxin; Prostaglandin-Endoperoxide Synthases; Prostaglandins E; Prostaglandins F; Seizures; Strychnine

Administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (30 mg/kg s.c. for 5 days) to mice resulted in complete abolishment of strychnine seizure and of the tonic phase of the maximal electroshock response. Bicuculline and picrotoxin convulsions were not significantly affected by MPTP treatment. The severity of the pentylenetetrazole seizures was mildly, but significantly affected in the protective way. MPTP depleted neostriatal dopamine and its metabolites, together with hippocampal norepinephrine. No nigral neuronal loss was detected histologically. Strychnine seizures and the tonic phase of the maximal electroshock response are thought to depend mostly on hindbrain (bulbo-spinal) structures. Thus, these experiments suggest that a caudally projecting system originates from the substantia nigra, pars compacta, and/or locus coeruleus, controlling seizures that involve bulbo-spinal centers. While neostriatal dopamine depletion offers a good index of seizure resistance, its role in the protection from seizures remains to be established.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Anticonvulsants; Biogenic Amines; Convulsants; Corpus Striatum; Electroshock; Hippocampus; Male; Mice; Pyridines; Seizures; Strychnine

Three compounds reportedly blocking the N-methyl-D-aspartate (NMDA) receptor, namely 2-amino-5-phosphonovalerate, gamma-D-glutamylglycine and 3-hydroxy-2-quinoxalinecarboxylic acid, were injected subdurally onto the cortex of freely moving rats. All 3 compounds effectively suppressed behavioral and electrographic seizure activity induced by strychnine, morphine and picrotoxin that were administered via the same route. The cortical application of the NMDA-receptor antagonists did not induce behavioral or electrographic changes, and behavioral side-effects commonly observed following intracerebroventricular administration of these compounds were absent. The anatomical separation of anticonvulsant action and side-effects induced by these compounds suggests that this class of compounds may eventually be useful as antiepileptic drugs.

Topics: 2-Amino-5-phosphonovalerate; Animals; Anticonvulsants; Aspartic Acid; Dipeptides; Morphine; N-Methylaspartate; Picrotoxin; Quinoxalines; Rats; Rats, Inbred Strains; Seizures; Strychnine; Valine

Betaine (N,N,N-trimethylglycine) and N,N-dimethylglycine have been reported to have anticonvulsant properties in animals. The purpose of the present study was to determine whether these compounds can antagonize strychnine-induced seizures when administered intraperitoneally and to compare their effects with those of sarcosine (N-methylglycine) and glycine. Betaine, N,N-dimethylglycine and sarcosine were equipotent in decreasing the incidence of seizures and death, causing a 38 to 72 percent decrease in the incidence of seizures and death at a dosage of 5 mmole/kg. Glycine had no effect. Thus anticonvulsant activity is conferred to glycine by a single N-methylation.

Topics: Animals; Anticonvulsants; Betaine; Female; Glycine; Mice; Sarcosine; Seizures; Strychnine

Topics: Animals; Dogs; Glycine; Mice; Neurotransmitter Agents; Seizures; Strychnine

Pipecolic acid (PA) is an alicyclic amino acid and putative neurotransmitter which may modulate GABAergic transmission in the central nervous system. The present study was designed to investigate the anticonvulsant effect of intrathecally (i.t.) injected PA on picrotoxin- and bicuculline-induced convulsions which are thought to be produced by interactions with GABAergic systems. Intrathecal injections of picrotoxin and bicuculline in mice produced convulsions which were characterized by a rapid onset and short duration. Coadministration of GABA with either bicuculline or picrotoxin, but not strychnine, attenuated the severity of the convulsions. Coadministration of PA also protected against bicuculline- and picrotoxin-induced convulsions. Intrathecal injections of PA produced a dose-related increase in the latency to the onset of these convulsions as well as a decrease in their duration, however PA failed to inhibit the duration of strychnine-induced seizures. The D isomer of PA was found to be more effective than the L isomer as an anticonvulsant in this study. When administered in a high dose (500 micrograms i.t.), the D isomer produced flaccid paralysis while injection of high doses (100-500 micrograms i.t.) of the L isomer actually elicited convulsions. These results further support an interaction between PA and GABAergic activity.

Topics: Animals; Bicuculline; gamma-Aminobutyric Acid; Injections, Spinal; Male; Mice; Nipecotic Acids; Picrotoxin; Pipecolic Acids; Proline; Receptors, GABA-A; Seizures; Strychnine

Glycine or its receptor antagonist, strychnine, were administered perispinally to investigate their effect on nociceptive responses elicited by activation of various cutaneous receptors. Strychnine produced dose-dependent sensory and motor disturbances; 1 and 5 micrograms doses were sub-convulsive, eliciting recurrent episodes of coordinated grooming, scratching and biting at the skin, which persisted for approximately 10 minutes post-injection; higher doses (25 and 100 micrograms) increased the intensity and duration of these effects, and produced convulsive motor seizures. Motor disturbances were not elicited by glycine (5, 25, 100 and 400 micrograms). Strychnine treated rats, at all doses, vocalized consistently in response to light cutaneous stimulation; a significant proportion of glycine treated rats also vocalized, but were not as sensitive to mild stimulation. Skin hyperalgesia persisted for at least 30 minutes in both strychnine and glycine treated rats. Both strychnine and glycine significantly reduced vocalization thresholds to tail shock. However, no clear effect on tail flick latency was observed following either strychnine or glycine. These results indicate that glycinergic neurons contribute to the tonic regulation of nociceptive input at the spinal cord.

Topics: Animals; Behavior, Animal; Castration; Female; Glycine; Hyperalgesia; Hyperesthesia; Injections, Spinal; Pain; Physical Stimulation; Rats; Rats, Inbred Strains; Seizures; Sensory Thresholds; Spinal Cord; Strychnine; Vocalization, Animal

The effects of glycine and other inhibitory amino acid neurotransmitters on strychnine convulsive threshold were studied in mice. The mean intravenous threshold dose for strychnine to produce its convulsive effects in briefly restrained mice was determined to be 1.386 +/- 0.035 mg/kg. The dose of strychnine produced 100% postconvulsive mortality in all the mice tested. Intraperitoneal administration of various doses (100-500 mg/kg) of glycine, beta-alanine and L-threonine, 15-20 minutes prior to strychnine infusion produced an increase of 13.92%, 25.73% and 17.15% respectively in strychnine convulsive threshold in mice. Diazepam, known to produce its anticonvulsant, sedative and muscle relaxant effects through its interaction either with central GABA or glycine receptors was found to be the most potent (48.39%) in increasing strychnine convulsive threshold. Taurine and Baclofen were found to be ineffective in raising strychnine convulsive threshold in mice. These observations favor the possible use of either glycine or beta-alanine in addition to diazepam in treating clinical cases of strychnine neurotoxicoses.

Topics: Alanine; Animals; beta-Alanine; Diazepam; Dose-Response Relationship, Drug; Glycine; Male; Mice; Mice, Inbred ICR; Seizures; Strychnine; Threonine

A typical case of suicidal strychnine poisoning by a rodenticide is presented. The forceful muscular convulsions were accompanied by a clear sensorium. Pathological findings consisted of an early onset of postmortem rigidity and microscopic hemorrhages with minimal degenerative neuronal changes in the spinal cord. The highest tissue concentrations of strychnine were found in the bile and liver. The pathophysiology and epidemiology of strychnine poisoning is reviewed and discussed in context.

Topics: Humans; Male; Middle Aged; Seizures; Spinal Cord; Strychnine; Suicide; Tissue Distribution

Ro 5-4864 is a benzodiazepine that differs from diazepam only in a p-chloro substituent and yet is inactive at the classical CNS binding sites. However it is a potent ligand for the peripheral type of benzodiazepine binding sites. PK 11195 is an isoquinoline carboxamide derivative that potently displaces [3H]-Ro 5-4864 from its binding sites. PK 11195 (30-60 mg kg-1) significantly reduced the incidence of convulsions caused by Ro 5-4864 (30 mg kg-1). PK 11195 (up to 120 mg kg-1) was ineffective at counteracting seizures caused by the convulsant benzodiazepine Ro 5-3663, although this dose did increase the latency to seize after injection with pentylenetetrazole. PK 11195 had no anticonvulsant actions against picrotoxin, and at 60 mg kg-1 reduced the latency to seize. This possible proconvulsant property of the isoquinoline was further explored. PK 11195 (30-90 mg kg-1) had proconvulsant actions when combined with subconvulsant doses of strychnine and picrotoxin, but had none when combined with pentylenetetrazole. No significant tolerance developed to the anticonvulsant action of PK 11195 (30 mg kg-1) even after 25 days of dosing daily. In contrast, there was rapid tolerance (within 5 days) to the proconvulsant action of PK 11195 (60 mg kg-1) with picrotoxin (3 mg kg-1). There was no cross-tolerance between the anticonvulsant actions of diazepam and PK 11195, which suggests that these two drugs act at different sites, as would be predicted from the results of the binding studies. The possible sites of action and clinical relevance of these effects are discussed.

Topics: Animals; Anticonvulsants; Benzodiazepinones; Convulsants; Diazepam; Drug Interactions; Drug Tolerance; Isoquinolines; Ligands; Male; Mice; Pentylenetetrazole; Picrotoxin; Receptors, GABA-A; Seizures; Strychnine

In the isolated frog spinal cord penicillin or strychnine produced spinal seizures with spontaneous slow paroxysmal ventral root depolarizations (pVRDs) and superimposed motoneuron spikes. Mn2+, tetrodotoxin, mephenesin and low [Na+]o suppressed pVRDs, an indication that paroxysmal activity requires intact excitatory synaptic transmission involving interneurons. Compounds reducing the release of amino acids [-)baclofen) or interfering with the activation of N-methyl-D-aspartic acid (NMDA) receptors (D,L-alpha-aminoadipate, D-2-amino-5-phosphonovalerate, gamma-D-glutamylglycine) eliminated pVRDs. The results suggest that synaptic release of excitatory amino acids (e.g. L-glutamate, L-aspartate) and subsequent activation of specific receptors sensitive to the action of NMDA underlie spinal convulsions.

Topics: Afferent Pathways; Amino Acids; Animals; Electric Stimulation; Evoked Potentials; Ganglia, Spinal; Penicillins; Ranidae; Receptors, Amino Acid; Receptors, Cell Surface; Seizures; Spinal Cord; Strychnine; Synapses; Synaptic Transmission

The effects of levodopa, apomorphine and 3,4-dihydroxyphenylserine (DOPS) on tonic seizures elicited by strychnine were investigated in mice. Levodopa (6.25-100 mg/kg), apomorphine (0.2-0.8 mg/kg) and FLA-63 (12.5 mg/kg) profoundly delayed the onset and reduced the incidence of strychnine seizures. In addition, these drugs decreased strychnine-induced mortality. DOPS (1-16 mg/kg) apparently shortened the onset of strychnine seizures and altered strychnine-induced mortality in a dose-dependent manner; low doses (1-2 mg/kg) enhanced while moderate doses (4-8 mg/kg) reduced the mortality rate. FLA-63 (12.5 mg/kg) potentiated the anticonvulsant effect of low doses of levodopa (6.25-12.5 mg/kg) while it had no significant influence on the anticonvulsant effect of higher doses (25-100 mg/kg) of levodopa. In addition, the onset of strychnine seizure was further delayed by FLA-63. Haloperidol (0.5 mg/kg) potentiated the convulsant effect of strychnine (1 mg/kg) as well as strychnine-induced mortality. It also antagonised the protective effect of levodopa (12.5 and 100 mg/kg) against strychnine (1 mg/kg). Phentolamine (5 mg/kg) and +/- propranolol (1 mg/kg) antagonised strychnine seizures. Strychnine-induced mortality was also reduced by these drugs. In addition, the effects of DOPS (2 mg/kg) on strychnine seizures were antagonised by phentolamine and propranolol. These results indicate that enhancement of dopaminergic and noradrenergic neurotransmission respectively attenuate and potentiate strychnine seizures in mice.

Topics: Animals; Apomorphine; Droxidopa; Levodopa; Mice; Phentolamine; Propranolol; Seizures; Serine; Strychnine

The authors describe the anticonvulsant activity of a new gamma-amino-butyric acid (GABA) derivative in several animal models of generalized epilepsy including photoepileptic baboons. In all the studies, 4,9-dioxo-5,10-diazatetradecane (CM 40 142) revealed potencies against chemically, electrically and photic-induced seizures very similar to those observed with sodium valproate. In chemically elicited seizures in mice, CM 40142 exhibited a higher potency than sodium valproate in antagonizing anti-GABAergic agents. Although CM 40142 was synthesized as a compound which would cross the blood-brain barrier and liberate GABA within the central nervous system, preliminary biochemical investigations in mice failed to demonstrate a rise in brain GABA levels after treatment with CM 40142. Furthermore, CM 40142 increased spontaneous motility in mice at anticonvulsant doses. The data suggest that CM 40142 could be a broad spectrum nonsedative antiepileptic agent.

Topics: 3-Mercaptopropionic Acid; Animals; Anticonvulsants; Behavior, Animal; Bicuculline; Electroshock; Female; gamma-Aminobutyric Acid; Male; Mice; Motor Activity; Papio; Pentylenetetrazole; Photic Stimulation; Seizures; Strychnine; Valproic Acid

To determine whether the convulsive action of intraventricularly injected dopamine sulfate, a dopamine metabolite present in rat brain and human cerebrospinal fluid, could be due to its interaction with GABAergic pathway, we compared the convulsive effect of dopamine sulfate with that of bicuculline in the conscious rat and determined the interaction of dopamine sulfate with [3H] GABA binding and uptake in rat brain tissues. The results showed that the convulsive effects of dopamine sulfate and of bicuculline could be abolished by GABA agonists diazepam and muscimol, but not by DA antagonists haloperidol and metoclopramide. In addition they were additive. Both dopamine 3-O-sulfate and dopamine-4-O-sulfate, like bicuculline, could displace sodium-independent [3H] GABA binding to rat brain synaptic membranes (IC50 = 400 microM) but had no action on GABA uptake. DA sulfate had no effect on [3H] strychnine binding to rat brain homogenates. This evidence together with the structural resemblance between dopamine sulfate and GABA suggested that the convulsive activity of dopamine sulfate may result from its interaction with central GABA receptors.

Topics: Animals; Bicuculline; Brain; Diazepam; Dopamine; Drug Interactions; gamma-Aminobutyric Acid; Male; Muscimol; Rats; Rats, Inbred Strains; Seizures; Strychnine; Synaptic Membranes

The effects of morphine, cyclazocine and naloxone on penicillin- and strychnine-induced epileptic foci were studied in rabbits. The intracortical injection of penicillin (75, 150 and 300 units) elicited isolated spikes followed by repeated ictal events. The application of strychnine (0.062 and 0.125%) over the cortical surface of one side induced appearance of ipsilateral spiking spreading to the contralateral cortex. Administration of morphine (0.25-0.75 mg/kg i.v.) or cyclazocine (0.05-3.0 mg/kg i.v.) inhibited the occurrence or the duration of the EEG and motor manifestations induced by penicillin (75 and 150 units) and strychnine (0.062 and 0.125%), while it did not influence the effect of 300 units of penicillin. High doses of morphine (up to 10 mg/kg i.v.) failed to affect the epileptic responses to penicillin and strychnine and at the same time significantly reduced the pO2 in arterial blood. Naloxone per se potentiated the effects of the lower doses of penicillin and strychnine. Only at very high doses (20 mg/kg i.v.) displayed a weak antagonism towards the anticonvulsant effect of the two opiates. A full antagonism is only observed towards the effect of cyclazocine (2 mg/kg i.v.) administered after penicillin. Present data provide additional evidence of the heterogeneity of regulation by opioids of convulsive phenomena. One can hypothesize that the anticonvulsant effect of the two opiate agonists is mediated by naloxone-insensitive opiate receptors, while the proconvulsant-convulsant effect of naloxone might be related to an inhibition of GABA and glycine-mediated transmission.

Topics: Animals; Anticonvulsants; Cerebral Cortex; Cyclazocine; Electroencephalography; Male; Morphine; Naloxone; Penicillins; Rabbits; Seizures; Strychnine

Topics: Alkaloids; Animals; Guinea Pigs; Humans; Mice; Neuromuscular Junction; Paralysis; Pentobarbital; Plants, Medicinal; Rats; Seizures; Skin; Strychnine

We are selectively breeding mice prone (WSP) and resistant (WSR) to ethanol withdrawal seizures assessed by handling induced convulsions (HIC). The possibility that differences between the lines in HIC scores are a result of differences in general CNS excitability not specific to ethanol withdrawal was examined. Using treatments which produce generalized seizures (electroconvulsive shock, strychnine, and flurothyl) and gamma amino-butyric acid (GABA) antagonists (picrotoxin, bicuculline, and pentylentetrazol), the ED50 for seizures was determined in the selected lines. In addition, the sensitivity of WSP and WSR mice to the anticonvulsant actions of ethanol against each treatment was determined. Neither the convulsant amperage 50 (CA50) for ECS nor the ED50 for any drug treatment differed for the selected lines. When ethanol (1.5 g/kg) was administered prior to ECS, there was a dramatic differential suppression of ECS in the lines: the CA50 of WSR mice was elevated 5-fold, whereas the CA50 of WSP mice increased only two fold. Ethanol pretreatment also elevated the ED50 for strychnine and flurothyl in WSR mice significantly more than WSP mice, but the line difference was smaller than for the anticonvulsant effect against ECS. The ED50s for the GABA antagonists were not different between the WSR and WSP lines after ethanol pretreatment. We conclude that genetic selection is producing lines of mice that differ specifically in the degree of seizure severity caused by withdrawal from ethanol physical dependence and not in generalized CNS excitability. An increased sensitivity to the anticonvulsant effects of ethanol against some convulsant treatments has appeared as a correlated response to selection in the WSR line.

Topics: Animals; Anticonvulsants; Electroshock; Ethanol; Flurothyl; GABA Antagonists; Humans; Male; Mice; Seizures; Strychnine; Substance Withdrawal Syndrome

An investigation was made of the effect of morphine dependence on the characteristics of seizures induced in mice by convulsant drugs with differing mechanisms of action. Morphine dependence was induced in 90-day-old mice (weighing 29 to 32 g) by a 6-day schedule of twice daily i.p. injections of increasing doses of morphine (5, 32.5, 58, 82.5, 100, and 135 mg kg-1). Thirty minutes after the last morphine administration, convulsant drugs (4-aminopyridine 8 mg kg-1, pentylenetetrazol 50 mg kg-1, bicuculline 2.5 mg kg-1, strychnine 2.0 mg kg-1, and beta-mercaptopropionic acid 50 mg kg-1) were injected. 4-Aminopyridine (4-AP) and pentylenetetrazol (PTZ) increased both the number of animals with convulsions and death and in the case of 4-AP the period of convulsion latency was also increased. Naloxone at 1.0 mg kg-1 blocked the 4-AP effects, indicating that this action was mediated through an opioid receptor. Strychnine and beta-mercaptopropionic acid had an effect opposite 4-AP and PTZ in the number of animals with convulsions and death. On the other hand bicuculline had an effect more like 4-AP and PTZ than other inhibitory synapse-blocking drugs. We conclude that chronic morphine treatment modified the response of convulsant drugs depending on their mechanisms of action.

Topics: 3-Mercaptopropionic Acid; 4-Aminopyridine; Aminopyridines; Animals; Bicuculline; Brain; Convulsants; Humans; Mice; Morphine Dependence; Pentylenetetrazole; Receptors, Opioid; Seizures; Strychnine

Topics: Animals; Brain; Convulsants; Electroencephalography; Electrophysiology; GABA Antagonists; Morphine; Naloxone; Narcotics; Nikethamide; Pentylenetetrazole; Seizures; Strychnine; Synaptic Transmission

The study was undertaken to test further whether diminished GABAergic transmission might be responsible for the increased susceptibility of rats to picrotoxin-induced convulsions. In rats kept individually in cages in a noise-free room, the time between the intraperitoneal injection of the convulsant agent and the onset of convulsions was measured. Acute and subacute treatment with low doses of dihydroergotoxine (0.01-1.0 mg/kg) increased the occurrence and decreased the latency of picrotoxin-induced convulsions. Acute administration of dihydroergotoxine, 1.0 mg/kg, caused convulsions in animals injected with the subconvulsive dose (3 mg/kg) of bicuculline and of 10.0 mg/kg dihydroergotoxine in animals injected with the subconvulsive dose (1.5 mg/kg) of strychnine. Some of the animals injected with the 100% convulsive dose of strychnine were protected by dihydroergotoxine pretreatment (1.0 mg/kg) as evidenced by the lower occurrence of convulsions and fewer animals dying, as well as by a delay in the appearance of convulsions at 10.0 mg/kg. These results together with the previous findings on the GABA system suggest that dihydroergotoxine potentiates the appearance of picrotoxin and bicuculline-induced convulsions by a diminution of GABAergic transmission.

Topics: Animals; Bicuculline; Convulsants; Dihydroergotoxine; Drug Synergism; gamma-Aminobutyric Acid; Male; Picrotoxin; Rats; Rats, Inbred Strains; Seizures; Strychnine

The anticonvulsant activity of a new drug, milacemide (2-(pentylamino)-acetamide), has been studied in animal models of convulsions like those induced by bicuculline, pentylenetetrazol, picrotoxin, strychnine, inhibitors of GABA synthesis as 3-mercaptopropionic acid, allylglycine, isoniazid and thiosemicarbazide and electroshock. Milacemide is particularly effective in inhibiting the convulsions induced by bicuculline. The ED50 is 5.7 mg/kg by oral route and the activity lasts for more than 48 hr. It is less active against pentylenetetrazol and only marginally active against electroshock. It has not be found active against the other types of convulsions. Milacemide has a low toxicity (LD50: 2585 mg/kg in the mouse) and alters the behaviour of mouse, rat and monkey, only at high doses (greater than or equal to 1000 mg/kg). Milacemide seems to be specially free of sedative potential.

Topics: Acetamides; Animals; Anticonvulsants; Behavior, Animal; Bicuculline; Electroshock; gamma-Aminobutyric Acid; Lethal Dose 50; Male; Mice; Pentylenetetrazole; Rats; Rats, Inbred Strains; Seizures; Strychnine

Strychnine poisoning results in a predictable and treatable sequence of events involving blockade of the inhibitory neurotransmitter, extensor muscle spasms, seizures, and respiratory paralysis. These spasms may lead to hyperthermia, profound lactic acidosis, and rhabdomyolysis. Acidosis is primarily attributable to lactate, as indicated by the correlation between arterial pH and log of lactic acid concentration (r = -0.878). Interruption of the strychnine blockade is the primary therapy for strychnine poisoning. Phenobarbital in moderate doses should be the first intervention and anesthetic doses should be used if necessary. Suppression of convulsions will permit successful management of the complications of strychnine poisoning. Our patient survived, even though at one point he had a pH of 6.55, a lactate level of 32 mM/liter, a temperature of 43 degrees C, and rhabdomyolysis with an increased creatine phosphokinase level of 359,000 mU/ml (5,983 mumol/s/liter).

Topics: Acidosis; Adult; Body Temperature; Creatine Kinase; Female; Fever; Glycine; Humans; Hydrogen-Ion Concentration; Lactates; Male; Motor Neurons; Myoglobinuria; Phenobarbital; Seizures; Strychnine; Time Factors

The reduction of postsynaptic inhibition tolerated before initiation of intrinsic spinal seizures was assessed using intracellular recording from lumbar motoneurons in spinal cats anesthetized by pentobarbital or alpha-chloralose or decerebrated and unanesthetized. The amplitude of antagonist group Ia and recurrent (Renshaw) IPSPs was monitored while incremental doses of the specific glycine antagonist, strychnine, were injected until seizures developed. Both kinds of IPSPs were reduced to less than 25% of control at seizure onset, independent of anesthesia. Assuming the recorded pathways were representative of all glycine-mediated spinal pathways, the results suggested that postsynaptic inhibition could be virtually eliminated before intrinsic spinal seizures were triggered. These results place a constraint on theories of spinal seizures initiation due to reduction of postsynaptic inhibition.

Topics: Animals; Cats; Motor Neurons; Neural Inhibition; Seizures; Spinal Cord; Strychnine

Topics: Age Factors; Animals; Bis(4-Methyl-1-Homopiperazinylthiocarbonyl)disulfide; Chickens; Dopamine; Male; Pimozide; Seizures; Strychnine

Topics: Action Potentials; Animals; Behavior, Animal; Brain; Diazepam; Electrophysiology; gamma-Aminobutyric Acid; Glutamates; Kainic Acid; Rats; Seizures; Strychnine; Urethane

The levels of prostaglandin D2 (PGD2) and prostaglandin F2 alpha (PGF2 alpha), being the major prostaglandins formed in mouse brain in vivo were determined using a radioimmunological technique. Under basal conditions, they were less than 8.49 ng/g for PGD2 and less than 3.76 ng/g for PGF2 alpha. During seizures, induced by the centrally acting convulsant pentylenetetrazol, cerebral concentrations of both prostaglandins were markedly enhanced as compared to basal conditions. The seizure evoked increase in brain prostaglandins could be attributed to the enhanced neuronal activity. If convulsions were induced with the spinal cord convulsant strychnine no increase in brain prostaglandins was seen although the occurring hypoxia was probably very similar. Therefore, hypoxia does not seem to play a significant role in the prostaglandin increase. The effect of pentylenetetrazol on cerebral prostaglandins was independent of the mechanical convulsions induced by the drug. Muscle relaxed mice showed the same increase in cerebral prostaglandins as convulsing mice. Muscle relaxation alone had no influence on prostaglandin formation in brain. These data indicate that the increased neuronal activity induced by centrally acting convulsants is likely to be the sole cause for the rise in cerebral prostaglandins. Brain hypoxia, another known stimulus of prostaglandin synthesis, does not seem to play an important role during convulsions.

Topics: Animals; Brain Chemistry; Hypoxia, Brain; Male; Mice; Muscle Relaxation; Neurons; Pancuronium; Pentylenetetrazole; Prostaglandins; Seizures; Strychnine; Time Factors

Topics: Animals; Autonomic Nervous System; Biological Evolution; Brain; Electrophysiology; Epilepsy; Humans; Interneurons; Motor Neurons; Nerve Tissue Proteins; Neuroglia; Physical Stimulation; Proprioception; Reflex, Abnormal; RNA; Seizures; Strychnine

The interaction between ethanol and various GABAergic drugs (muscimol, bicuculline, picrotoxin) with regard to their effects on locomotor activity, drug-induced sleep, body temperature, and convulsions was studied. It was demonstrated that the GABA receptor agonist muscimol potentiated the sedative properties of ethanol, while the opposite effect, a reduction of ethanol-produced sedation, was seen upon administration of the GABA receptor blocking agent picrotoxin. Consequently, the results from the present series of experiments indicate that ethanol enhances central GABAergic activity.

Topics: Animals; Behavior, Animal; Bicuculline; Body Temperature Regulation; Dose-Response Relationship, Drug; Ethanol; Female; Motor Activity; Muridae; Muscimol; Oxazoles; Pentylenetetrazole; Picrotoxin; Receptors, Cell Surface; Receptors, GABA-A; Seizures; Sleep Stages; Strychnine

Topics: Animals; Antidepressive Agents; Bicuculline; Brain; Convulsants; Dextroamphetamine; Escape Reaction; Male; Mice; Motivation; Motor Activity; Muridae; Picrotoxin; Seizures; Sleep, REM; Strychnine

Topics: Amino Acid Metabolism, Inborn Errors; Glycine; Humans; Infant; Infant, Newborn; Muscle Hypotonia; Seizures; Strychnine

The effect of trimethyltin (TMT; 4.26 mg/kg i.p.), at 1 and 14 h following administration, on chemically-induced seizures in mice is reported. At 1 h following administration, TMT decreased seizure responsiveness and protected animals from bicuculline, isonicotinic acid hydrazide (INH) and pentylenetetrazol (PTZ) induced seizures. At 14 h following administration, TMT provided little protection against bicuculline, INH or PTZ induced seizures. Only slight decreases in seizure responsiveness were observed with strychnine induced seizures at either 1 or 14 h. By 16 h following administration, animals exhibited spontaneous tremors and convulsions. The results indicate that TMT exerts a biphasic effect on central nervous system excitability.

Topics: Animals; Anticonvulsants; Bicuculline; Isoniazid; Male; Mice; Pentylenetetrazole; Seizures; Strychnine; Time Factors; Trialkyltin Compounds; Trimethyltin Compounds

Topics: Animals; Excitatory Amino Acid Antagonists; Female; Glutamates; Pentylenetetrazole; Rats; Rats, Inbred Strains; Seizures; Strychnine

With the use of weak strychnine solutions foci of enhanced excitability working in independent modes were created in the brain cortex of rabbits during acute experiments. The hyperactive excitability focus induced by concentrated solutions of strychnine played the role of a determinant structure. It enhanced the activity of other foci, united them into a single functional complex and determined the activity pattern of the entire complex. This complex of foci could be destroyed by depression of the determinant focus activity. Disconnection of any other (dependent) focus failed to destroy the complex. The results derived during the research on the new model confirm the general concept of the role played by the determinant structures in the activity of the central nervous system.

Topics: Action Potentials; Animals; Cerebral Cortex; Rabbits; Rats; Seizures; Species Specificity; Strychnine

Harmane and other related beta-carbolines are putative endogenous ligands of the benzodiazepine receptor. Since the compounds are potent convulsants they may have agonist activities at the benzodiazepine receptor while the benzodiazepines may be antagonists. This hypothesis was proved by comparing the in vivo and in vitro antagonism of benzodiazepines by harmane and other beta-carbolines. Harmane is clearly a competitive inhibitor of benzodiazepine receptor binding in vitro. Moreover, harmane-induced convulsions can be inhibited reversibly by diazepam in a manner which is consistent with the assumption of competitive antagonism in vivo. For some beta-carboline derivatives a correlation was found between the affinity for the benzodiazepine receptor in vitro and the convulsive potency in vivo. Thus, the data reported suggest that harmane or other related beta-carbolines are putative endogenous agonists of the benzodiazepine receptor. This suggestion is further supported by the observation that diazepam is equally potent in inhibiting harmane- or picrotoxin-induced convulsions, indicating a convulsive mechanism within the GABA receptor-benzodiazepine receptor system.

Topics: Alkaloids; Animals; Anti-Anxiety Agents; Benzodiazepines; Brain; Carbolines; Female; gamma-Aminobutyric Acid; Glycine; Harmine; In Vitro Techniques; Indoles; Rats; Receptors, Cell Surface; Receptors, Drug; Seizures; Spinal Cord; Strychnine

Topics: Administration, Topical; Animals; Calcium; Cats; Cerebral Cortex; Evoked Potentials; Forelimb; Models, Neurological; Neurons; Seizures; Skin; Strychnine; Synaptic Transmission; Touch

The effect of halothane on cerebellar control of motor activity and on cerebellar cyclic 3',5'-guanosine monophosphate (cGMP) content was studied in mice. Isoniazide and picrotoxin were used to increase motor activity and induce seizures associated with an increase in cerebellar cGMP content. Halothane markedly decreased the cerebellar cGMP content (by 60 per cent at 0.61 per cent, the concentration at which 50 per cent of mice lost righting reflex) and prevented the isoniazide-induced increase in cGMP content. Halothane, 0.61 per cent, significantly reduced both isoniazide- and picrotoxin-induced motor activity; the ED50 convulsive dose of isoniazide (137.7 +/- 7.04) and of picrotoxin (1.9 +/- 0.2 mg x kg-1, sc) was about three times higher (402.2 +/- 17.9 and 5.8 +/- 0.6 mg x kg-1, sc, respectively) in mice exposed to halothane. In contrast, halothane did not alter the ED50 convulsive dose of strychnine, which has a different site and mechanism of action, blockade of glycine receptors, a mechanism not involving the cerebellar system. These results indicate that halothane has a significant effect on the cerebellar control of motor activity and that cGMP plays an important role in the alteration of cerebellar function by halothane.

Topics: Animals; Cerebellum; Cyclic GMP; Halothane; Isoniazid; Male; Mice; Motor Activity; Picrotoxin; Seizures; Strychnine

Acute experiments on cats have shown that nicotinamide (100-500 mg/kg) injected intravenously suppresses the epileptic activity in solitary foci produced in the cortex by application for several seconds of a 0.5% solution of penicillin as well as in the complex of foci produced by application of a 0.1--3% solution of strychnine to various cortical zones. Nicotinamide (500-100 mg/kg) does not affect the character of the epileptic activity of foci created by application of 1% penicillin to the cerebral cortex or on the generalized epileptic activity produced by application of concentrated solutions of strychnine or penicillin. In an epileptic focus produced by application of 5-10% acetylcholine and 0.5% proserine, injection of nicotinamide leads at first to the disappearance of after-effect discharge and then of spike potential. It is concluded that nicotinamide has an antiepileptic activity.

Topics: 3-Mercaptopropionic Acid; Acetylcholine; Animals; Anticonvulsants; Brain; Cats; gamma-Aminobutyric Acid; Neostigmine; Niacinamide; Penicillins; Seizures; Strychnine

In experiments on cats it was shown that nicotinamide injected intravenously in a dose of 300 to 500 mg per kg body weight depressed singular epileptic foci and groups of foci with synchronized activity induced in the animals' brain cortex by application of strychnine (0.1 ml of 3% solution). The vitamin was also effective, though to a lesser degree, in depressing foci induced by application of penicillin (2% solution). Pyridoxal-5-phosphate (Pyr-5-Ph) injected intravenously in a dose of 10 mg/kg depressed singular foci and groups of foci with synchronized activity induced by application of 2% solution of penicillin, but was less effective in depressing strychnine-induced foci. Combined application of both drugs even in lower doses (nicotinamide, 200 mg/kg; Pyr-5-Ph, 5 mg/kg) resulted in depression of groups of epileptic foci induced by combined application of strychnine and penicillin. Mechanisms of the effects discovered are discussed. A question on possible use of combined nicotinamide and pyridoxal-5-phosphate in the treatment of epilepsy is raised.

Topics: Animals; Cats; Drug Therapy, Combination; gamma-Aminobutyric Acid; Niacinamide; Penicillins; Pyridoxal Phosphate; Seizures; Strychnine

Cat spinal motoneurons were examined by the technique of somatic voltage clamp during strychnine-induced spinal seizures. No clear alteration of voltage-dependent ionic currents was required in order for typical strychnine-induced paroxysmal depolarization shifts (PDSs) to develop in contrast to results previously obtained during penicillin-induced spinal seizures. Voltage clamp of evoked and spontaneous PDSs indicates these are generated by a synchronized mixture of excitatory and inhibitory synaptic currents wih excitation predominating.

Topics: Animals; Cats; Membrane Potentials; Motor Neurons; Sciatic Nerve; Seizures; Spinal Cord; Strychnine

L-glycine (1-12.5 micrograms, intracerebroventricularly, i.c.v.) completely prevented seizures induced by i.c.v. administration of L-kynurenine, and practically did not modify those induced by another convulsant quinolinic acid, a metabolite of tryptophan, and by strychnine. L-Glycine administered intraperitoneally (i.p.) (1000 mg/kg) decreased lethality after K-kynurenine and quinolinic acid; at doses of 3000 and 4000 mg/kg which are sedative and hypothermic it prolonged the latency of strychnine and L-kynurenine seizures. The convulsant action of pentylenetetrazol was not modified. Kynurenine seizures are suggested to be related to the action of kynurenine on glycine receptors in the central nervous system.

Topics: Animals; Glycine; Kynurenine; Male; Mice; Pyridines; Quinolinic Acids; Seizures; Strychnine

Topics: Amphetamine; Animals; Drug Interactions; Pentylenetetrazole; Quinazolines; Rats; Seizures; Strychnine; Tranquilizing Agents

Topics: Animals; Chlorpromazine; Diazepam; Drug Therapy, Combination; Electroshock; Male; Mice; Pentylenetetrazole; Propranolol; Seizures; Strychnine

Topics: 3-Mercaptopropionic Acid; Animals; Anticonvulsants; Bicuculline; Dose-Response Relationship, Drug; Drug Synergism; Hydroxybutyrates; Male; Mice; Muscimol; Oxazoles; Pentylenetetrazole; Seizures; Sodium Oxybate; Strychnine; Sulfhydryl Compounds

Topics: 4-Aminobutyrate Transaminase; Aminocaproates; Animals; Anticonvulsants; Bicuculline; Brain Chemistry; Dose-Response Relationship, Drug; gamma-Aminobutyric Acid; Isoniazid; Male; Mice; Seizures; Strychnine; Transaminases; Vigabatrin

Acute experiments on cats demonstrated that cerebellectomy resulted in the shortened latency period of the appearance of seizure discharges produced in the neocortex by strychnine application. The time during which the amplitude of spikes was increasing up to the maximal size declined as well. Meanwhile the period of the existence of the spikes of maximal amplitude and the total time of potential generation were greater. A conclusion is made that the cerebellum is an important component of the brain antiepileptic system.

Topics: Animals; Brain Mapping; Cats; Cerebellum; Cerebral Cortex; Electrophysiology; Seizures; Strychnine

Caerulein and the C-terminal octapeptide of cholecystokinin (CCK-8), after subcutaneous administration to mice, both delayed the onset and retarded the development of toxic effects of convulsants such as strychnine, pentetrazol, bicuculline, and picrotoxin. They also increased the seizure threshold doses of intravenously infused pentetrazol and picrotoxin. In this regard, both peptides were at least equipotent with diazepam.

Topics: Animals; Anticonvulsants; Bicuculline; Ceruletide; Cholecystokinin; Diazepam; Kinetics; Male; Mice; Pentylenetetrazole; Seizures; Sincalide; Strychnine; Time Factors

The experiments on cats showed that intravenous administration of nicotinamide suppresses the epileptic activity in a solitary epileptic focus as well as in the complex of epileptic foci produced by strychnine application to various cortical zones under the influence of the most powerful focus that plays the role of a determinant. After the intravenous injection of nicotinamide (50-70 mg/kg) the complex was destabilized and broken down. The epileptic activity in the dependent foci of the complex disappeared first in the more remote from the determinant focus and then in the nearer one. The determinant focus was the last to disappear. The inhibitory effect of nicotinamide is associated with antiepileptic activity. Nicotinamide is suggested to be one of the endogenous drugs which may suppress brain hyperactivity and activate the antiepileptogenic system.

Topics: Animals; Anticonvulsants; Cats; Cerebral Cortex; Electroencephalography; Niacinamide; Seizures; Strychnine

It was shown in experiments on cats that electrostimulation (ES) of the nucleus caudalis reticularis pontis under the destruction of the central grey matter suppressed discharges in a single epileptic focus, created with application of strychnine to the brain cortex and did not suppress the epileptic activity in the complex of foci, formed under the influence of a determinant focus after local application of strychnine to different zones of the neocortex. After increasing the number of foci in the complex the resistance of the latter to suppressive effects of ES of the nucleus caudalis increases too. The complex reduction owing to liquidation of its foci (local application of nembutal) facilitates the suppressive effects of ES of the nucleus caudalis. Under prolonged inhibition of the epileptic activity in the focus, the coagulation of the nucleus caudalis leads after its long-term ES to the recovery of the epileptic activity. The evidence obtained is discussed from the standpoint of the properties of the pathological system (epileptic complex) and the role of the "antisystem" in suppression of its activity.

Topics: Animals; Cats; Cerebral Cortex; Electric Stimulation Therapy; Pons; Seizures; Strychnine

Muscimol is a potent agonist at GABA-inhibitory synapses in mammalian brain. Given systemically at 7 mumol per kilogram, it blocks topical penicillin seizures and delays the onset of generalized metrazol convulsions in rats. It has no effect against generalized seizures caused by picrotoxin or strychnine. Higher doses of muscimol cause bradykinesia, ataxia, catatonic posturing, and slowing of the electroencephalogram. When applied topically to cortex, muscimol blocks focal penicillin, bicuculline, and picrotoxin discharges in a dose-response relationship. It has no effect against topical strychnine. Muscimol offers a potential new approach to the treatment of epilepsy.

Topics: Animals; Bicuculline; GABA Antagonists; Muscimol; Neurons; Oxazoles; Penicillins; Picrotoxin; Rats; Receptors, Drug; Seizures; Strychnine

A strychnine focus created in the cat neocortex preparations with mediopontine section and encephale isolé, increased activity in other weaker foci, synchronized discharges in them, united them into a functional complex and determined the character of the whole complex activity. Such an hyperactive focus plays an active role of the determinant structure. In cortex isolé and preparations with mesencephalic section of the stem, a more rapid formation of functional complexes occurred under the effect of determinant focus. Complete elimination of the afferent and thalamo-cortical interactions seems to hinder neither the hypersynchronization of cortex neuronal elements, nor the formation of functional complexes, nor the generalization of seizure activity over the cortex.

Topics: Animals; Cats; Cerebral Cortex; Cortical Synchronization; Decerebrate State; Electroencephalography; Pentobarbital; Seizures; Strychnine

Effect of diazepam on the activity of the epileptic complex consisting of a number of foci created with strychnine applications to the brain cortex under conditions of intact brain and at different levels of it neuronal isolation was studied in acute and chronic experiments on cats. It was shown that in the preparations of cerveau isolé and cortex isolé a more rapid formation of the epileptic complex under the influence of the determinant focus, and marked generalizaiton of convulsant activity could be observed. Diazepam induced a decrease in the amplitude and frequency of convulsive discharges. There was a break in the synchronization of their appearance first in the dependent foci and then in the determinant one. The diazepam effects were seen both in the intact brain and in the preparations of cerveau isolé and cortex isolé. These findings indicate that diazepam may exert an indirect action on the brain cortex that does not exclude the participation of other brain structures in the realization of the diazepam effect under conditions of intact brain.

Topics: Acute Disease; Animals; Cats; Cerebral Cortex; Decerebrate State; Diazepam; Electrophysiology; Seizures; Strychnine

Ethosuximide provoked in encéphale isolé cats a dose-dependent suppression or facilitation of strychnine focus spiking activity, and in combination with high frequency stimulation of formatio reticularis mesencephali a significant activation of the cortical focus. The results seem to show that the influence of ethosuximide on the formatio reticularis mesencephali is one--if not the main--component of the drug effect.

Topics: Action Potentials; Animals; Cats; Cerebral Cortex; Decerebrate State; Electroencephalography; Ethosuximide; Female; Male; Rats; Reticular Formation; Seizures; Strychnine

Foci of increased excitability were created in acute experiments on rats by means of weak strychnine solutions working at independent regimens. The hyperactive excitability focus induced by means of concentrated strychnine solutions played the role of a determinant structure. The importance of the latter is in the fact that it determines the activity character of other epileptogenic foci, enhances their convulsive activity, unites them into a single functional complex and determines the behaviour of the complex as a whole. This complex can be destroyed by depression of the determinant focus activity. Switching off any dependent foci included into this complex fails to destroy that latter. Results of the investigations confirmed on the new model the general concept of the role played by the determinant structures in the brain activity.

Topics: Acute Disease; Animals; Cerebral Cortex; Disease Models, Animal; Electroencephalography; Epilepsies, Partial; Evoked Potentials; Rats; Seizures; Strychnine

The effects of four neural excitants (damphetamine, cocaine, nicotine, and strychnine) on myoclonic and clonic seizure susceptibility were investigated in two age groups (30 and 120 days) of short-sleep mice. Amphetamine and cocaine decreased susceptibility to myoclonus in young mice and increased susceptibility in mature mice. These effects were attenuated by pretreatment with haloperidol, indicating mediation by a dopaminergic system. Amphetamine did not alter clonic susceptibility in either age group of mice, whereas cocaine affected clonic susceptibility and myoclonus. These effects were not attenuated by haloperidol, indicating mediation by systems other than dopamine. Nicotine decreased susceptibility to myoclonus and increased susceptibility to clonus, whereas strychnine increased susceptibility to both types of seizure. Haloperidol, however, failed to alter any of these effects. These results are consistent with our previous work which suggests that a dopaminergic mechanism in these mice undergoes marked developmental changes between 30 and 120 days of age.

Topics: Aging; Animals; Cocaine; Dextroamphetamine; Dopamine; Mice; Myoclonus; Nicotine; Seizures; Strychnine

Topics: Animals; Bicuculline; Cerebral Cortex; Deoxyglucose; Electroencephalography; Female; Male; Penicillins; Rats; Seizures; Strychnine; Synaptic Transmission

Topics: Animals; Anticonvulsants; Bicuculline; gamma-Aminobutyric Acid; Isoniazid; Male; Muscimol; Oxazoles; Pentylenetetrazole; Picrotoxin; Rats; Seizures; Strychnine; Synaptic Transmission

Foci of increased excitability were created by means of weak strychnine and penicillin dilutions in experiments on cats. These foci worked at individual regimens. Creation with acetylcholine and proserine of a hyperactive focus led to increase of the amplitude and frequency of convulsive discharges at first in the nearest activity foci, and then in the ones remote from the hyperactive focus. The next stage was attended by qualitative changes in the activity pattern of strychnine and penicillin foci (the appearance of acetylcholine activity in them) and by the formation of a single functional focal complex working in the regimen of acetylcholine focus. Thus, the latter played the role of a determinant structure. Suppression of the determinant focus activity led to disappearance of the acetylcholine activity in all the other foci, restoration of the initial (penicillin and strychnine) activity, and to the epileptic complex decay.

Topics: Acetylcholine; Animals; Cats; Cerebral Cortex; Electroencephalography; Electrophysiology; Penicillins; Seizures; Strychnine

The action of intravenously injected taurine, glycine and GABA has been tested on convulsions induced by strychnine using electroencephalographic and electromyographic recordings. The dose of strychnine necessary to produce a generalized tonic-clonic seizure was 0.55 +/- 0.15 mg/kg intravenously for rabbits pretreated with taurine, which was significantly higher than for control animals (0.38 +/- 0.13 mg/kg). After pretreatment with glycine, the strychnine dose required to evoke convulsions (0.51 +/- 0.22 mg/kg) was also higher than the control values, but the difference was statistically not significant. The convulsive dose of strychnine in animals pretreated with GABA was slightly but not significantly lower than in control animals (0.31 +/- 0.13 mg/kg). These results suggest that taurine is the most effective amino acid to protect rabbits from seizures induced by strychnine.

Topics: Animals; Electroencephalography; gamma-Aminobutyric Acid; Glycine; Male; Rabbits; Seizures; Strychnine; Taurine

Topics: Animals; Anticonvulsants; Dose-Response Relationship, Drug; Injections, Intraventricular; Isoniazid; Male; Mice; Pentylenetetrazole; Picrotoxin; Prostaglandins E; Seizures; Strychnine

The effect of gamma-hydroxy, gamma-ethyl, gamma-phenyl-butyramide (HEPB) on afterdischarges produced by hippocampal stimulation in cats was studied. HEPB notably diminished the duration of afterdischarges and in some cats blocked their propagation into the substantia nigra and the amygdala. HEPB treatment also antagonized the enhancement of afterdischarge duration produced by subconvulsive doses of bicuculline, whereas treatment with diphenylhydantoin strongly potentiated this effect of bicuculline. The intracisternal injection of HEPB or gamma-aminobutyric acid (GABA) in mice resulted in a potentiation of strychnine-induced convulsions. On the other hand, neurochemical experiments in mouse brain cortex slices and in synaptosomes demonstrated that HEPB did not affect the high affinity uptake of [3H] GABA, its spontaneous or Ca2+ dependent release stimulated by depolarizing K+ concentrations, and its Na+ independent binding to synaptic plasma membranes.

Topics: Amygdala; Animals; Anticonvulsants; Bicuculline; Brain; Cats; Cerebral Cortex; Drug Synergism; Electric Stimulation; Evoked Potentials; gamma-Aminobutyric Acid; Hippocampus; Mice; Phenylbutyrates; Phenytoin; Potassium; Seizures; Strychnine; Substantia Nigra

Strychnine intoxication is manifested by agitation, muscle spasms, and convulsions. We report a case in which intractable convulsions led to severe lactic acidosis which secondarily resulted in visceral (lung, heart, kidney, liver, and brain) collapse and death. Aggressive therapy instituted in the emergency department and aimed at control of seizure activity and lactic acidosis may be lifesaving.

Topics: Acidosis; Adult; Emergency Service, Hospital; Humans; Male; Muscle Spasticity; Seizures; Strychnine

Topics: Aging; Animals; Animals, Newborn; Dose-Response Relationship, Drug; Female; Male; Penicillins; Pentylenetetrazole; Rats; Seizures; Strychnine

Topics: Adrenergic beta-Antagonists; Anesthesia; Animals; Anticonvulsants; Blood Pressure; Chickens; Heart Rate; Male; Propranolol; Rabbits; Seizures; Strychnine; Thiopental

Effects of intraventricular injection of sheep anti-somatostatin gamma-globulin (anti-SSG) on strychnine-induced seizures, strychnine LD50, and pentobarbital LD50 were examined in male rats under light ether anesthesia. Ten microliters of anti-SSG given 2 h earlier significantly decreased the duration of strychnine-induced seizures as compared with that in the control rats pretreated with normal sheep gamma-globulin (NSG). This effect of anti-SSG seemed to be specific, as there was no difference in seizure duration between sheep anti-LHRH gamma-globulin (anti-LHRHG)- and NSG-pretreated rats. Survival rates in anti-SSG-pretreated rats after injection of strychnine and pentobarbital were significantly larger (P less than 0.01 and P less than 0.05, respectively) than those in the control rats receiving NSG. The administration of anti-SSG resulted in 26.7% and 22.9% increases in the LD50 of strychnine and pentobarbital, respectively. These results indicate that endogenous somatostatin in the cerebrospinal fluids and/or the periventricular tissue nodulates the response of the central nervous system to strychnine and pentobarbital in rats.

Topics: Animals; gamma-Globulins; Injections, Intraventricular; Lethal Dose 50; Male; Pentobarbital; Rats; Seizures; Somatostatin; Strychnine

Topics: Amnesia; Animals; Behavior, Animal; Bemegride; Diazepam; Humans; Male; Mice; Motor Activity; Motor Skills; Picrotoxin; Rats; Seizures; Strychnine

The onset of sustained multiple unit activity (MUA) in corticofugal axons was found to precede the onset of tonic EEG activity in 91 of 92 seizures produced by administering pentylenetetrazol, strychnine, or dieldrin to cats. Latency differences from 0-8 sec were observed with a mean of 3 sec. A trend was noted for shorter latencies with subsequent seizures in the same subject. No differences in latency were seen for spontaneous as compared to evoked seizures. Much variation was encountered in the pattern of MUA and EEG development at seizure onset. In general seizures with well-defined EEG components of desynchronization, tonic and clonic activity had the greatest latency differences and the least correspondence between MUA and EEG. Seizures with the abrupt emergence of tonic or clonic activity had the smallest latency differences and the best correspondence between MUA and EEG. Large changes in the activity along corticofugal axons were observed without EEG correlates. The evidence supports the concept that the degree of synchrony within the cortical (pyramidal) cell population is critical to the emergence and development of EEG during the tonic and clonic phases of a seizure. The data suggest that, in some cases, important changes in corticofugal output may contribute to and reinforce the activity in subcortical loci implicated in generalized seizure onset.

Topics: Action Potentials; Animals; Axons; Cats; Cerebral Cortex; Dieldrin; Electroencephalography; Male; Pentylenetetrazole; Seizures; Strychnine; Time Factors

Experiments on cats under nembutal anesthesia demonstrated that the focus in cerebral cortex with a high level of convulsive activity increases the activity in foci with a low level of convulsive activity, unites them into a functional complex of epileptic activity and determines the behaviour of this complex. Such a focus has been named a determinant. An abolishment of the determinant focus entails a breakage of this complex. The abolishment of any dependent foci fails to produce such effect. The dependent foci are suppressed first of all under ether or halothane anesthesia. Bemegrid injected intravenously revealed first of all the latent determinant foci. The results of such studies as well as some problems of the pathogenesis, diagnosis, therapy and terminology of focal epilepsia are discussed from the point of view of a general conception of the role of the determinant structures in the CNS activity and the theories of generator mechanisms of neuropathologic syndromes characterized by hyperactivity of the systems.

Topics: Animals; Bemegride; Cats; Cerebral Cortex; Electrophysiology; Ether; Halothane; Seizures; Strychnine

It was shown in the experiments on cats anesthetized by nembutal that by forming a hyperactive focus with a high level of excitation in the temporal cortex and a number of foci with a less higher level of the excitation in other parts of neocortex, it is possible to create a functional complex, working in a single routine, determined by the activity of hyperactive focus. The latter plays a role of a determinant structure. The inhibition of the determinant focus results in the disturbance of the epileptic complex. Focus nature has no sufficient importance in the realization of the following interrelations: both the determinant focus and dependent foci may be created by means of strychnin and penicillin, disturbing different forms of the inhibition. The results of our investigations evidence a common conception on the role of determinant structures in the activity of the nervous system.

Topics: Animals; Cats; Cerebral Cortex; Electrophysiology; Penicillins; Seizures; Strychnine; Temporal Lobe

It was shown in experiments on cats under nembutal anesthesia that creation of a hyperactive focus with a high excitation level in the orbital or coronary cortex of one hemisphere and of a number of foci in the neocortex of the contralateral hemisphere led to formation of a functional complex working in a unified regimen determined by the hyperactive focus activity. The latter plays the role of a determinant structure. Suppression of the determinant focus with nembutal was followed by a decay of the epileptic complex. Section of the corpus callossum (its rostral part) led to derangement in synch ronization of the work between the determinant and other epileptic activity foci. The results of investigation confirmed the conception on the role of the determinant structure in the nervous system activity.

Topics: Animals; Cats; Cerebral Cortex; Corpus Callosum; Cortical Synchronization; Dominance, Cerebral; Electrophysiology; Ethyl Ethers; Seizures; Strychnine

Topics: Animals; Brain; Glycogen; Phosphoglucomutase; Phosphorylases; Rats; Seizures; Strychnine

Topics: Animals; Anticonvulsants; Cyclohexanes; Male; Mice; Motor Activity; Pentylenetetrazole; Propanolamines; Seizures; Sleep; Strychnine

Topics: Animals; Bemegride; Catecholamines; Central Nervous System; Female; Male; Mice; Neurotransmitter Agents; Pentylenetetrazole; Picrotoxin; Procaine; Seizures; Strychnine

Interaction between epileptic foci and spreading depression (SD) was studied in the cerebral cortex of rats anesthetized with Nembutal. At comparable discharge rates, picrotoxin and penicillin caused complete and partial SD blockade respectively, strychnine and Metrazol were ineffective and Aldactone facilitated SD. Conversely, the duration of SD-induced blockade of epileptic activity was maximal for Aldactone and minimal for picrotoxin. Treatment of the picrotoxin focus with tetrodotoxin (10(-4)M) reduced the discharge rate and reinstated SD propagation into the focus. [K+]e measured with ion-selective K+ electrodes 1 mm below the cortical surface increased to 8 mM in penicillin foci blocking SD and remained below 5 mM in Aldactone foci. It is concluded that the differential effect of various convulsants on SD propagation depends on the potassium concentration in the depth of the focus rather than on the discharge rate or on the mechanism of the the epileptogenic effect.

Topics: Animals; Cerebral Cortex; Convulsants; Cortical Spreading Depression; Electroencephalography; Male; Penicillin G; Pentylenetetrazole; Picrotoxin; Potassium; Rats; Seizures; Spironolactone; Strychnine

The effects of bicuculline, strychnine, and picrotoxin on photically evoked afterdischarges (PhADs) in rat visual cortex were compared with those of pentylenetetrazol (a known PhAD potentiator) and a diazepam (a known PhAD suppressor) challenge. Bicuculline was found to augment PhADs in a manner similar to that found with pentylenetetrazol, with the exception that potentiation only occurred at convulsive levels whereas pentylenetetrazol augmentation occurred at both subconvulsive and convulsive levels. Diazepam suppressed bicuculline-potentiated PhADs. Picrotoxin was found to have some limited augmenting effect on PhAD activity but in a manner unlike that observed with either bicuculline or pentylenetetrazol. Strychnine had no systematic augmenting effect on PhADs. These results were discussed in terms of the possible role of GABA in thalamic systems responsible for PhAD production.

Topics: Animals; Bicuculline; Dose-Response Relationship, Drug; Electroencephalography; Isoquinolines; Light; Pentylenetetrazole; Picrotoxin; Rats; Seizures; Strychnine; Visual Cortex

Topics: Aminobutyrates; Animals; Bicuculline; Diazepam; Dose-Response Relationship, Drug; gamma-Aminobutyric Acid; Glycine; Male; Mice; Pentylenetetrazole; Seizures; Strychnine

Topics: Afferent Pathways; Animals; Auditory Cortex; Auditory Perception; Cats; Electroencephalography; Evoked Potentials; Neural Conduction; Pentylenetetrazole; Reticular Formation; Seizures; Stimulation, Chemical; Strychnine; Thalamus

Experiments were conducted on cats; foci of increased excitability working in the individual activity regimens were created by the subconvulsive strychminization. A focus of more powerful excitation induced also by means of strychine played the role of a determinant dispatch station (DDS). Its importance consists in determining the character of the other excitation foci activity in enhancing the excitation in them, in uniting them into a functional complex, and in determining the character of the whole complex activity. This complex can be destroyed by nembutal suppression of DDS. Exclusion of any other destination stations included into the complex failed to effect this complex.

Topics: Animals; Cats; Electrophysiology; Frontal Lobe; Pentobarbital; Seizures; Strychnine

gamma-Acetylenic gamma-aminobutyric acid (gamma-acetylenic GABA) produces several-fold sustained elevations of brain GABA concentrations when administered intraperitoneally to mice. It protects mice against seizures induced by audiogenic stimuli, electroshock, thiosemicarbazide, isoniazid and strychnine. The duration and degree of audiogenic seizure protection appears to correlate with elevations in whole brain GABA levels. gamma-Acetylenic GABA does not protect against seizures induced by pentylenetetrazol or picrotoxin even at doses that increase brain GABA concentrations approximately 6-fold. This differential antiseizure activity suggests that the GABA system may play a role in some, but not all experimentally produced seizures.

Topics: 4-Aminobutyrate Transaminase; Aminobutyrates; Animals; Anticonvulsants; Brain Chemistry; Electroshock; gamma-Aminobutyric Acid; Isoniazid; Mice; Seizures; Strychnine; Thiosemicarbazones; Transaminases

1. The anticonvulsive potencies of diazepam, phenobarbital and baclofen against convulsions induced by oxygen under high pressure (OHP), by isoniazid and by strychnine were investigated in mice and rats. 2. The anticonvulsive potency of diazepam was much higher than that of phenobarbital and baclofen against all three types of convulsions. 3. The selective activity of diazepam against isoniazid induced convulsions in rats (dose ratio ED50 phenobarbital/ED50 diazepam: 400) could not be confirmed in mice (dose ratio ED50 phenobarbital/ED50 diazepam: 20-40), where diazepam was equipotent against all three types of convulsions. 4. Baclofen which does not inhibit strychnine induced convulsions was equipotent in inhibiting convulsions evoked by isoniazid and OHP in mice. 5. The results are in agreement with the postulated GABA-inhibitory mechanism of OHP induced convulsions, whereas they make a glycine inhibitory mechanism very unlikely. Although the results do not allow further conclusions about the mode of action of diazepam, a clinical trial of diazepam in OHP-induced convulsions should be considered.

Topics: Aminobutyrates; Animals; Baclofen; Diazepam; Female; gamma-Aminobutyric Acid; Glycine; Hyperbaric Oxygenation; Isoniazid; Male; Mice; Phenobarbital; Rats; Seizures; Strychnine

Topics: Animals; Cats; Electrophysiology; Geniculate Bodies; Models, Neurological; Penicillins; Reaction Time; Seizures; Strychnine; Visual Cortex; Visual Pathways

In experiments on male albino mice it has been established that upon intracerebroventricular administration in doses of 50, 100 and 300 mug per mouse GABA markedly inhibits the convulsive-seizure reactions in pentylenetetrazol and electroconvulsions and has no substantial effect on strychnine convulsions (the dose of 300 mug is toxic). Diethyldithiocarbamate (DDC) in a dose of 400 mg/kg, introduced i.p. 3 hours in advance, increases the convulsive reactivity in pentylenetetrazol and electroconvulsions. On the background of DDC the inhibitory effect of GABA is expressed only in antagonizing of the DDC effect increasing the convulsive reactivity. Alpha-methyl-paratyrosine (a-MT) in a dose of 250 mg/kg, introduced i.p. 4 hours in advance, has no substantial effect on the convulsive reactivity. On the background of alpha-MT the inhibitory effect of GABA in electroconvulsions does not change essentially, however, in pentylenetetrazol convulsions the GABA effect is practically not manifested. The results obtained show that the changes in the correlations between the catecholamines and GABA in the central nervous system result in substantial changes in the convulsive-seizure reactivity. The lower catecholamines level does not permit the marked manifestation of the GABA inhibitory effect. However, GABA counteracts to a certain extent the rise in the convulsive reactivity as a result of the drop in the brain level of the catecholamines.

Topics: Aminobutyrates; Animals; Ditiocarb; Electroshock; gamma-Aminobutyric Acid; Injections, Intraventricular; Male; Methyltyrosines; Mice; Pentylenetetrazole; Seizures; Strychnine; Sympathetic Nervous System

The anticonvulsant effect of di-n-propylacetic acid (n-DPA) was studied in mice and compared to those of phenobarbital, trimethadione and ethosuximide. n-DPA was only weakly active in the maximal electroshock test, but had an ED50 of 420 mg/kg orally in the pentetrazole seizure threshold test, which corresponds rather well to the activity of trimethadione and ethosuximide. The duration of action was only short, and the first signs of neurotoxicity--inability to perform in the chimney test--appeared well below the anticonvulsant ED50 against pentetrazole. n-DPA proved to be most active against convulsions induced by picrotoxin (ED50 200 mg/kg orally), which might indicate a role of the elevation of the central levels of gamma-aminobutyric acid in the anticonvulsant effect of the drug.

Topics: Animals; Anticonvulsants; Bicuculline; Dose-Response Relationship, Drug; Electroshock; Ethosuximide; Female; Male; Mice; Pentylenetetrazole; Phenobarbital; Picrotoxin; Seizures; Strychnine; Trimethadione; Valerates; Valproic Acid

An intravenous injection of 0.85 mg/kg strychnine nitrate produced typical convulsions in all cockerels, aged 4 to 12 weeks, as well as adult hens. Convulsions consisted of an initial excitement, tonic stage associated with opisthotonos, transient clonic movement, and finally vigorous tonic convulsions. Strychnine spikes in the Wulst EEG were not induced by the same intravenous does of strychnine in both cockerels and adult hens.

Topics: Animals; Brain; Chickens; Female; Male; Poultry Diseases; Seizures; Strychnine

Topics: Animals; Dose-Response Relationship, Drug; gamma-Aminobutyric Acid; Male; Memory; Picrotoxin; Rats; Reaction Time; Retention, Psychology; Seizures; Strychnine; Substantia Nigra

Acetylcholine (ACh) levels were determined in the brain of rats killed by decapitation or focussed microwave radiation during drug-induced convulsions. During metrazol or strychnine-induced convulsions a diffuse decrease in ACh levels was found in rats killed by decapitation. When the rats were killed by radiation and the brain was only divided into three large regions, strychnine caused no changes in ACh levels; metrazol caused a decrease in the cerebral cortex and lower brainstem. When discrete brain regions were investigated in rats killed by radiation, metrazol-induced convulsions were associated with a decrease in ACh level in all regions dissected and strychnine-induced convulsions with a decrease in the hippocampus and caudate nucleus only. Picrotoxin-induced convulsions were associated with a decrease in ACh level in the cerebral cortex, hippocampus, midbrain and medulla-pons, those induced by bicuculline with an increase in ACh level in the frontal cortex, hippocampus, midbrain and medulla-pons, by dimefline with an increase in the frontal cortex, midbrain and medulla-pons and a decrease in the caudate nucleus. The experiments show that each type of convulsant affects ACh levels in discrete brain regions in a different way.

Topics: Acetylcholine; Animals; Bicuculline; Brain Chemistry; Male; Pentylenetetrazole; Picrotoxin; Rats; Seizures; Strychnine

In experiments on male albino rats and mice a study is made of the effects of imidazol which is a phosphodiesterase stimulator, papaverine which inhibits phosphodiesterase and histamine which stimulates adenylate cyclase, on the convulsive-seizure reactivity. The substances are introduced intraventricularly and intracerebroventricularly, imidazol also intraperitoneally in different doses and at different intervals before the convulsive agent. Electrical, pentylenetetrazol (Cor) and strychnine convulsion models are used. The effect of imidazol on the spontaneous cortical bioelectrical activity is studied throuth its i. v. administration in rabbits. Imidazol markedly increases the convulsive reactivity, and in large doses it alone results in electrographic and motor convulsions. Paperine slightly lowers the convulsive-seizure reactivity only in pentylenetetrazol convulsions. The results obtained and their comparison with the results of previous experiments of ours with other drugs affecting the cyclic adenosinemonophosphate (cAMP) system, such as lithium, haloperidol, caffeine and theophyline, do not permit to assume a considerable significance of the influence of these substances (in the doses tested) on the cAMP system in the mechanisms of their effects on the convulsive-seizure reactivity.

Topics: Animals; Electric Stimulation; Histamine; Imidazoles; Male; Mice; Papaverine; Pentylenetetrazole; Rabbits; Rats; Seizures; Strychnine; Time Factors

Topics: Action Potentials; Animals; Cell Membrane; Cerebral Cortex; Neurons; Rats; Seizures; Strychnine

Topics: Animals; Benzodiazepinones; Central Nervous System; Depression, Chemical; Male; Mice; Nicotine; Pentylenetetrazole; Reflex; Seizures; Strychnine; Triazoles

Delta9-tetrahydrocannabinol (THC) was compared with diphenylhydantoin (DPH), phenobarbital (PB) and chlordiazepoxide (CDP) using several standard laboratory procedures to determine anticonvulsant activity in mice, i.e., the maximal electroshock test (MES), and seizures induced by pentylenetetrazol, strychnine and nicotine. In the MES test, THC was the least potent and DPH the most potent blocker of hind limb tonic extensor convulsions whereas THC was the most potent and DPH the least potent in increasing the latency to this response and in preventing mortality. Seizures and mortality induced by pentylenetetrazol or by strychnine were enhanced by THC and DPH and were blocked by PB and CDP. In the test with nicotine, none of the four anticonvulsant agents prevented seizures; DPH was the only one which failed to increase latency; THC and DPH were less potent than PB and CDP in preventing mortality. THC most closely resembled DPH in the tests with chemical convulsant agents, but a sedative action of THC, resembling that of PB and CDP, was indicated by low ED5 0 for increased latency and for prevention of mortality in the MES test.

Topics: Animals; Anticonvulsants; Cannabis; Chlordiazepoxide; Dronabinol; Electroshock; Male; Mice; Nicotine; Pentylenetetrazole; Pharmaceutical Vehicles; Phenobarbital; Phenytoin; Seizures; Strychnine; Time Factors

1 In cats, anaesthetized with pentobarbitone, intravenous diazepam (minimum dose 3.0 mg/kg) enhanced dorsal root potentials but did not significantly diminish the reduction by electrophoretic strychnine of the inhibitory action of electrophoretic glycine on dorsal horn interneurones. 2 In mice, intraperitoneal diazepam (2.5 mg/kg) had no appreciable effect on the potency of strychnine as a convulsant, although providing some protection against bicuculline. 3 These observations, together with the failure of chlordiazepoxide to either inhibit the firing of spinal interneurones or reduce antagonism between strychnine and glycine when administered locally, provide no support for the interaction between benzodiazepines and mammalian central glycine receptors which has been proposed on the basis of in vitro studies of strychnine binding.

Topics: Action Potentials; Animals; Bicuculline; Cats; Chlordiazepoxide; Diazepam; Glycine; Mice; Receptors, Drug; Seizures; Species Specificity; Spinal Cord; Strychnine; Time Factors

Topics: Adult; Diazepam; Female; Gastric Lavage; Humans; Male; Pancuronium; Poisoning; Respiration, Artificial; Rodenticides; Seizures; Strychnine; Suicide, Attempted

The effect of p-chlorophenylalaine (pCPA)on the central nervous excitability threshold for the neurostimulants pentetrazol, picrotoxin and strychnine inflused intravenously was evaluated in male albino mice. The effect of pCPA pretreatment was also studied in mice treated both with the neurostimulants and with central depressants meta-tolylcarbamide (MTC), phenacemide (phenylacetylurea, Phenurone) or phenobarbitol sodium (PBS). pCPA applied alone or together with MTC, phenacemide and pbs lowered the central nervous excitability threshold for the three central stimulants used in the majority of the experiments.

Topics: Animals; Central Nervous System; Depression, Chemical; Fenclonine; Hypnotics and Sedatives; Injections, Intraperitoneal; Injections, Intravenous; Male; Mice; Pentylenetetrazole; Phenobarbital; Phenylacetates; Picrotoxin; Seizures; Strychnine; Time Factors; Toluene; Urea

Topics: Acoustic Stimulation; Animals; Antipsychotic Agents; Brain Mapping; Cats; Caudate Nucleus; Cerebral Cortex; Disease Models, Animal; Electric Stimulation; Electroencephalography; Epilepsy, Absence; Epilepsy, Tonic-Clonic; Hippocampus; Humans; Mesencephalon; Myoclonus; Neural Pathways; Pentylenetetrazole; Phenothiazines; Psychotic Disorders; Reticular Formation; Seizures; Spinal Cord; Strychnine

Topics: Animals; Brain Mapping; Cats; Cerebral Cortex; Electric Stimulation; Membrane Potentials; Neural Inhibition; Neural Pathways; Penicillin G; Pentobarbital; Reaction Time; Seizures; Strychnine; Synaptic Membranes; Thalamic Nuclei

Topics: Animals; Chemical Phenomena; Chemistry; Female; Lethal Dose 50; Mice; Seizures; Strychnine

Topics: Acute Disease; Animals; Cats; Dendrites; Motor Cortex; Seizures; Strychnine

Topics: Animals; Animals, Newborn; Bis(4-Methyl-1-Homopiperazinylthiocarbonyl)disulfide; Chickens; Dopamine; Female; Male; Pimozide; Seizures; Strychnine

Topics: Action Potentials; Animals; Cats; Female; Male; Membrane Potentials; Motor Neurons; Seizures; Spinal Cord; Strychnine

Several toxic agents were compared in order to test the effect of various types of illness in producing learned taste aversions. After a 10-min sucrose drinking trial, groups of rats were injected intraperitoneally with lithium chloride or with a strong, near lethal dose of a rodenticide. Strong sucrose aversions were acquired by groups injected with lithium chloride, copper sulfate, sodium fluoroacetate, or red squill, and very weak or no aversions were learned by groups injected with thallium, warfarin cyanide, or strychnine. The results were discussed in terms of onset of symptoms, duration of symptoms, and kinds of physiological effects necessary to produce aversions. It was concluded that the effects of different drugs may be mediated by different physiological systems learned taste aversions.

Topics: Animals; Avoidance Learning; Copper; Cyanides; Diarrhea; Female; Fluoroacetates; Lithium; Male; Motor Activity; Plants, Medicinal; Rats; Rodenticides; Seizures; Sex Factors; Strychnine; Sulfates; Taste; Thallium; Time Factors; Warfarin

Topics: Aggression; Animals; Anti-Anxiety Agents; Behavior, Animal; Bemegride; Benzodiazepinones; Cats; Chlorprothixene; Diazepam; Drug Synergism; Electroencephalography; Electroshock; Female; Fluorobenzenes; Hexobarbital; Humans; Lethal Dose 50; Male; Mice; Motor Activity; Muscle Tonus; Olfactory Bulb; Pentylenetetrazole; Rats; Reflex; Seizures; Septum Pellucidum; Strychnine

Topics: Animals; Anticonvulsants; Antineoplastic Agents; Aziridines; Convulsants; Drug Antagonism; Drug Synergism; Penicillin G; Rats; Seizures; Strychnine; Sulfonic Acids; Thiazines

Topics: Aggression; Amphetamine; Animals; Anti-Anxiety Agents; Avoidance Learning; Carbamates; Chlordiazepoxide; Diazepam; Drug Synergism; Electroencephalography; Electroshock; Female; Humans; Male; Mice; Motor Activity; Muscle Tonus; Pentobarbital; Pentylenetetrazole; Rabbits; Rats; Seizures; Sleep; Strychnine

Topics: Acetylcholine; Administration, Oral; Animals; Anura; Blood Pressure; Cats; Central Nervous System Stimulants; Depression, Chemical; Drug Synergism; Fusidic Acid; Gastrointestinal Motility; Injections, Intravenous; Mice; Motor Activity; Movement Disorders; Muscle Contraction; Muscle, Smooth; Nervous System; Neuromuscular Nondepolarizing Agents; Nictitating Membrane; Pentylenetetrazole; Rabbits; Rats; Seizures; Strychnine; Vagus Nerve

Topics: Animals; Brain; Cerebellum; Cerebral Cortex; Curare; Electroencephalography; Hippocampus; Rabbits; Red Nucleus; Seizures; Strychnine; Synaptic Transmission; Tetanus Toxin

Topics: Animals; Brain; Cerebral Cortex; Cerebrovascular Disorders; Dogs; Electroencephalography; Ischemia; Seizures; Strychnine

Topics: Aggression; Animals; Anticonvulsants; Depression, Chemical; Dose-Response Relationship, Drug; Exploratory Behavior; Humans; Hydroxybutyrates; Mice; Pentylenetetrazole; Rats; Seizures; Semicarbazides; Sexual Behavior, Animal; Stimulation, Chemical; Strychnine; Sulfhydryl Compounds

Topics: Aggression; Animals; Anticonvulsants; Avoidance Learning; Benzazepines; Benzodiazepines; Cats; Diazepam; Dose-Response Relationship, Drug; Electroshock; Female; Fluorobenzenes; Humans; Male; Mice; Muscle Relaxants, Central; Muscle Rigidity; Pentylenetetrazole; Rats; Reflex; Seizures; Strychnine; Time Factors

Topics: Animals; Behavior, Animal; Cerebral Cortex; Evoked Potentials; Female; Hexobarbital; Humans; Lethal Dose 50; Male; Mice; Motor Activity; Pentylenetetrazole; Piperazines; Rabbits; Rage; Rats; Reserpine; Seizures; Stereotyped Behavior; Strychnine

Topics: Animals; Anticonvulsants; Behavior, Animal; Biotransformation; Central Nervous System; Dose-Response Relationship, Drug; Glycols; Mice; Motor Activity; Paralysis; Propranolol; Seizures; Strychnine; Time Factors

Topics: Administration, Topical; Animals; Cerebral Cortex; Electroencephalography; Female; Hypothalamus; Luteinizing Hormone; Prolactin; Rats; Seizures; Strychnine; Superior Colliculi

Topics: Age Factors; Animals; Chickens; Consciousness; Electrocardiography; Electroencephalography; Electromyography; Female; Injections, Intraperitoneal; Male; Muscles; Neck; Poultry Diseases; Respiration, Artificial; Seizures; Strychnine; Telencephalon

Topics: Acetylcholine; Adrenal Glands; Adrenal Medulla; Alkaloids; Aminobutyrates; Animals; Calcium; Catecholamines; Cattle; Dioxoles; Dose-Response Relationship, Drug; Glutamates; Glycine; In Vitro Techniques; Isoquinolines; Picrotoxin; Potassium; Seizures; Strychnine

Topics: Administration, Oral; Analgesics; Animals; Anticonvulsants; Barbiturates; Butanes; Central Nervous System; Depression, Chemical; Dose-Response Relationship, Drug; Drug Synergism; Female; Hypnotics and Sedatives; Injections, Intraperitoneal; Lethal Dose 50; Male; Mice; Pentylenetetrazole; Proadifen; Rats; Seizures; Sleep; Strychnine; Time Factors; Urea

Topics: Aminobutyrates; Animals; Anticonvulsants; Behavior, Animal; Central Nervous System Stimulants; Drug Synergism; Excitatory Amino Acid Antagonists; Hydrazones; Male; Mice; Motor Activity; Pentylenetetrazole; Phenytoin; Pyridoxal Phosphate; Pyrrolidinones; Reflex; Seizures; Sleep; Strychnine; Thiosemicarbazones; Time Factors

Topics: Animals; Anticonvulsants; Brain; Central Nervous System Stimulants; Electron Transport Complex IV; Monoamine Oxidase; Pentylenetetrazole; Phenobarbital; Rats; Seizures; Strychnine; Transaminases

Topics: Animals; Anticonvulsants; Bemegride; Benzazepines; Brain; Cats; Central Nervous System; Chemical Phenomena; Chemistry; Child; Child, Preschool; Evoked Potentials; Haplorhini; Humans; Ketones; Lethal Dose 50; Male; Mice; Nitro Compounds; Papio; Pentylenetetrazole; Rabbits; Rats; Seizures; Semicarbazides; Spinal Cord; Strychnine

Topics: Animals; Blood Pressure; Cerebrovascular Circulation; Electroencephalography; Ischemic Attack, Transient; Oxygen; Pentylenetetrazole; Rabbits; Seizures; Strychnine

Topics: Amobarbital; Animals; Bradykinin; Brain; Brain Chemistry; Brain Stem; Cerebellum; Cerebral Cortex; Ethyl Ethers; Kininogens; Kinins; Lysine Carboxypeptidase; Male; Nerve Tissue Proteins; Pentylenetetrazole; Peptidyl-Dipeptidase A; Rats; Seizures; Strychnine; Time Factors

Topics: Alkaloids; Aminobutyrates; Animals; Cats; Dioxoles; Electroencephalography; Glycine; Injections, Intravenous; Iontophoresis; Isoquinolines; Medulla Oblongata; Neural Inhibition; Picrotoxin; Seizures; Sensory Receptor Cells; Strychnine; Synaptic Transmission

Topics: Animals; Cervical Vertebrae; Cordotomy; Male; Norepinephrine; Pentylenetetrazole; Picrotoxin; Rats; Reserpine; Seizures; Strychnine

Topics: Animals; Blood Glucose; Fasting; Insulin; Male; Mice; Pentylenetetrazole; Seizures; Strychnine; Time Factors

Topics: Aminobutyrates; Animals; Brain; Brain Chemistry; Hyperbaric Oxygenation; Lithium; Magnesium; Male; Manganese; Oxygen; Pentylenetetrazole; Picrotoxin; Pulmonary Edema; Rats; Seizures; Strychnine; Thiosemicarbazones; Zinc

Topics: Animals; Anticonvulsants; Behavior, Animal; Carbazoles; Central Nervous System; Diuresis; Diuretics; Electroshock; Lethal Dose 50; Mice; Monoamine Oxidase Inhibitors; Motor Activity; Pentylenetetrazole; Seizures; Strychnine

Topics: Animals; Dog Diseases; Dogs; Legislation, Drug; Seizures; Strychnine; Vomiting

Topics: Alkaloids; Animals; Auditory Threshold; Cerebral Ventricles; Dioxoles; Electroshock; Folic Acid; Folic Acid Antagonists; Glutamates; Injections; Injections, Intravenous; Isoquinolines; Mice; Ouabain; Pentylenetetrazole; Phenobarbital; Phenytoin; Picrotoxin; Seizures; Strychnine

Topics: Animals; Behavior, Animal; Chromatography, Gas; Glycols; Mass Spectrometry; Mephenesin; Mice; Propranolol; Seizures; Strychnine

Topics: Animals; Behavior, Animal; Central Nervous System; Electroshock; Glyoxylates; Indoles; Methyl Ethers; Mice; Motor Activity; Seizures; Structure-Activity Relationship; Strychnine; Tryptamines

Topics: Aminobutyrates; Animals; Chickens; Drug Interactions; Drug Synergism; Male; Motor Activity; Postural Balance; Seizures; Strychnine; Sucrose; Time Factors

Topics: Alkaloids; Aminobutyrates; Animals; Anticonvulsants; Dioxoles; Hydrazones; Isoquinolines; Mice; Motor Activity; Pentylenetetrazole; Phenytoin; Pyridoxal Phosphate; Pyrrolidinones; Seizures; Semicarbazides; Strychnine; Thiones; Time Factors

Topics: Animals; Blood Pressure; Brain; Cerebral Arteries; Cerebral Cortex; Cerebrovascular Circulation; Dogs; Electroencephalography; Mathematics; Oxygen Consumption; Regional Blood Flow; Seizures; Strychnine; Vascular Resistance

Topics: Animals; Body Temperature; Chickens; Electrocardiography; Electroencephalography; Electromyography; Female; Gallamine Triethiodide; Injections, Intravenous; Muscles; Poultry Diseases; Rectum; Respiration, Artificial; Seizures; Strychnine; Telencephalon

Topics: Animals; Central Nervous System; Dose-Response Relationship, Drug; Ethanol; Humans; Male; Mice; Pentylenetetrazole; Picrotoxin; Reserpine; Seizures; Strychnine; Substance Withdrawal Syndrome; Time Factors

Topics: Animals; Rats; Seizures; Strychnine; Succinates; Vitamin B 12 Deficiency

Topics: Animals; Aorta; Blood Flow Velocity; Blood Pressure; Brain Chemistry; Cerebrovascular Circulation; Circle of Willis; Cranial Sinuses; Dogs; Mathematics; Oxygen; Seizures; Strychnine; Vascular Resistance

Topics: Animals; Histocytochemistry; Hypothalamo-Hypophyseal System; Male; Neurosecretion; Pituitary Gland, Posterior; Rats; Rats, Inbred Strains; Rosaniline Dyes; Seizures; Staining and Labeling; Strychnine

Topics: Animals; Behavior, Animal; Bemegride; Body Temperature; Brain; Central Nervous System; Central Nervous System Stimulants; Electroencephalography; Evoked Potentials; Pentylenetetrazole; Picrotoxin; Receptors, Adrenergic; Receptors, Cholinergic; Seizures; Snakes; Strychnine; Synapses

Topics: Animals; Cats; Cerebral Cortex; Electric Stimulation; Electroencephalography; Ethyl Chloride; Female; Freezing; Male; Neural Conduction; Neurons; Rabbits; Seizures; Stimulation, Chemical; Strychnine

Topics: Animals; Anticonvulsants; Anura; Chlorpromazine; Mephenesin; Muscle Contraction; Orphenadrine; Rana temporaria; Reserpine; Seizures; Strychnine

Topics: Animals; Cyclohexanes; Electroshock; Limbic System; Male; Mice; Olfactory Bulb; Pentylenetetrazole; Picrotoxin; Seizures; Strychnine

Topics: Action Potentials; Aluminum Hydroxide; Animals; Cats; Electroencephalography; Haplorhini; Hypothermia, Induced; Macaca; Membrane Potentials; Motor Cortex; Seizures; Strychnine; Tungsten

Topics: Administration, Oral; Amidines; Animals; Anticonvulsants; Behavior, Animal; Chemical Phenomena; Chemistry; Electroshock; Lethal Dose 50; Mice; Pentylenetetrazole; Seizures; Strychnine

Topics: Amnesia; Animals; Avoidance Learning; Electroshock; Humans; Injections, Intraperitoneal; Male; Memory; Memory, Short-Term; Mice; Reaction Time; Seizures; Strychnine; Time Factors

1. The effects of amino-oxyacetic acid (AOAA) on the central nervous system and on skeletal muscle have been examined in the chicken.2. AOAA had both anticonvulsant and convulsant effects, depending on the dose, as in other species.3. The convulsant effect, accompanied by EEG spiking, decreased rapidly with increase in age of young chicks.4. The convulsant effect was exerted primarily through supraspinal centres.5. Of control depressants tested, only troxidone and small doses of AOAA afforded significant protection against AOAA seizures.

Topics: Acetates; Age Factors; Animals; Anticonvulsants; Central Nervous System; Chickens; Electroencephalography; Muscles; Rats; Seizures; Strychnine; Trimethadione

Topics: Animals; Behavior, Animal; Cyproheptadine; Dibenzazepines; Drug Antagonism; Electroshock; Lethal Dose 50; Male; Mice; Mice, Inbred Strains; Motor Activity; Pentylenetetrazole; Pilocarpine; Pyrazines; Reserpine; Salivation; Seizures; Serotonin Antagonists; Strychnine; Tremorine

Topics: Alcoholism; Animals; Auditory Threshold; Behavior, Animal; Electroshock; Ethanol; Female; Humans; Pentylenetetrazole; Rats; Seizures; Strychnine; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: Animals; Behavior, Animal; Benzazepines; Drug Synergism; Electroshock; Ethanol; Fluorine; Ketones; Male; Mice; Mice, Inbred Strains; Motor Activity; Nicotine; Pentylenetetrazole; Seizures; Structure-Activity Relationship; Strychnine; Thiosemicarbazones

Topics: Animals; Behavior, Animal; Benzazepines; Carbamates; Central Nervous System; Depression, Chemical; Drug Antagonism; Drug Synergism; Electroshock; Ethanol; Male; Mice; Mice, Inbred Strains; Motor Activity; Pentylenetetrazole; Seizures; Sleep; Strychnine; Thiosemicarbazones

Topics: Animals; Avoidance Learning; Behavior, Animal; Dose-Response Relationship, Drug; Drug Interactions; Electroshock; Eugenol; Glycols; Hexobarbital; Injections, Intraperitoneal; Lethal Dose 50; Male; Methylation; Mice; Mice, Inbred Strains; Motor Activity; Pentylenetetrazole; Seizures; Structure-Activity Relationship; Strychnine

Topics: Amides; Amino Acids; Animals; Bemegride; Brain; Brain Chemistry; Caffeine; Carbon Isotopes; Central Nervous System; Depression, Chemical; Glutamine; Hexobarbital; Liver; Male; Mice; Pentylenetetrazole; Picrotoxin; Piperidines; Seizures; Sleep; Strychnine

Topics: Adenosine Diphosphate; Animals; Blood Pressure; Cats; Cerebral Cortex; Fluorometry; Hypoxia; Mitochondria; NAD; NADP; Norepinephrine; Oxidation-Reduction; Oxidative Phosphorylation; Oxygen Consumption; Pentylenetetrazole; Polarography; Seizures; Strychnine; Time Factors

Topics: Animals; Cats; Cerebral Cortex; Electroencephalography; Evoked Potentials; Light; Penicillinase; Penicillins; Seizures; Strychnine; Time Factors; Visual Cortex

Topics: Aldehydes; Animals; Anticonvulsants; Central Nervous System; Drug Antagonism; Glycolates; Glycols; Glyoxylates; Mice; Pentylenetetrazole; Rabbits; Rats; Seizures; Strychnine

Topics: Animals; Brain; Cats; Cerebral Ventricles; Dopamine; Methysergide; Muscle Contraction; Pentylenetetrazole; Prostaglandins; Seizures; Stomach; Strychnine

Topics: Animals; Auditory Cortex; Auditory Perception; Brain; Corpus Callosum; Dogs; Dominance, Cerebral; Ear; Electroencephalography; Memory, Short-Term; Mesencephalon; Nerve Degeneration; Neural Pathways; Ocular Physiological Phenomena; Seizures; Strychnine; Visual Cortex; Visual Perception

Topics: Animals; Anticonvulsants; Carbonic Anhydrase Inhibitors; Diuresis; Electroshock; Enzyme Activation; Lethal Dose 50; Mice; Pentylenetetrazole; Phenobarbital; Phenytoin; Rats; Seizures; Strychnine; Sulfonamides

Topics: Adolescent; Diazepam; Female; Humans; Injections, Intravenous; Poisoning; Seizures; Strychnine

Topics: Animals; Blood Pressure; Brain Stem; Caffeine; Cats; Chlordiazepoxide; Chlorpromazine; Cocaine; Depression, Chemical; Dextroamphetamine; Drug Antagonism; Hypnotics and Sedatives; Male; Mice; Morphine; Morpholines; Motor Activity; Pentylenetetrazole; Piperazines; Propiophenones; Rats; Reflex; Respiration; Seizures; Strychnine; Tranquilizing Agents

Topics: 5-Hydroxytryptophan; Animals; Anura; Dihydroxyphenylalanine; Injections, Subcutaneous; Muscle Contraction; Pentylenetetrazole; Seizures; Serotonin; Strychnine; Synapses; Synaptic Transmission

Topics: Age Factors; Aminobutyrates; Animals; Animals, Newborn; Brain Chemistry; Central Nervous System Stimulants; Centrifugation; Chickens; Freeze Drying; Picrotoxin; Seizures; Semicarbazides; Strychnine; Thiosemicarbazones

1. When administered to intact white mice, the central depressants-diphenhydramine, promethazine, chlorpromazine, gammahydroxybutyrate, gammabutyrolactone, hyoscine, and pethidine-produced sedation in small doses, but excitement and convulsions in higher doses. When given to mice pretreated with subanaesthetic doses of phenobarbitone these drugs abolished the righting reflex both in convulsant doses (hyoscine excepted) and in non-convulsant doses. These effects are similar to the effects previously observed with local anaesthetics.2. Meprobamate, diazepam and chlorpromazine produced a loss of righting reflex both when given alone and following phenobarbitone. When given alone in higher doses, chlorpromazine induced convulsions.3. The central stimulants bemegride and picrotoxin antagonized the loss of righting reflex produced by phenobarbitone, but nikethamide, caffeine and strychnine did not alter the depressant effects of phenobarbitone.4. On the basis of these and previous studies with intact white mice a tentative classification of drugs having generalized depressant and stimulant effects on the central nervous system was proposed and discussed.

Topics: Adjuvants, Anesthesia; Aminobutyrates; Animals; Bemegride; Caffeine; Central Nervous System; Central Nervous System Stimulants; Chlorpromazine; Diazepam; Diphenhydramine; Female; Glutamates; Hydroxybutyrates; Lactones; Meperidine; Meprobamate; Mice; Motor Activity; Nikethamide; Phenobarbital; Picrotoxin; Promethazine; Reflex; Scopolamine; Seizures; Strychnine; Tranquilizing Agents

1. In the neuronally isolated cortex of the cat, local application of bemegride, picrotoxin, nikethamide, caffeine and strychnine facilitated the surface positive response of the isolated cortex and lowered the stimulus threshold for this response. Excepting nikethamide, they all produced convulsive discharge in the isolated cortex unrelated to the applied stimulus.2. Local application of glutamate to the cortex produced spreading depression, which was sometimes preceded by spontaneous positive bursting.3. In contrast to the "general depressants" which produce a relatively consistent pattern of effects on the electrical responses of isolated cortex, the "general stimulants", although they all have excitatory effects on isolated cortex, each produced a greatly different type of electrical response in the isolated cortex, suggesting that several different mechanisms of action are responsible for their effects.

Topics: Action Potentials; Animals; Bemegride; Caffeine; Cats; Central Nervous System Stimulants; Cerebral Cortex; Female; Glutamates; In Vitro Techniques; Male; Nikethamide; Picrotoxin; Seizures; Stimulation, Chemical; Strychnine

Topics: Aggression; Animals; Avoidance Learning; Behavior, Animal; Benzazepines; Cats; Chlordiazepoxide; Diazepam; Dogs; Electroshock; Escape Reaction; Female; Haplorhini; Humans; Male; Meprobamate; Mice; Motor Activity; Muscle Contraction; Muscle, Smooth; Pentylenetetrazole; Phenobarbital; Rats; Reflex; Seizures; Strychnine; Time Perception; Tranquilizing Agents

Topics: Animals; Central Nervous System; DDT; Dieldrin; Electroshock; Female; Injections, Subcutaneous; Intubation, Gastrointestinal; Pentobarbital; Pentylenetetrazole; Rats; Seizures; Strychnine; Time Factors

Topics: Animals; Mephenesin; Mice; Paralysis; Phenobarbital; Plants, Medicinal; Pyrans; Reflex; Seizures; Strychnine

Topics: Animals; Azoles; Blood Pressure; Chloral Hydrate; Drug Antagonism; Drug Synergism; Glutarates; Hexobarbital; Mice; Movement; Respiration; Seizures; Strychnine

Topics: Animals; Central Nervous System; DDT; Drug Antagonism; Drug Synergism; Electroshock; Female; Pentobarbital; Pentylenetetrazole; Rats; Reflex; Seizures; Strychnine

Topics: Anesthesia; Animals; Male; Mice; Pentylenetetrazole; Secobarbital; Seizures; Stereoisomerism; Strychnine

Topics: Aluminum; Animals; Cats; Electroencephalography; Electroshock; Hydroxides; Seizures; Strychnine

Topics: Animals; Brain Chemistry; Caudate Nucleus; Dopamine; Electroshock; Pentylenetetrazole; Rabbits; Seizures; Strychnine; Succinylcholine

Topics: Alkaloids; Animals; Female; Mice; Seizures; Strychnine

Topics: Animals; Atmospheric Pressure; Cobalt; Hydroxylamines; Hyperbaric Oxygenation; Injections, Intraperitoneal; Ions; Lung; Male; Manganese; Metals; Methods; Oxygen; Pentylenetetrazole; Picrotoxin; Potassium; Pulmonary Edema; Rats; Seizures; Strychnine; Thiosemicarbazones; Zinc

Topics: Animals; Asphyxia; Cerebral Arteries; Cerebral Cortex; Female; Ischemic Attack, Transient; Male; Muscle, Smooth; Rabbits; Seizures; Strychnine

Topics: Animals; Anticonvulsants; Azoles; Mice; Oils, Volatile; Rats; Seizures; Strychnine

Topics: Adult; Asphyxia; Charcoal; Humans; Kidney; Male; Middle Aged; Seizures; Strychnine; Suicide

Topics: Aminobutyrates; Animals; Anura; Electroencephalography; Electroshock; Evoked Potentials; Lizards; Physiology, Comparative; Reptiles; Seizures; Strychnine; Telencephalon; Turtles

Topics: Animals; Cats; Cerebral Cortex; Cobalt; Electric Stimulation; Electrophysiology; Evoked Potentials; Neurons; Rabbits; Seizures; Strychnine; Visual Cortex

Topics: Aluminum; Animals; Animals, Newborn; Cats; Electric Stimulation; Electroencephalography; Epilepsy; Seizures; Strychnine

Topics: Action Potentials; Animals; Cats; Corpus Callosum; Dogs; Seizures; Strychnine; Synaptic Transmission

Topics: Age Factors; Animals; Barbiturates; Brain; Central Nervous System; Electric Stimulation; Electroshock; Fetus; Pentylenetetrazole; Phenytoin; Picrotoxin; Rats; Reflex; Seizures; Spinal Cord; Strychnine; Synaptic Transmission; Time Factors

Topics: Action Potentials; Animals; Cats; Computers; Electrophysiology; Feedback; Hippocampus; Interneurons; Models, Neurological; Neurons, Efferent; Penicillins; Seizures; Strychnine; Synaptic Transmission; Time Factors

Topics: Acetates; Animals; Anticonvulsants; Cerebral Cortex; Chlorpromazine; Electroencephalography; Electroshock; Female; Male; Penicillins; Pentobarbital; Phenobarbital; Phenytoin; Rabbits; Seizures; Sound; Strychnine; Synaptic Transmission

Topics: Aluminum; Aminobutyrates; Animals; Bemegride; Central Nervous System Stimulants; Chlordiazepoxide; Chlorpromazine; Diazepam; Diphenhydramine; Electroencephalography; Ethers; Fluorine; Haplorhini; Hydroxides; Hydroxylamines; Isoflurophate; Pentylenetetrazole; Picrotoxin; Pyridoxine; Reserpine; Seizures; Semicarbazides; Strychnine

Topics: Age Factors; Animals; Liver; Proadifen; Rats; Seizures; Strychnine

Topics: Anesthetics; Animals; Antidotes; Ataxia; Electromyography; Isonicotinic Acids; Male; Mephenesin; Mice; Muscle Relaxants, Central; Paralysis; Phenobarbital; Rabbits; Seizures; Strychnine; Tetanus; Tetanus Toxin

Topics: Acetates; Aminobutyrates; Animals; Anticonvulsants; Body Temperature; Electroshock; Hydrazines; Injections, Intraperitoneal; Injections, Subcutaneous; Isoniazid; Male; Peptides; Rats; Rectum; Seizures; Strychnine; Thiosemicarbazones; Time Factors

Topics: Animals; Cats; Chlordiazepoxide; Denervation; Diazepam; Electric Stimulation; Evoked Potentials; Female; Injections, Intraperitoneal; Male; Mice; Picrotoxin; Reflex; Seizures; Solvents; Spinal Cord; Strychnine; Synapses; Time Factors

Topics: Animals; Depression, Chemical; Male; Mice; Neuromuscular Junction; Prostaglandins; Seizures; Strychnine; Time Factors

Topics: Absorption; Amphetamine; Animals; Blood Pressure; Central Nervous System; Depression; Drug Antagonism; Drug Synergism; Ethyl Ethers; Hexobarbital; Humans; Hyperkinesis; Indoles; Injections, Intraperitoneal; Mice; Pentylenetetrazole; Rabbits; Seizures; Serotonin; Strychnine

Topics: Animals; Biological Assay; Brain Chemistry; Cattle; Chromatography; Chromatography, Gel; Gastrointestinal Motility; Guinea Pigs; Ileum; In Vitro Techniques; Mice; Muscle, Smooth; Peptides; Reflex; Seizures; Strychnine; Substance P

Topics: Animals; Anura; Cats; Cerebral Cortex; Geniculate Bodies; Light; Mesencephalon; Models, Neurological; Neural Analyzers; Optic Lobe, Nonmammalian; Penicillins; Rabbits; Retina; Seizures; Strychnine; Synaptic Transmission; Tectum Mesencephali; Thalamus

Topics: Animals; Injections, Intravenous; Mice; Pilocarpine; Seizures; Stimulation, Chemical; Strychnine; Synaptic Transmission

Topics: Animals; Anticonvulsants; Blood Glucose; Carbonic Anhydrases; Central Nervous System; Central Nervous System Stimulants; Ligases; Male; Mice; Pentylenetetrazole; Phenobarbital; Rats; Seizures; Strychnine; Sulfonamides

Topics: Animals; Atropine; Barbiturates; Cyclopentanes; Depression, Chemical; Electric Stimulation; Male; Mephenesin; Mice; Pentylenetetrazole; Picrotoxin; Reflex; Seizures; Sleep; Spinal Cord; Strychnine

Topics: Action Potentials; Animals; Anura; Electric Stimulation; Electromyography; Motor Neurons; Muscles; Reflex; Seizures; Sodium Chloride; Spinal Cord; Stimulation, Chemical; Strychnine; Thalamus

1. The maturation of the convulsogenic activity of the caudal brainstem and spinal cord in the developing albino rat was studied by intraperitoneal injections of strychnine sulphate.2. The observed responses were classed as hyperexcitability and hypertonic responses, graded 1 to 4. The complete tonic seizure (grade 4 hypertonic reaction, strychnine tetanus, maximal response) was obtained in all age groups, from birth to adulthood. The responses were grouped in sequences, and two patterns were distinguished: an infant one (from birth to 3 weeks) and an adult one (from 3 weeks on).3. All doses varied according to age. The curve obtained for the median convulsive dose falls into two parts: descending, from birth to 3 weeks, and ascending, from 3 weeks on. Each part corresponded to a sequence pattern, the descending one to the infant pattern, and the ascending one to the adult pattern.4. From these patterns and the corresponding median effective doses, three stages of the convulsogenic maturation of the spinal cord were distinguished: immaturity, pharmacological maturity and convulsogenic maturity.5. It is suggested that the mechanism responsible for the complete tonic seizure is fully functional from birth, while that responsible for clonic seizure only reaches full maturity at 3 weeks of age.

Topics: Age Factors; Animals; Animals, Newborn; Cauda Equina; Female; Male; Rats; Seizures; Spinal Cord; Strychnine; Tetanus

Topics: Alkylation; Amphetamine; Animals; Central Nervous System; Drug Antagonism; Drug Synergism; Hexobarbital; Methods; Mice; Pyrimidinones; Reserpine; Seizures; Strychnine

Topics: Aminobutyrates; Animals; Body Temperature; Central Nervous System; Esters; Male; Mice; Motor Activity; Pentylenetetrazole; Rats; Seizures; Strychnine

Topics: Action Potentials; Animals; Brain; Cats; Electric Stimulation; Electroencephalography; Evoked Potentials; Pentylenetetrazole; Pineal Gland; Seizures; Strychnine; Tissue Extracts

Topics: Aminopyrine; Animals; Blood Transfusion; Cats; Electroencephalography; Picrotoxin; Seizures; Strychnine

Topics: Animals; Autoradiography; Blood Pressure; Blood-Brain Barrier; Brain; Capillary Permeability; Carbon Dioxide; Cats; Hypercapnia; Methionine Sulfoximine; Oxygen; Partial Pressure; Pentylenetetrazole; Seizures; Serum Albumin, Radio-Iodinated; Strychnine; Sulfates; Sulfur Isotopes

Topics: Analgesics; Animals; Benzazepines; Chlordiazepoxide; Diazepam; Drug Antagonism; Drug Synergism; Electroshock; Ethanol; Guinea Pigs; Mice; Morphine; Motor Activity; Neurons; Pentobarbital; Pentylenetetrazole; Rats; Seizures; Sleep; Strychnine

Topics: Aminobutyrates; Animals; Anura; Axons; Cerebral Cortex; Dendrites; Electric Stimulation; Electrophysiology; Evoked Potentials; Seizures; Strychnine; Synapses

Topics: Amitriptyline; Animals; Anticonvulsants; Cerebral Cortex; Humans; Imipramine; Mice; Pain; Paresthesia; Seizures; Strychnine; Trigeminal Neuralgia

Topics: Animals; Behavior, Animal; Chemistry, Organic; Electric Stimulation; Electrophysiology; Electroshock; Hexobarbital; Imides; Male; Mice; Naphthalenes; Organic Chemistry Phenomena; Pentylenetetrazole; Seizures; Sleep; Strychnine

Topics: Amides; Animals; Anticonvulsants; Behavior, Animal; Cats; Central Nervous System; Chemistry, Organic; Drug Antagonism; Electric Stimulation; Electrophysiology; Electroshock; Glutethimide; Hypnotics and Sedatives; Imides; Locomotion; Mice; Organic Chemistry Phenomena; Phenytoin; Seizures; Strychnine

Topics: Animals; Brain; Cats; Female; Liver; Male; Methocarbamol; Muscles; Nerve Tissue; Seizures; Strychnine; Sulfates; Sulfur Isotopes; Trimethadione

Topics: Animals; Behavior, Animal; Benzoates; Carbamates; Carisoprodol; Chlordiazepoxide; Chlormezanone; Chlorzoxazone; Dogs; Drug Antagonism; Electroshock; Male; Mephenesin; Meprobamate; Methocarbamol; Mice; Muscles; Pentobarbital; Phenethylamines; Phenobarbital; Phenytoin; Rats; Reflex; Seizures; Sleep; Strychnine; Trimethadione; Zoxazolamine

Topics: Alanine; Aminobutyrates; Animals; Atmospheric Pressure; Brain Chemistry; Hypertonic Solutions; Injections, Intraperitoneal; Male; Organ Size; Oxygen; Pentylenetetrazole; Picrotoxin; Potassium; Rats; Seizures; Sodium; Sodium Chloride; Strychnine; Succinates; Sucrose; Urea

Topics: Animals; Cerebral Cortex; Lysergic Acid Diethylamide; Rabbits; Seizures; Strychnine

Topics: Animals; Chronaxy; Dieldrin; Dimethyl Sulfoxide; In Vitro Techniques; Mice; Nervous System; Pentylenetetrazole; Phenytoin; Phrenic Nerve; Rats; Seizures; Strychnine; Tetany

Topics: Aging; Animals; Animals, Newborn; Central Nervous System; Male; Pentylenetetrazole; Radiation Effects; Rats; Seizures; Strychnine

Topics: Action Potentials; Anesthesia; Animals; Autonomic Agents; Cats; Caudate Nucleus; Chloralose; Decerebrate State; Drug Antagonism; Electroencephalography; Electroshock; Imidazoles; Male; Mice; Motor Activity; Paralysis; Pentylenetetrazole; Pyrimidines; Rabbits; Reflex; Respiration, Artificial; Seizures; Spinal Cord; Stimulation, Chemical; Strychnine; Zoxazolamine

Topics: Animals; Electroencephalography; Lysergic Acid Diethylamide; Rabbits; Seizures; Strychnine

Topics: Animals; Body Temperature; Central Nervous System; Environmental Exposure; Male; Mice; Pentylenetetrazole; Seizures; Stress, Physiological; Strychnine; Temperature; Thebaine

Topics: Animals; Cerebral Cortex; Cerebrovascular Circulation; Electroencephalography; Hypothalamus; Mesencephalon; Pentylenetetrazole; Rabbits; Seizures; Strychnine; Thalamus

Topics: Animals; Anticonvulsants; Cerebral Cortex; Electroshock; Mice; Penicillins; Pentylenetetrazole; Pyrrolidinones; Rabbits; Rats; Seizures; Strychnine

Topics: Acetylcholine; Animals; Autonomic Nervous System; Carbachol; Central Nervous System Stimulants; Histamine; Hormones; Indoles; Mice; Nicotine; Parasympathomimetics; Physostigmine; Pilocarpine; Piperazines; Pyridines; Pyrrolidines; Quaternary Ammonium Compounds; Seizures; Serotonin; Strychnine; Tremor; Tremorine; Tubocurarine

Topics: Aminobutyrates; Animals; Cats; Electroencephalography; Evoked Potentials; Hippocampus; Male; Picrotoxin; Seizures; Semicarbazides; Stereotaxic Techniques; Strychnine; Tubocurarine

Topics: 5-Hydroxytryptophan; Amphetamine; Animals; Anticonvulsants; Atropine; Azoles; Brain; Chlordiazepoxide; Chlorpromazine; Citrates; Dihydroxyphenylalanine; Disulfiram; Drug Antagonism; Drug Synergism; Kidney; Lysergic Acid Diethylamide; Male; Methyldopa; Mice; Morphine; Nialamide; Norepinephrine; Pargyline; Phenobarbital; Phenytoin; Reserpine; Seizures; Serotonin; Strychnine; Tetrabenazine; Trimethadione; Tyrosine; Urea

Topics: Animals; Anticonvulsants; Blood Pressure; Cocaine; Depression, Chemical; Heart; Higher Nervous Activity; Mescaline; Mice; Muscle Contraction; Pentylenetetrazole; Quinazolines; Seizures; Strychnine; Thiopental

Topics: Alcohols; Animals; Binding Sites; Body Temperature; Dextrans; Dialysis; Drug Synergism; Mice; Pentylenetetrazole; Povidone; Rectum; Seizures; Strychnine; Viscosity

Topics: Action Potentials; Animals; Anticonvulsants; Chlordiazepoxide; Diazepam; Electroencephalography; Female; Male; Morphine; Nicotine; Oxazepam; Phenobarbital; Phenytoin; Rabbits; Seizures; Strychnine

Topics: Animals; Cats; Electrophysiology; Heterocyclic Compounds; Muscle Spindles; Neuromuscular Junction; Paralysis; Parasympathomimetics; Physostigmine; Pilocarpine; Piperidines; Seizures; Strychnine; Synapses; Tachyphylaxis

Topics: Animals; Anticonvulsants; Bulgaria; Central Nervous System Stimulants; Electroshock; Mice; Plants, Medicinal; Rats; Seizures; Strychnine

Topics: Animals; Cats; Cerebral Cortex; Electrophysiology; Motor Neurons; Seizures; Strychnine

Topics: Aminobutyrates; Animals; Cats; Cerebral Cortex; Electric Stimulation; Electrophysiology; Seizures; Strychnine

Topics: Acetates; Adenosine Triphosphate; Aminobutyrates; Animals; Brain; Carboxy-Lyases; Electroconvulsive Therapy; In Vitro Techniques; Mice; Nerve Endings; Pentylenetetrazole; Picrotoxin; Seizures; Strychnine

Topics: Animals; Camphor; Drug Antagonism; Mice; Pentylenetetrazole; Saponins; Seizures; Spinal Cord; Strychnine

Topics: Animals; Anticonvulsants; Behavior, Animal; Chemistry, Organic; Dicarboxylic Acids; Drug Antagonism; Electric Stimulation; Electroshock; Fatty Acids; Hydrazines; Male; Mice; Organic Chemistry Phenomena; Seizures; Sleep; Stress, Physiological; Strychnine

Topics: Amygdala; Animals; Behavior, Animal; Body Temperature Regulation; Brain; Cats; Cerebral Cortex; Cerebral Ventricles; Desoxycorticosterone; Electrocardiography; Epinephrine; Gallamine Triethiodide; Hippocampus; Hypothalamus; Pentylenetetrazole; Perfusion; Reflex; Seizures; Shivering; Strychnine

Topics: Animals; Fractures, Bone; Paralysis; Rabbits; Seizures; Spinal Cord Injuries; Strychnine

Topics: Animals; Cats; Cerebrovascular Circulation; Electroencephalography; Krypton; Seizures; Strychnine

Topics: Aminopropionitrile; Animals; Anticonvulsants; Blood Circulation; Blood Pressure; Cats; Electroshock; Mice; Nicotine; Nitriles; Rats; Reflex; Seizures; Strychnine

Topics: Animals; Anura; Ascorbic Acid; Birds; Cats; Citrus; Fruit; Mice; Pharmacology; Poisoning; Rats; Research; Seizures; Strychnine; Toxicology

Topics: Aminobutyrates; gamma-Aminobutyric Acid; Pharmacology; Rats; Research; Seizures; Strychnine; Toxicology

Topics: Aminobutyrates; Brain; Cats; Cerebral Cortex; Electrophysiological Phenomena; Electrophysiology; gamma-Aminobutyric Acid; Pharmacology; Research; Seizures; Strychnine; Trichloroacetic Acid

Topics: Cats; Electrodes; Electroencephalography; Epilepsy; Research; Seizures; Somatosensory Cortex; Strychnine; Toxicology

Topics: Aminobutyrates; gamma-Aminobutyric Acid; Pharmacology; Rats; Research; Seizures; Strychnine; Synapses; Toxicology

Topics: Anticonvulsants; Electric Stimulation; Electroshock; Hydroxylamine; Hydroxylamines; Isoniazid; Mortality; Nervous System Physiological Phenomena; Pentylenetetrazole; Pharmacology; Rats; Reflex; Research; Seizures; Strychnine; Toxicology

Topics: Acetylcholine; Animals; Cats; Cerebral Cortex; Electrophysiology; Seizures; Stereotaxic Techniques; Strychnine; Tubocurarine

Topics: Brain; Carotid Sinus; Cats; Dogs; Electric Stimulation; Electroencephalography; Electrophysiology; Glossopharyngeal Nerve; Research; Reticular Formation; Seizures; Strychnine

Topics: Adrenal Glands; Animals; Brain Stem; Central Nervous System; Cerebral Cortex; Mice; Nerve Tissue; Oxygen; Pentylenetetrazole; Research; Seizures; Spinal Cord; Strychnine

Topics: Carotid Sinus; Cats; Electric Stimulation; Electrocardiography; Electroencephalography; Pharmacology; Research; Seizures; Strychnine; Toxicology; Vagus Nerve

Topics: Anticonvulsants; Electricity; Language; Mice; Pentylenetetrazole; Pharmacology; Plants, Medicinal; Rats; Research; Seizures; Strychnine; Toxicology

Topics: Animals; Brain Diseases; Brain Edema; Cerebral Cortex; Electrons; Injections, Intravenous; Microscopy; Microscopy, Electron; Rabbits; Research; Seizures; Strychnine

Topics: Aminobutyrates; Brain; Cats; Cerebral Cortex; Electromyography; Electrophysiological Phenomena; Electrophysiology; gamma-Aminobutyric Acid; Pharmacology; Research; Seizures; Strychnine

Topics: Anticonvulsants; Arisaema; Caffeine; Electric Injuries; Epilepsy; Mice; Pentylenetetrazole; Pharmacology; Plants, Medicinal; Research; Seizures; Strychnine

Topics: Acclimatization; Acetazolamide; Altitude; Anticonvulsants; Convulsants; Electric Stimulation; Neurophysiology; Pentylenetetrazole; Pharmacology; Phenytoin; Rats; Research; Seizures; Strychnine

Topics: Anticonvulsants; Cats; Chemistry, Pharmaceutical; Mice; Naphthalenes; Pentylenetetrazole; Pharmacology; Rats; Reflex; Research; Seizures; Strychnine; Toxicology

The actions of sodium 4-hydroxybutyrate, gamma-aminobutyric acid and meprobamate have been studied in unanaesthetized animals, in local anaesthetic tests, on isolated organ preparations, on convulsions induced by picrotoxin and strychnine, and on monosynaptic (patellar) and polysynaptic (plantar) reflexes of the spinal cord. Sodium 4-hydroxybutyrate induced a sleep-like state with three unusual features: the righting reflex was remarkably persistent, respiration was good throughout and recovery was abrupt. gamma-Aminobutyric acid was inactive and meprobamate caused flaccid paralysis with loss of the righting reflex. None of the agents affected the responses of the rat diaphragm either to direct stimulation of the muscle or to indirect stimulation through the phrenic nerve. Only meprobamate reduced the responses of theguinea-pig isolated ileum preparation, showed local anaesthetic action and had an anticonvulsant action. All three compounds were capable, after intravenous or topical application, of blocking plantar reflexes in doses which did not affect the patellar reflex. The spinal animal responded in the same way, to the same dose of sodium 4-hydroxybutyrate, as the decerebrate preparation. Topical application to the motor cortex had no effect on spinal reflexes. We conclude that sodium 4-hydroxybutyrate acts preferentially on the internuncial neurones in the spinal cord but differs from meprobamate in its other actions. The similarity between the actions of sodium 4-hydroxybutyrate and of gamma-aminobutyric acid provides furtherevidence in support of the hypothesis that sodium 4-hydroxybutyrate is involved in the gamma-aminobutyric acid metabolic pathways.

Topics: Aminobutyrates; Anesthesia; Anesthesia, Local; Anesthesiology; Animals; Blood Pressure Determination; Cats; Diaphragm; gamma-Aminobutyric Acid; Hydroxybutyrates; Injections, Intraperitoneal; Injections, Intravenous; Meprobamate; Mice; Nervous System Physiological Phenomena; Neuromuscular Junction; Pharmacology; Phrenic Nerve; Picrotoxin; Poultry; Rats; Reflex; Research; Seizures; Sodium; Sodium Oxybate; Spinal Cord; Strychnine; Swine; Toxicology

Topics: Atropine; Mice; Pharmacology; Research; Seizures; Sex; Strychnine; Testosterone; Toxicology

Topics: Mice; Pharmacology; Research; Seizures; Sex; Strychnine; Testosterone; Toxicology

Topics: Motor Neurons; Pathology; Picrotoxin; Rats; Research; Seizures; Spinal Cord; Strychnine; Tetanus Toxin; Toxicology

Topics: Aging; Animals, Newborn; Carisoprodol; Diphosphates; Hexobarbital; Insecticides; Liver; Meprobamate; Metabolism; Microsomes; NADP; Oxidoreductases; Pentobarbital; Pharmacology; Rats; Research; Seizures; Strychnine; Toxicology

Topics: Aminobutyrates; Anesthesia; Anesthesia, Intravenous; Behavior, Animal; Brain Chemistry; Cats; Chlorpromazine; Electroencephalography; Electroshock; gamma-Aminobutyric Acid; Hydroxylamines; Metabolism; Neuropharmacology; Pentobarbital; Pentylenetetrazole; Pharmacology; Phenytoin; Research; Reserpine; Seizures; Strychnine; Toxicology

Topics: Aminobutyrates; Bemegride; Benzene; Calcium; Central Nervous System Stimulants; Chlorides; Coronary Vessels; Electrocardiography; Epinephrine; Flavones; Flavonoids; Guinea Pigs; Heart; Nikethamide; Pentylenetetrazole; Pharmacology; Picrotoxin; Research; Seizures; Strychnine; Toxicology; Ventricular Fibrillation

Topics: Alkaloids; Animals; Birds; Cats; Cochlear Nerve; Cordotomy; Electric Stimulation; Electrocardiography; Electroencephalography; Gallamine Triethiodide; Paralysis; Pharmacology; Piperidines; Research; Seizures; Spinal Cord; Strychnine; Toxicology

Topics: Acetylcholine; Anesthesia; Atropine; Cholinesterase Inhibitors; Isoflurophate; Mice; Neostigmine; Pentylenetetrazole; Pharmacology; Phenobarbital; Physostigmine; Research; Seizures; Strychnine; Thiopental; Toxicology

Topics: Cardiovascular Agents; Humans; Muscle Relaxants, Central; Poisoning; Seizures; Strychnine; Suicidal Ideation; Suicide; Toxicology

Topics: Animals; Cell Nucleus; Cell Physiological Phenomena; Cytoplasm; Electrons; Endoplasmic Reticulum; Golgi Apparatus; Histological Techniques; Microscopy; Microscopy, Electron; Mitochondria; Motor Neurons; Neurons; Nissl Bodies; Rats; Research; Seizures; Spinal Cord; Strychnine; Toxicology

Topics: Acclimatization; Acetazolamide; Altitude; Anticonvulsants; Convulsants; Electricity; Electroshock; Pentylenetetrazole; Pharmacology; Phenytoin; Physiology; Rats; Research; Seizures; Strychnine; Toxicology

Topics: Animals; Azo Compounds; Benzimidazoles; Cats; Central Nervous System; Central Nervous System Depressants; Cricetinae; Dogs; Indoles; Lagomorpha; Mephenesin; Mice; Muscle Relaxants, Central; Phenylacetates; Pyrroles; Quinolines; Rabbits; Rats; Research; Seizures; Strychnine; Toxicology

Topics: Amphetamine; Amphetamines; Analgesics; Analgesics, Non-Narcotic; Antipyretics; Behavior, Animal; Blood Glucose; Body Temperature; Central Nervous System; Coumarins; Electroshock; Fluorescent Dyes; Hypnotics and Sedatives; Injections, Intraperitoneal; Mice; Neurochemistry; Pharmacology; Pyrazoles; Rabbits; Rats; Research; Respiration; Seizures; Stilbenes; Strychnine; Toxicology

Topics: Amygdala; Animals; Cats; Cerebral Cortex; Electroencephalography; Electromyography; Epilepsy; Eye Movements; Hippocampus; Limbic System; Seizures; Sleep; Strychnine

Topics: Acetylcholine; Animals; Cerebral Cortex; Electroencephalography; Epilepsy; Haplorhini; Research; Seizures; Strychnine

Topics: Anticonvulsants; Chemical Phenomena; Chemistry; Mice; Pentylenetetrazole; Pharmacology; Phenylurea Compounds; Rats; Research; Seizures; Strychnine

Topics: Animals; Anticonvulsants; Atropine; Bemegride; Central Nervous System Agents; Central Nervous System Stimulants; Chlorisondamine; Chlorpromazine; Diazepam; Mephenesin; Meprobamate; Mice; Pentylenetetrazole; Pharmacology; Phenobarbital; Phenytoin; Picrotoxin; Research; Seizures; Strychnine; Tranquilizing Agents

Topics: 4-Aminobenzoic Acid; Amides; Animals; Anticonvulsants; Antipsychotic Agents; Benzamides; Mice; Pentylenetetrazole; Research; Seizures; Strychnine

Topics: Atropine; Biuret; Chemistry, Pharmaceutical; Gastric Juice; Meprobamate; Mice; Nicotine; Pentylenetetrazole; Peptic Ulcer; Pharmacology; Phenformin; Phenobarbital; Picrotoxin; Rats; Research; Seizures; Strychnine; Toxicology; Urea

Topics: Animals; Anticonvulsants; Brain; Carbonic Anhydrase Inhibitors; Chemistry, Pharmaceutical; Mice; Pentylenetetrazole; Pharmacology; Research; Seizures; Strychnine; Sulfanilamide; Sulfanilamides; Sulfonamides

Topics: Animals; Anticonvulsants; Cardiovascular Agents; Mice; Muscle Relaxants, Central; Neuromuscular Agents; Seizures; Strychnine

Topics: Chemical Phenomena; Chemistry; Heterocyclic Compounds; Mice; Pharmacology; Rabbits; Research; Seizures; Strychnine; Toxicology

Topics: Aging; Animals; Rats; Seizures; Strychnine

Topics: Animals; Central Nervous System Agents; Pentylenetetrazole; Rats; Seizures; Sodium Fluoride; Strychnine

Injections of 20 to 30 mug. of 48/80 into the cerebral ventricular spaces of mice produced a condition of motor excitement termed "delirium ambulatorium." This condition was aggravated by previous intraperitoneal injection of tranquillizers, atropine, and promethazine, not affected by previous injection of mepyramine and abolished by a previous injection of pentobarbitone. When an intraperitoneal injection of strychnine was followed by an intraventricular injection of 48/80, the strychnine convulsions became more violent, but the pattern of delirium ambulatorium was not produced.

Topics: Animals; Atropine; Central Nervous System; Cerebral Ventricles; Histamine; Injections; Injections, Intraperitoneal; Injections, Intraventricular; Mice; Promethazine; Seizures; Strychnine

Topics: Aminopyrine; Convulsants; Pentylenetetrazole; Seizures; Strychnine; Tranquilizing Agents

Topics: Adrenalectomy; Animals; Pentylenetetrazole; Rats; Seizures; Sound; Strychnine

Topics: Animals; Electroencephalography; Lagomorpha; Rabbits; Seizures; Strychnine

Topics: Cholinesterases; Seizures; Strychnine

Topics: Aminopyrine; Anticonvulsants; Humans; Seizures; Strychnine

Topics: Epilepsy; Epinephrine; Seizures; Strychnine

Topics: Animals; Electrocardiography; Rabbits; Seizures; Strychnine

Topics: Anticonvulsants; Caffeine; Central Nervous System Depressants; Pentylenetetrazole; Seizures; Strychnine

Topics: Amphetamine; Amphetamines; Chlorpromazine; Cocaine; Histamine H1 Antagonists; Phenobarbital; Phenothiazines; Picrotoxin; Seizures; Strychnine

Topics: Antihypertensive Agents; Camphor; Pentylenetetrazole; Rauwolfia; Reserpine; Secologanin Tryptamine Alkaloids; Seizures; Strychnine

Topics: Electricity; Epilepsy; Humans; Seizures; Strychnine; Vestibule, Labyrinth

Topics: Contracture; Mephenesin; Seizures; Strychnine

Topics: 4-Aminobenzoic Acid; Seizures; Strychnine

Topics: Seizures; Strychnine

Topics: Electric Stimulation; Epilepsy; Extrapyramidal Tracts; Humans; Pyramidal Tracts; Seizures; Strychnine

Topics: Anticonvulsants; Seizures; Strychnine

Topics: Cell Nucleus; Piperidines; Seizures; Strychnine

Topics: Oxalates; Seizures; Strychnine

Topics: Anticonvulsants; Epilepsy; Humans; Infusions, Intravenous; Pentylenetetrazole; Seizures; Strychnine

Topics: Animals; Biological Assay; Biometry; Mice; Reference Standards; Seizures; Strychnine