piperidines and Seizures

The piperidin-4-ones have been reported as versatile intermediates. They have been synthesized using a variety of methods, including Mannich reaction and stereoselective synthesis. The piperidin-4-ones have been reported to possess various pharmacological activities, including anticancer and anti HIV activities. The pharmacophore can be suitably modified in order to achieve better receptor interactions and biological activities. The renewed interest in the nucleus has re-established the importance of piperidin-4-ones in medicinal chemistry. The review intends to discuss the current research trends in the synthetic protocols, characterization, stereochemistry and important biological activities of piperidin-4-ones during the last decade.

Topics: Anti-Bacterial Agents; Anti-HIV Agents; Anticonvulsants; Antineoplastic Agents; Antitubercular Agents; Bacteria; Cell Survival; HIV Integrase; Humans; Mycobacterium tuberculosis; Piperidines; Seizures; Stereoisomerism

Remifentanil is the newest of the fentanyl family of short-acting phenylpiperidine derivatives to be released into clinical practice. Remifentanil is a pure agonist at the mu opioid receptor with relatively little binding at the kappa, sigma or delta receptors. This is precisely the same profile as the other opioids currently popular in anaesthetic practice (fentanyl, alfentanil, sufentanil) and it offers the same advantages (profound analgesia, sedation, attenuation of the stress response). This has led to widespread use of remifentanil as an adjunct to general anaesthesia in a variety of clinical settings. The unique pharmacology of remifentanil, in particular its rapid offset, has more recently attracted clinicians and investigators to the use of remifentanil by bolus injection, especially for procedures requiring a brief, intense, opioid effect. The clinical effects of remifentanil, both therapeutic and adverse, are consistent with that of the other fentanyl congeners. However, the pharmacokinetic profile of remifentanil, that is, its rapid effect site equilibration, has also revealed a significant potential for therapeutic misadventure. The untoward effects of remifentanil, given by continuous infusion, are well-described in the literature. They are predictable and easily managed by experienced clinicians. This review will concentrate on the adverse effects of remifentanil given by bolus injection, either alone or in the context of a background infusion.

Topics: Analgesics, Opioid; Heart Rate; Humans; Injections, Intravenous; Muscle Rigidity; Piperidines; Remifentanil; Respiratory Insufficiency; Safety; Seizures

Remifentanil is a synthetic opioid that was developed in the early 1990s and introduced into clinical use in 1996. It is a methyl ester and is metabolised by nonspecific tissue and plasma esterases. Consequently, it is a drug that undergoes rapid elimination and has a reported terminal elimination half-life of between 10 and 35 minutes. Because there is no drug accumulation, the context-sensitive half-time remains constant; thus the pharmacokinetics of the drug do not change regardless of the duration of infusion. The organ-independent elimination of remifentanil, coupled with the fact that its clearance is greater in infants and neonates compared with older age groups, make its pharmacokinetic profile different from any other opioid. In addition, its unique metabolism confers predictability in its clinical use. Like other opioid mu receptor agonists, remifentanil provides dose-dependent analgesia, while the adverse effects of this drug, e.g. respiratory depression, are also thought to be dose related. The incidence of nausea and vomiting appear similar to other opioids. Its rapid and consistent metabolism regardless of duration of infusion has made remifentanil an attractive analgesic/anaesthetic option for paediatric care providers.

Topics: Analgesics, Opioid; Anesthesia, General; Anesthetics, Intravenous; Blood Pressure; Child; Heart Rate; Humans; Nausea; Piperidines; Remifentanil; Respiratory Insufficiency; Seizures; Vomiting

Today, organophosphorus nerve agents are still considered as potential threats in both military or terrorism situations. These agents act as potent irreversible inhibitors of acetylcholinesterase in both central and peripheral nervous systems. Conventional treatment of organophosphate poisoning includes the combined administration of a cholinesterase reactivator (an oxime), a muscarinic cholinergic receptor antagonist (atropine) and a benzodiazepine anticonvulsant (diazepam). However, numerous studies have demonstrated that the excitatory amino acid glutamate also plays a prominent role in the maintenance of organophosphate-induced seizures and in the subsequent neuropathology especially through an overactivation of the N-methyl-D-aspartate (NMDA) receptor subtype. Contrary to other non-competitive NMDA antagonists successfully tested in rodents exposed to organophosphate, gacyclidine is a novel antiNMDA compound which is in the process of approval for human use in France for neurotraumatology. This review summarizes the therapeutic value of gacyclidine as a complement to the available emergency treatment against severe organophosphate poisoning. Previous data obtained from experiments on primates in several scenarios mimicking military or terrorist attacks, using soman as the nerve agent, were used. Primates pretreated with pyridostigmine and receiving conventional emergency therapy at the first signs of poisoning survive. However, only gacyclidine is able to ensure complete management of nerve agent poisoning for rapid normalization of EEG activity, clinical recovery and neuroprotection. Gacyclidine also ensures optimal management of severe nerve agent poisoning in animals neither pretreated nor receiving emergency therapy likewise during an unexpected exposure. However, this beneficial effect is obtained provided that medical intervention is conducted rapidly after intoxication. Globally, the current lack of any other NMDA receptor antagonist suitable for human use reinforces the therapeutic value of gacyclidine as a central nervous system protective agent for the treatment of OP poisoning.

Topics: Animals; Cyclohexanes; Cyclohexenes; Excitatory Amino Acid Antagonists; Haplorhini; Humans; N-Methylaspartate; Organophosphorus Compounds; Piperidines; Receptors, N-Methyl-D-Aspartate; Seizures; Soman; Time Factors

Topics: Cisapride; Colonic Pseudo-Obstruction; Female; Humans; Middle Aged; Parasympathomimetics; Piperidines; Seizures; Serotonin Antagonists

Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are rare treatment-resistant childhood epilepsies classed as developmental and epileptic encephalopathies. ELEKTRA investigated the efficacy and safety of soticlestat (TAK-935) as adjunctive therapy in children with DS or LGS (NCT03650452).. ELEKTRA was a phase 2, randomized, double-blind, placebo-controlled study of soticlestat (≤300 mg twice daily, weight-adjusted) in children (aged 2-17 years) with DS, demonstrating three or more convulsive seizures/month, or with LGS, demonstrating four or more drop seizures/month at baseline. The 20-week treatment period comprised an 8-week dose-optimization period and a 12-week maintenance period. Efficacy endpoints included change from baseline in seizure frequency versus placebo. Safety assessments included incidence of treatment-emergent adverse events (TEAEs).. ELEKTRA enrolled 141 participants; 126 (89%) completed the study. The modified intent-to-treat population included 139 participants who received one or more doses of study drug and had one or more efficacy assessments (DS, n = 51; LGS, n = 88). ELEKTRA achieved its primary endpoint: the combined soticlestat-treated population demonstrated a placebo-adjusted median reduction in seizure frequency of 30.21% during the maintenance period (p = .0008, n = 139). During this period, placebo-adjusted median reductions in convulsive and drop seizure frequencies of 50.00% (p = .0002; patients with DS) and 17.08% (p = .1160; patients with LGS), respectively, were observed. TEAE incidences were similar between the soticlestat (80.3%) and placebo (74.3%) groups and were mostly mild or moderate in severity. Serious TEAEs were reported by 15.5% and 18.6% of participants receiving soticlestat and placebo, respectively. TEAEs reported in soticlestat-treated patients with ≥5% difference from placebo were lethargy and constipation. No deaths were reported.. Soticlestat treatment resulted in statistically significant, clinically meaningful reductions from baseline in median seizure frequency (combined patient population) and in convulsive seizure frequency (DS cohort). Drop seizure frequency showed a nonstatistically significant numerical reduction in children with LGS. Soticlestat had a safety profile consistent with previous studies.

Topics: Anticonvulsants; Child; Double-Blind Method; Epilepsies, Myoclonic; Epileptic Syndromes; Humans; Lennox Gastaut Syndrome; Piperidines; Pyridines; Seizures; Spasms, Infantile; Treatment Outcome

Intravenous immunoglobulin (IVIg) has been a candidate as a potential anti-amyloid immunotherapy for Alzheimer disease (AD) because it contains anti-amyloid β (Aβ) antibodies. Although several studies with IVIg in AD have been published, changing levels of Aβ efflux from the brain, or disaggregation of Aβ species induced by immunotherapy, have not been properly investigated. Here, we carried out an open label study of therapy with IVIg in five patients with AD. We collected plasma from a peripheral vein (peripheral-plasma) and from the internal jugular vein (jugular-plasma) to estimate directly the efflux of soluble Aβ from the brain. We also measured high molecular weight (HMW) Aβ oligomers in CSF as a marker to detect disaggregated Aβ. IVIg infusions were well tolerated in the majority of cases. However, one study subject had epileptic seizures after IVIg. Levels of HMW CSF Aβ oligomers in all participants were significantly increased after IVIg. Aβ40 and Aβ42 levels in jugular-plasma were continuously or temporarily elevated after treatment in three of five patients who showed preserved cognitive function, whereas levels of those in peripheral-plasma did not correlate with reactivity to the treatment. Other conventional biomarkers including 11C-Pittsburgh compound B retention were not altered after the treatment. These findings imply that HMW Aβ oligomer levels could be a better biomarker to reflect the anti-amyloid effects of IVIg than conventional Aβ species; moreover, Aβ in jugular-plasma seems to be a more direct and precise biomarker to estimate clearance of Aβ from the brain rather than Aβ in peripheral-plasma.. UMIN000022319.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Brain; Cognition; Donepezil; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunoglobulins, Intravenous; Immunologic Factors; Indans; Jugular Veins; Male; Mental Status Schedule; Middle Aged; Nootropic Agents; Piperidines; Positron-Emission Tomography; Seizures; Treatment Outcome

To compare the anaesthetic and convulsive effects of sevoflurane/remifentanil versus propofol/remifentanil combination in electroconvulsive therapy (ECT).. In this prospective, randomized double-blind study, patients diagnosed with treatment-resistant depression were included for ECT. Prior to treatment, 1 µg/kg remifentanil was intravenously administered to all patients, followed by anaesthetic induction with either 0.5 mg/kg propofol or 8% sevoflurane. Following muscular paralysis with succinylcholine and hypnosis, bitemporal ECT was applied. Vital signs, depth of sedation, recovery parameters, motor and electroencephalography (EEG) convulsion activity and postictal suppression index scores were recorded.. A total of 120 sessions of ECT were administered to 12 patients. Heart rate was higher in the sevoflurane group than the propofol group. Compared with the sevoflurane group, bispectral index level was lower in the propofol group during the induction period and higher during the recovery period. Anaesthetic induction and recovery times were lower, and average motor and EEG convulsion activity was longer, in the propofol group than in the sevoflurane group.. Propofol/remifentanil is more successful compared with sevoflurane/remifentanil in anaesthesia management during ECT since it provides quick induction and recovery, longer seizure activity and stable haemodynamics.

Topics: Adult; Double-Blind Method; Drug Therapy, Combination; Electroconvulsive Therapy; Female; Hemodynamics; Humans; Male; Methyl Ethers; Middle Aged; Piperidines; Propofol; Remifentanil; Seizures; Sevoflurane

Magnetoencephalography (MEG) provides source localization of interictal spikes. We use total intravenous anesthesia (TIVA) with propofol to immobilize uncooperative children. We evaluate the effect of TIVA on interictal spikes in children who have intractable epilepsy with or without MRI lesions.. We studied 28 children (3-14 years; mean, 6.6). We intravenously administered propofol (30-60 microg/kg/min) to record MEG with simultaneous EEG. We evaluated MEG spike sources (MEGSSs). We compared spikes on simultaneous EEG under TIVA with those on scalp video-EEG without TIVA.. There was a significant decrease in frequent spikes (10 patients, 36%) on simultaneous EEG under TIVA compared to those (22 patients, 79%) on scalp video-EEG without TIVA (P<0.01). MEGSSs were present in 21 (75%) of 28 patients. Clustered MEGSSs occurred in 15 (83%) of 18 lesional patients but in 3 (30%) of 10 nonlesional patients (P<0.05). MEGSSs were more frequently absent in nonlesional (6 patients, 60%) than lesional (one patient, 5%) patients (P<0.01). Thirteen patients with MRI and/or histopathologically confirmed neuronal migration disorder most frequently showed clustered MEGSSs (11 patients, 85%) compared to those of other lesional and nonlesional patients.. Propofol-based TIVA reduced interictal spikes on simultaneous EEG. TIVA for MEG still had utility in identifying spike sources in a subset of pediatric patients with intractable epilepsy who were uncooperative and surgical candidates. In lesional patients, MEG under TIVA frequently localized the clustered MEGSSs. Neuronal migration disorders were intrinsically epileptogenic and produced clustered MEGSSs under TIVA. Nonlesional patients often had no MEGSS under TIVA.

Topics: Action Potentials; Adolescent; Anesthesia, Intravenous; Anesthetics, Intravenous; Brain; Brain Mapping; Child; Child, Preschool; Electroencephalography; Epilepsies, Partial; Epilepsy; Epilepsy, Generalized; Female; Humans; Magnetic Resonance Imaging; Magnetoencephalography; Male; Piperidines; Propofol; Remifentanil; Seizures

Among the drugs used for the induction of anesthesia for electroconvulsive therapy (ECT), thiopental induces a greater degree of cardiovascular alteration than other agents. Remifentanil has been found to reduce blood pressure and heart rate when administered as an adjuvant during general anesthesia, with unknown effects on the duration of motor or electroencephalographic seizure activity during ECT. The purpose of this prospective, randomized, double-blind, placebo-controlled, crossover study was to evaluate the effects of supplementing thiopental anesthesia with remifentanil on convulsion duration and cardiovascular response during ECT.. Twenty-four American Society of Anesthesiologists I and II patients receiving 6 sessions of ECT were randomly allocated to 2 groups. All patients were premedicated with atropine (0.4 mg, intravenously), then anesthesia was induced by thiopental (1.0 mg/kg), succinylcholine (0.5 mg/kg), and remifentanil (1.0 microg/kg) in the case group or normal saline (3 mL) in the control group in a crossover format. Stimulus amplitude for applying ECT was kept constant during the sessions of treatment in the course of study for each patient. Hemodynamic parameters, convulsion duration, and recovery parameters were recorded. Statistical analysis was done using paired t tests.. There was no statistically significant difference between the groups regarding convulsion duration, recovery times to eye opening, obeying specific commands, and walking without help. Remifentanil significantly attenuated the increase in heart rate and arterial blood pressure (P < 0.05).. Remifentanil (1 microg/kg) administered before thiopental (1 mg/kg) has no adverse effect on the duration of ECT-induced convulsion and recovery time, but it can attenuate the increase in heart rate and arterial blood pressure.

Topics: Adolescent; Adult; Anesthesia; Blood Pressure; Double-Blind Method; Electroconvulsive Therapy; Female; Heart Rate; Hemodynamics; Humans; Hypnotics and Sedatives; Male; Middle Aged; Piperidines; Prospective Studies; Remifentanil; Seizures; Thiopental; Young Adult

Propofol may decrease seizure duration in electroconvulsive therapy. Although not proven, prolonged seizures may be more efficacious. The goal of this study was to evaluate and compare effects of alfentanil and remifentanil on seizure duration, recovery parameters and degree of stimulus amplitude in patients undergoing electroconvulsive therapy.. Twenty-four ASA I-II patients enrolled in this prospective, randomized trial, each receiving a total of seven electroconvulsive therapies. Patients were randomized to receive only Propofol, group P (0.75 mg kg-1, n=8), Propofol with alfentanil, group A (10 microg kg-1 alfentanil+0.5 mg kg-1 Propofol, n=8) and Propofol with remifentanil, group R (1 microg kg-1 remifentanil +0.5 mg kg-1 propofol, n=8) via an iv route. Supplemental doses of propofol were given as required to achieve loss of consciousness. Succinylcholine 0.5 mg kg-1 iv was given to all groups for muscular paralysis. We recorded hemodynamic parameters, cortical and motor seizure durations, and recovery parameters.. Mean motor seizure duration was found to be significantly longer in patients receiving propofol-remifentanil anesthesia (53.3+/-13.6 s) and propofol-alfentanil anesthesia (52.2+/-0.4 s) compared with propofol anesthesia (37.6+/-9.2 s) (P=0.001). Recovery parameters and stimulus amplitudes were similar in groups A and R; significantly different from group P (P=0.001).. Adding 10 microg kg-1 alfentanil or 1 microg kg-1 remifentanil to reduced doses of propofol provided unconsciousness and increased seizure durations. For patients who need higher stimulus amplitudes for longer seizure durations, combining low-dose propofol with alfentanil or remifentanil may be good alternative regimens for ECT.

Topics: Adult; Aged; Alfentanil; Analgesics, Opioid; Anesthesia Recovery Period; Anesthetics, Combined; Anesthetics, Intravenous; Dose-Response Relationship, Drug; Electroconvulsive Therapy; Female; Hemodynamics; Humans; Male; Middle Aged; Neuromuscular Depolarizing Agents; Piperidines; Propofol; Prospective Studies; Remifentanil; Seizures; Succinylcholine; Time Factors

The object of this study was to test whether substituting part of the methohexital dose with the short-acting opioid remifentanil would prolong seizure duration in middle-aged patients while providing a similar depth of anesthesia as with methohexital alone. This has been reported for the combined use of methohexital and remifentanil in elderly patients, but has not been investigated in middle-aged patients likely to require a higher total dose of methohexital for inducing anesthesia.. Seven patients (42+/-10 years; mean +/-SD) receiving electroconvulsive therapy (ECT) were anesthetized with methohexital (1.25 mg kg-1) or with methohexital (0.625 mg kg-1) plus remifentanil (1 micro g kg-1) in this randomized, double blind, crossover study. Additional methohexital was given as needed until loss of eyelash reflex was observed. Suxamethonium (1 mg kg-1) was used for muscular paralysis.. Motor and EEG seizure durations were significantly longer after induction with methohexital plus remifentanil (45+/-14 and 58+/-15 s) than with methohexital alone (31+/-11 and 42+/-18 s). A methohexital dose of 1.2+/-0.3 and 1.9+/-0.3 mg was necessary to achieve loss of eyelash reflex if methohexital was used with and without remifentanil. Peak heart rate after ECT was significantly higher if remifentanil was coadministered with methohexital (148+/-12 vs. 126+/-24 b.p.m).. Substituting part of the methohexital dose with remifentanil is a useful anesthetic technique to prolong seizure duration in middle-aged patients requiring a 1.5-fold higher induction dose of methohexital than elderly patients, the only population studied to date for the combined use of methohexital and remifentanil in ECT.

Topics: Adult; Anesthesia; Cross-Over Studies; Double-Blind Method; Electroconvulsive Therapy; Female; Heart Rate; Humans; Male; Methohexital; Middle Aged; Piperidines; Remifentanil; Seizures; Time Factors

The formation of 24S-hydroxycholesterol is a brain-specific mechanism of cholesterol catabolism catalyzed by cholesterol 24-hydroxylase (CYP46A1, also known as CH24H). CH24H has been implicated in various biological mechanisms, whereas pharmacological lowering of 24S-hydroxycholesterol has not been fully studied. Soticlestat is a novel small-molecule inhibitor of CH24H. Its therapeutic potential was previously identified in a mouse model with an epileptic phenotype. In the present study, the anticonvulsive property of soticlestat was characterized in rodent models of epilepsy that have long been used to identify antiseizure medications.. The anticonvulsive property of soticlestat was investigated in maximal electroshock seizures (MES), pentylenetetrazol (PTZ) acute seizures, 6-Hz psychomotor seizures, audiogenic seizures, amygdala kindling, PTZ kindling, and corneal kindling models. Soticlestat was characterized in a PTZ kindling model under steady-state pharmacokinetics to relate its anticonvulsive effects to pharmacodynamics.. Among models of acutely evoked seizures, whereas anticonvulsive effects of soticlestat were identified in Frings mice, a genetic model of audiogenic seizures, it was found ineffective in MES, acute PTZ seizures, and 6-Hz seizures. The protective effects of soticlestat against audiogenic seizures increased with repetitive dosing. Soticlestat was also tested in models of progressive seizure severity. Soticlestat treatment delayed kindling acquisition, whereas fully kindled animals were not protected. Importantly, soticlestat suppressed the progression of seizure severity in correlation with 24S-hydroxycholesterol lowering in the brain, suggesting that 24S-hydroxycholesterol can be aggressively reduced to produce more potent effects on seizure development in kindling acquisition.. The data collectively suggest that soticlestat can ameliorate seizure symptoms through a mechanism distinct from conventional antiseizure medications. With its novel mechanism of action, soticlestat could constitute a novel class of antiseizure medications for treatment of intractable epilepsy disorders such as developmental and epileptic encephalopathy.

Topics: Animals; Anticonvulsants; Cholesterol 24-Hydroxylase; Disease Models, Animal; Epilepsy; Kindling, Neurologic; Mice; Pentylenetetrazole; Piperidines; Pyridines; Seizures

Studies have shown that brain histamine has a role in seizure pathophysiology. Histamine acts by four distinct receptor subtypes (H1R-H4R). Previous reports signified the anticonvulsant activity of histamine H3R antagonists. We evaluated the effect of intra-amygdala injection of pitolisant the H3R inverse agonist on seizures induced by the electrical kindling model of epilepsy. Eighteen adult male rats with an approximate weight of 300 g were used. A tri-polar electrode twisted with the guide cannula, and two monopolar electrodes were implanted into the basolateral amygdala or the surface of the skull using stereotaxic surgery. One week after surgery, the threshold was determined in the animals. Twenty-four hours afterward, the animals received six stimuli daily with the threshold intensity until the generation of three consecutive stages five seizures. Then, saline, and 24 h later, pitolisant at three doses (1, 10, and 100 μg) were injected into the amygdala in distinct rats. Thirty minutes after injection of the drug or its solvent, seizure parameters including after-discharge duration (ADD), seizure stage (SS), and stage five duration (S5D) were recorded. Data analysis indicated that pitolisant reduced S5D at all doses, significantly. Pitolisant at the dose of 100 µg also decreased ADD and SS, significantly. However, pitolisant at the doses of 1 and 10 µg did not change ADD and SS. The dose-response curves showed that the anticonvulsant activity of pitolisant changed in a dose-dependent manner. In conclusion, the results confirmed the powerful anticonvulsant effects of pitolisant in the electrical kindling model of epilepsy.

Topics: Animals; Anticonvulsants; Epilepsy; Histamine; Histamine Agonists; Histamine Antagonists; Kindling, Neurologic; Male; Piperidines; Rats; Receptors, Histamine H3; Seizures

Therapies for epilepsy mainly provide symptomatic control of seizures since most of the available drugs do not target disease mechanisms. Moreover, about one-third of patients fail to achieve seizure control. To address the clinical need for disease-modifying therapies, research should focus on targets which permit interventions finely balanced between optimal efficacy and safety. One potential candidate is the brain-specific enzyme cholesterol 24-hydroxylase. This enzyme converts cholesterol to 24S-hydroxycholesterol, a metabolite which among its biological roles modulates neuronal functions relevant for hyperexcitability underlying seizures. To study the role of cholesterol 24-hydroxylase in epileptogenesis, we administered soticlestat (TAK-935/OV935), a potent and selective brain-penetrant inhibitor of the enzyme, during the early disease phase in a mouse model of acquired epilepsy using a clinically relevant dose. During soticlestat treatment, the onset of epilepsy was delayed and the number of ensuing seizures was decreased by about 3-fold compared to vehicle-treated mice, as assessed by EEG monitoring. Notably, the therapeutic effect was maintained 6.5 weeks after drug wash-out when seizure number was reduced by about 4-fold and their duration by 2-fold. Soticlestat-treated mice showed neuroprotection of hippocampal CA1 neurons and hilar mossy cells as assessed by post-mortem brain histology. High throughput RNA-sequencing of hippocampal neurons and glia in mice treated with soticlestat during epileptogenesis showed that inhibition of cholesterol 24-hydroxylase did not directly affect the epileptogenic transcriptional network, but rather modulated a non-overlapping set of genes that might oppose the pathogenic mechanisms of the disease. In human temporal lobe epileptic foci, we determined that cholesterol 24-hydroxylase expression trends higher in neurons, similarly to epileptic mice, while the enzyme is ectopically induced in astrocytes compared to control specimens. Soticlestat reduced significantly the number of spontaneous seizures in chronic epileptic mice when was administered during established epilepsy. Data show that cholesterol 24-hydroxylase contributes to spontaneous seizures and is involved in disease progression, thus it represents a novel target for chronic seizures inhibition and disease-modification therapy in epilepsy.

Topics: Animals; Cholesterol; Cholesterol 24-Hydroxylase; Disease Models, Animal; Epilepsy; Epilepsy, Temporal Lobe; Hippocampus; Humans; Mice; Piperidines; Pyridines; RNA; Seizures

Early post-stroke seizure frequently occurs in stroke survivors within the first few days and is associated with poor functional outcomes. Therefore, efficient treatments of such complications with less adverse effects are pivotal. In this study, we investigated the possible beneficial effects of lasmiditan and sumatriptan against post-stroke seizures in mice and explored underlying mechanisms in their effects.. Stroke was induced by double ligation of the right common carotid artery in mice. Immediately after the ligation, lasmiditan (0.1 mg/kg, intraperitoneally [i.p.]) or sumatriptan (0.03 mg/kg, i.p.) were administered. Twenty-four hours after the stroke induction, seizure susceptibility was evaluated using the pentylenetetrazole (PTZ)-induced clonic seizure model. In separate experiments, naltrexone (a non-specific opioid receptor antagonist) and glibenclamide (a K. Lasmiditan (0.1 mg/kg, i.p.) and sumatriptan (0.03 mg/kg, i.p.) remarkably decreased seizure susceptibility in stroke animals by reducing inflammatory cytokines and neuronal apoptosis. Concurrent administration of naltrexone (10 mg/kg, i.p.) or glibenclamide (0.3 mg/kg, i.p.) with lasmiditan or sumatriptan resulted in a higher neuroprotection against clonic seizures and efficiently reduced the inflammatory and apoptotic markers.. Lasmiditan and sumatriptan significantly increased post-stroke seizure thresholds in mice by suppressing inflammatory cytokines and neuronal apoptosis. Lasmiditan and sumatriptan seem to exert higher effects on seizure threshold with concurrent administration of the opioid receptors or K

Topics: Adenosine Triphosphate; Animals; Anticonvulsants; bcl-2-Associated X Protein; Benzamides; Disease Models, Animal; Dose-Response Relationship, Drug; Glyburide; Mice; Models, Theoretical; Naltrexone; Narcotic Antagonists; Neuroprotective Agents; Pentylenetetrazole; Piperidines; Potassium Channel Blockers; Potassium Channels; Pyridines; Receptors, Opioid; Seizures; Stroke; Sumatriptan; Tumor Necrosis Factor-alpha

Dravet syndrome is a severe developmental and epileptic encephalopathy (DEE) most often caused by de novo pathogenic variants in SCN1A. Individuals with Dravet syndrome rarely achieve seizure control and have significantly elevated risk for sudden unexplained death in epilepsy (SUDEP). Heterozygous deletion of Scn1a in mice (Scn1a. In this study, the novel compound soticlestat, a CH24H inhibitor, was administered to Scn1a. Soticlestat treatment reduced seizure burden, protected against hyperthermia-induced seizures, and completely prevented SUDEP in Scn1a. This study demonstrates that soticlestat-mediated inhibition of CH24H provides therapeutic benefit for the treatment of Dravet syndrome in mice and has the potential for treatment of DEEs.

Topics: Animals; Cholesterol 24-Hydroxylase; Epilepsies, Myoclonic; Epilepsy; Epileptic Syndromes; Mice; Mortality, Premature; Mutation; NAV1.1 Voltage-Gated Sodium Channel; Piperidines; Pyridines; Seizures; Seizures, Febrile; Sudden Unexpected Death in Epilepsy

Based on the biological importance of the thiazole nucleus, we decided to prepare and evaluate the biological activity of some new isatin derivatives containing thiazole moiety. The 5-(piperidin-1-ylsulfonyl)indoline-2,3-dione (1) was prepared and used as a starting material in the synthesis of many isatin derivatives for anticonvulsant evaluation. All the newly synthesized thiazlidino/thiosemicarbazide-indolin-2-one derivatives screened in vivo for their anticonvulsant activity against pentylenetetrazole-induced convulsions in mice. The results were compared with phenobarbitone sodium as a standard anticonvulsant drug. Most of the tested compounds exhibited anticonvulsant activity with relative potency ranging from 0.02 to 0.2 in comparison to standard drug phenobarbitone. The most active compounds 3, 6a, 6c and 8, were exposed to further investigations in rats to evaluate the effect of most active derivatives on the haematological, liver, kidney functions as well as histopathological studies of the liver and kidney tissues. Finally, the most potent compounds 3, 6a, 6c and 8 observed good toxic properties for both liver and kidney function with mild variability changes on RBCs, WBCs, Platelets, Hb, AST, ALT, and creatinine level, as well as kidney and liver tissue and these good results obtained rather than used low dose from phenobarbitone.

Topics: Animals; Anticonvulsants; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Injections, Intraperitoneal; Male; Mice; Molecular Structure; Oxindoles; Pentylenetetrazole; Piperidines; Seizures; Structure-Activity Relationship; Thiazoles; Thiosemicarbazones

Mounting evidence suggests that modulation of cannabinoid 2 receptors (CB2Rs) is therapeutic in mouse models of neurological disorders, including neuropathic pain, neurodegenerative disease, and stroke. We previously showed that reducing CB2R activity increases seizure susceptibility in mice. In the present study, we evaluated the therapeutic potential of the CB2R positive allosteric modulator, Ec21a, against induced seizures in mice. The pharmacokinetic profile of Ec21 demonstrated a similar distribution in brain and plasma, with detection up to 12 h following injection. Ec21a increased resistance to induced seizures in CF1 wild-type mice and mice harboring the SCN1A R1648H human epilepsy mutation. A rotarod test provided evidence that Ec21a does not cause neurotoxicity-induced motor deficits at its therapeutic dose, and seizure protection was maintained with repeated drug administration. The selectivity of Ec21a for CB2R was supported by the ability of the CB2R antagonist AM630, but not the CB1R antagonist AM251, to block Ec21a-conferred seizure protection in mice, and a lack of significant binding of Ec21a to 34 brain-expressed receptors and transporters in vitro. These results identify allosteric modulation of CB2Rs as a promising therapeutic approach for the treatment of epilepsy.

Topics: Allosteric Regulation; Animals; Benzeneacetamides; Cannabinoids; Indoles; Male; Mice; Mice, Transgenic; Piperidines; Pyrazoles; Pyridines; Receptor, Cannabinoid, CB2; Rotarod Performance Test; Seizures

Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are the most recognized omega-3 unsaturated fatty acids showing neuroprotective activity in animal and clinical studies. Docosahexaenoyl ethanolamide (DHEA) and eicosapentaenoyl ethanolamide (EPEA) are non-oxygenated endogenous metabolites of DHA and EPA, which might be in charge of the anti-seizure activity of the parent molecules. We examined the effect of these metabolites on the threshold of clonic seizures induced by pentylenetetrazole (PTZ). DHEA and EPEA possess similar chemical structure to the endogenous cannabinoids. Therefore, involvement of cannabinoid (CB) receptors in the anti-seizure effect of these metabolites was also investigated. DHA, DHEA, EPEA, AM251 (CB1 receptor antagonist), and AM630 (CB2 receptor antagonist) were administered to mice by intracerebroventricular (i.c.v.) route. Threshold of clonic seizures was determined 10 and/or 15 min thereafter by intravenous infusion of PTZ. The effect of DHA and DHEA on seizure threshold was then determined in mice, which were pretreated with AM251 and/or AM630. DHA (300μM), and DHEA (100 and 300 μM) significantly increased seizure threshold, 15 (p < 0.05) and 10 min (p < 0.01) after administration, respectively. DHEA was more potent than its parent lipid, DHA in decreasing seizure susceptibility. EPEA (300 and 1000 μM) did not change seizure threshold. AM251 fully prevented the increasing effect of DHA and DHEA on seizure threshold (p < 0.05). AM630 did not inhibit the effect of DHA and DHEA on seizure threshold. This is the first report indicating that DHEA but not EPEA, possesses anti-seizure action via activating CB1 receptors. DHEA is more potent than its parent ω-3 fatty acid DHA in diminishing seizure susceptibility.

Topics: Animals; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Docosahexaenoic Acids; Fatty Acids, Omega-3; Indoles; Male; Mice; Pentylenetetrazole; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Seizures

The total synthesis of both the double bond isomers of indolizine alkaloid 8-deoxypumiliotoxin 193H has been accomplished. Both the double bond isomers Z-4 and E-4 induced convulsions and inhibited neuro-muscular activity at a dose of 25 mg/kg after intraperitoneal injection in mice. The lethal dose of Z-4 and E-4 was 100 mg/kg, indicating that 8-deoxypumiliotoxin 193H is 10-times less toxic than the known pumiliotoxin (+)-251 D.

Topics: Alkaloids; Animals; Body Temperature; Dose-Response Relationship, Drug; Indolizines; Injections, Intraperitoneal; Isomerism; Male; Mice, Inbred Strains; Muscle Strength; Piperidines; Rotarod Performance Test; Seizures; Structure-Activity Relationship

Epilepsy of infancy with migrating focal seizures (EIMFS) is one of the early-onset epileptic encephalopathies resistant to antiepileptic drugs, therefore carrying an extremely poor neurodevelopmental outcome. KCNT1, encoding for a sodium-activated potassium channel (K. Our case was an infant diagnosed with EIMFS with confirmed mutation in KCNT1 gene. Quinidine therapy was started as early as 9 months old. Within the first month of treatment, the number of seizures reduced to about one third. However, seizure-free state was not obtained and his neuropsychological development remained severely delayed. After 16 months of treatment, quinidine had to be discontinued because of cardiac side effects. At 27 months of age, however, his seizures suddenly stopped and he remained seizure-free for five days. This coincided with the prescription of tipepidine, a commonly used antitussive, administered for his persistent cough. Reduction in seizure frequency was also observed with dextromethorphan, another conventional antitussive drug. Although the relation between these treatments and his symptom improvement is a matter of elucidation, there is a possibility that these nonnarcotic antitussive drugs might play a role in the treatment of EIFMS.

Topics: Antitussive Agents; Dextromethorphan; Electroencephalography; Epilepsy; Humans; Infant; Magnetic Resonance Imaging; Male; Mutation; Nerve Tissue Proteins; Piperidines; Potassium Channels, Sodium-Activated; Quinidine; Seizures; Treatment Failure; Treatment Outcome

Topics: Animals; Antioxidants; Brain-Derived Neurotrophic Factor; Cytoskeletal Proteins; Epilepsy; Ergothioneine; Gene Knockout Techniques; HEK293 Cells; Humans; Male; Mice, Inbred C57BL; Nerve Tissue Proteins; Organic Cation Transport Proteins; Pentylenetetrazole; Piperidines; Seizures; Symporters; Xenobiotics

Abnormalities in social behavior are a co-morbid symptom of idiopathic generalized epilepsies such as childhood absence epilepsy. The Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model is a spontaneously occurring absence epilepsy phenotype closely correlated to that of human absence epilepsies. Similar to the human conditions, GAERS display social abnormalities. Previous studies have only demonstrated social abnormalities in female GAERS, whereas social problems are observed in male and female patients. Seizures in GAERS result in part due to a gain-of-function missense mutation in the Cav3.2 T-type calcium channel gene. This study examined the effects of the pan-T-type calcium channel antagonist, Z944, on social interaction behaviors in male and female GAERS using an open field social interaction test. A second objective of this study was to examine the effects of Z944 on anxiety-like behavior in an open field locomotion test and elevated plus maze. Results showed a decrease in social activity in GAERS relative to non-epileptic control (NEC) rats. Acute, systemic Z944 (5 mg/kg; i.p.) consistently reduced introductory and aggressive behaviors in both GAERS and NECs whereas strain effects were observed for over-and-under crawl behaviors. In the open field locomotion test and elevated plus maze, Z944 increased anxiety-like behaviors in GAERS, whereas, Z944 produced inconsistent effects on anxiety-like behaviors in NECs. The results of this study suggest that the regulation of T-type calcium channel activity may be a useful strategy for the development of new therapeutic approaches for the treatment of social and affective abnormalities observed in absence epilepsy disorders.

Topics: Animals; Anxiety; Behavior, Animal; Brain; Calcium Channel Blockers; Calcium Channels, T-Type; Disease Models, Animal; Electroencephalography; Epilepsy, Absence; Epilepsy, Generalized; Female; Locomotion; Male; Piperidines; Rats; Rats, Wistar; Seizures; Social Behavior

STXBP1 and SCN2A gene mutations are observed in patients with epilepsies, although the circuit basis remains elusive. Here, we show that mice with haplodeficiency for these genes exhibit absence seizures with spike-and-wave discharges (SWDs) initiated by reduced cortical excitatory transmission into the striatum. Mice deficient for Stxbp1 or Scn2a in cortico-striatal but not cortico-thalamic neurons reproduce SWDs. In Stxbp1 haplodeficient mice, there is a reduction in excitatory transmission from the neocortex to striatal fast-spiking interneurons (FSIs). FSI activity transiently decreases at SWD onset, and pharmacological potentiation of AMPA receptors in the striatum but not in the thalamus suppresses SWDs. Furthermore, in wild-type mice, pharmacological inhibition of cortico-striatal FSI excitatory transmission triggers absence and convulsive seizures in a dose-dependent manner. These findings suggest that impaired cortico-striatal excitatory transmission is a plausible mechanism that triggers epilepsy in Stxbp1 and Scn2a haplodeficient mice.

Topics: Action Potentials; Animals; Anticonvulsants; Corpus Striatum; Dioxoles; Electroencephalography; Epilepsy, Absence; Ethosuximide; Gene Expression Regulation; Haploinsufficiency; Interneurons; Mice; Mice, Knockout; Munc18 Proteins; NAV1.2 Voltage-Gated Sodium Channel; Neocortex; Neural Pathways; Piperidines; Receptors, AMPA; Seizures; Signal Transduction; Synaptic Transmission; Thalamus

This study aimed to investigate whether 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), a soluble epoxide hydrolase inhibitor with anti-inflammatory effects, could alleviate spontaneous recurrent seizures (SRS) and epilepsy-associated depressive behaviours in the lithium chloride (LiCl)-pilocarpine-induced post-status epilepticus (SE) rat model.. The rats were intraperitoneally (IP) injected with LiCl (127 mg/kg) and pilocarpine (40 mg/kg) to induce SE. A video surveillance system was used to monitor SRS in the post-SE model for 6 weeks (from the onset of the 2nd week to the end of the 7th week after SE induction). TPPU (0.1 mg/kg/d) was intragastrically given for 4 weeks from the 21st day after SE induction in the SRS + 0.1 TPPU group. The SRS + PEG 400 group was given the vehicle (40% polyethylene glycol 400) instead, and the control group was given LiCl and PEG 400 but not pilocarpine. The sucrose preference test (SPT) and forced swim test (FST) were conducted to evaluate the depression-like behaviours of rats. Immunofluorescent staining, enzyme-linked immunosorbent assay, and western blot analysis were performed to measure astrocytic and microglial gliosis, neuronal loss, and levels of soluble epoxide hydrolase (sEH), cytokines [tumour necrosis factor alpha (TNF-α), interleukin (IL)-1β, and IL-6], and cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB).. The frequency of SRS was significantly decreased at 6 weeks and 7 weeks after SE induction in the 0.1TPP U group compared with the SRS + PEG 400 group. The immobility time (IMT) evaluated by FST was significantly decreased, whereas the climbing time (CMT) was increased, and the sucrose preference rate (SPR) evaluated by SPT was in an increasing trend. The levels of sEH, TNF-α, IL-1β, and IL-6 in the hippocampus (Hip) and prefrontal cortex (PFC) were all significantly increased in the SRS + PEG 400 group compared with the control group; neuronal loss, astrogliosis, and microglial activation were also observed. The astrocytic and microglial activation and levels of the pro-inflammatory cytokines in the Hip and PFC were significantly attenuated in the TPPU group compared with the SRS + PEG 400 group; moreover, neuronal loss and the decreased CREB expression were significantly alleviated as well.. TPPU treatment after SE attenuates SRS and epilepsy-associated depressive behaviours in the LiCl-pilocarpine induced post-SE rat model, and it also exerts anti-inflammatory effects in the brain. Our findings suggest a new therapeutic approach for epilepsy and its comorbidities, especially depression.

Topics: Animals; Astrocytes; Brain; Depression; Depressive Disorder; Disease Models, Animal; Epilepsy; Epoxide Hydrolases; Hippocampus; Lithium Chloride; Male; Microglia; Neurons; Phenylurea Compounds; Pilocarpine; Piperidines; Rats; Rats, Sprague-Dawley; Seizures; Status Epilepticus; Tumor Necrosis Factor-alpha

2-Arachidonoylglycerol (2-AG) and anandamide are two major endocannabinoids produced, released and eliminated by metabolic pathways. Anticonvulsive effect of 2-AG and CB1 receptor is well-established. Herein, we designed to investigate the anticonvulsive influence of key components of the 2-AG and anandamide metabolism. Tonic-clonic seizures were induced by an injection of Pentylenetetrazol (80 mg/kg, i.p.) in adult male Wistar rats. Delay and duration for the seizure stages were considered for analysis. Monoacylglycerol lipase blocker (JJKK048; 1 mg/kg) or alpha/beta hydroxylase domain 6 blocker (WWL70; 5 mg/kg) were administrated alone or with 2-AG to evaluate the anticonvulsive potential of these enzymes. To determine the CB1 receptor involvement, its blocker (MJ15; 3 mg/kg) was administrated associated with JJKK048 or WWL70. To assess anandamide anticonvulsive effect, anandamide membrane transporter blocker (LY21813240; 2.5 mg/kg) was used alone or associated with MJ15. Also, fatty acid amide hydrolase blocker (URB597; 1 mg/kg; to prevent intracellular anandamide hydrolysis) were used alone or with AMG21629 (transient receptor potential vanilloid; TRPV1 antagonist; 3 mg/kg). All compounds were dissolved in DMSO and injected i.p., before the Pentylenetetrazol. Both JJKK048 and WWL70 revealed anticonvulsive effect. Anticonvulsive effect of JJKK048 but not WWL70 was CB1 receptor dependent. LY2183240 showed CB1 receptor dependent anticonvulsive effect. However, URB597 revealed a TRPV1 dependent proconvulsive effect. It seems extracellular accumulation of 2-AG or anandamide has anticonvulsive effect through the CB1 receptor, while intracellular anandamide accumulation is proconvulsive through TRPV1.

Topics: Amidohydrolases; Animals; Arachidonic Acids; Disease Models, Animal; Endocannabinoids; Glycerides; Male; Pentylenetetrazole; Piperidines; Polyunsaturated Alkamides; Rats, Wistar; Receptor, Cannabinoid, CB1; Seizures; TRPV Cation Channels

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

We have previously demonstrated that blockade of T-type calcium channels by the non-selective antagonist, ethosuximide (ETX), is effective at reducing electrographical and behavioral correlates of alcohol-withdrawal (WD) seizure. Here, we investigated whether blockade of these calcium channels with the selective antagonist TTA-P2 also reduces alcohol-WD seizure.. The non-specific T-type calcium channel antagonist, ETX, is protective against alcohol-WD seizure. However, the mechanism of this effect is unclear. Here, we provide evidence that further suggests selective blockade of T-type calcium channels are protective against alcohol-WD seizure and WD-related mortality.. We used an intermittent ethanol exposure model to produce WD-induced hyperexcitability in DBA/2 J mice. Seizure severity was intensified with the chemoconvulsant pentylenetetrazole (PTZ).. TTA-P2 (10 mg/kg) reduced seizure severity in mice undergoing alcohol WD with concurrent PTZ treatment (20 mg/kg). Moreover, TTA-P2 (20 and 40 mg/kg) was also protective against PTZ-induced (40 mg/kg) seizure and mortality.. These results are consistent with prior results using ETX, and suggest that the protective effects of ETX and TTA-P2 against EtOH WD seizures are mediated by T-type calcium channels.

Topics: Alcohol Withdrawal Seizures; Animals; Benzamides; Calcium Channel Blockers; Calcium Channels, T-Type; Dose-Response Relationship, Drug; Ethanol; Male; Mice; Mice, Inbred DBA; Pentylenetetrazole; Piperidines; Seizures

Acetaminophen is one of the most commonly used analgesic and antipyretic drugs. It has been reported that acetaminophen has anticonvulsant effects in several animal models of seizure. An active metabolite of acetaminophen, AM404, inhibits the uptake of the endocannabinoid anandamide. However, the mechanism of the anticonvulsant effect of acetaminophen is unknown.. This study was performed to examine whether or not acetaminophen can protect against pentylenetetrazol-induced kindling in mice and to investigate the precise mechanisms of the anticonvulsant effect of acetaminophen using the fully kindled mouse models.. Repeated administration of acetaminophen significantly delayed the progression of seizure severity induced by pentylenetetrazol. Additionally, acetaminophen showed a dose-dependent anticonvulsant activity against fully pentylenetetrazol-kindled seizures. AM404 also exhibited a dose-dependent anticonvulsant activity in fully kindled animals. The anticonvulsant activity of acetaminophen was antagonized by capsazepine and AMG9810, two transient receptor potential vanilloid-1 (TRPV1) antagonists. However, the transient receptor potential ankyrin 1 (TRPA1) antagonist HC030031 and CB1 receptor antagonist AM251 had no effect.. These findings suggest that acetaminophen has an anticonvulsant effect in pentylenetetrazol-kindled mouse models and TRPV1 mediates the anticonvulsant action.

Topics: Acetaminophen; Acetanilides; Acrylamides; Animals; Anticonvulsants; Bridged Bicyclo Compounds, Heterocyclic; Capsaicin; Disease Models, Animal; Dose-Response Relationship, Drug; Kindling, Neurologic; Male; Mice; Mice, Inbred ICR; Pentylenetetrazole; Piperidines; Purines; Pyrazoles; Seizures; Time Factors; TRPV Cation Channels

Stressful conditions affect the brain's neurotransmission and neural pathways that are involved in seizure susceptibility. Stress alters the intensity and/or frequency of seizures. Although evidence indicates that chronic stress exerts proconvulsant effects and acute stress has anticonvulsant properties, the underlying mechanisms which mediate these effects are not well understood. In the present study, we assessed the role of endogenous opioids, endocannabinoids, as well as functional interaction between opioid and cannabinoid systems in the anticonvulsant effects of acute foot-shock stress (FSS) against pentylenetetrazole (PTZ)-induced seizures in mice.. Prolonged intermittent FSS was chosen as an acute stress model. Seizure threshold was determined after 30 min of stress induction in male Naval Medical Research Institute (NMRI) mice (20-30 g). Opioid and cannabinoid receptor antagonists were administered before animal placement in the FSS apparatus.. Opioid and cannabinoid systems are involved in the anticonvulsant effects of acute FSS, and these neurotransmission systems interact functionally in response to acute FSS.

Topics: Analgesics, Opioid; Animals; Cannabinoid Receptor Antagonists; Convulsants; Disease Models, Animal; Electroshock; Male; Mice; Naltrexone; Narcotic Antagonists; Pentylenetetrazole; Piperidines; Pyrazoles; Receptors, Cannabinoid; Seizures; Stress, Psychological

Despite the availability of multiple antiepileptic drugs (AED), failure to adequately control seizures is a challenge for approximately one third of epilepsy patients, and new therapies with a differentiated mechanism of action are needed. The neuroactive steroid, SGE-516, is a positive allosteric modulator of both gamma- and delta-containing GABA

Topics: Action Potentials; Animals; Anticonvulsants; Convulsants; Disease Models, Animal; Electroshock; Fragile X Mental Retardation Protein; gamma-Aminobutyric Acid; Hippocampus; Kindling, Neurologic; Male; Mice; Mice, Knockout; Pentylenetetrazole; Piperidines; Potassium Channel Blockers; Pregnanolone; Rats; Rats, Sprague-Dawley; Seizures

Recent data demonstrated that activation of the muscarinic M

Topics: Allosteric Regulation; Amphetamine; Animals; Ataxia; Diarrhea; Dogs; Donepezil; Drug Design; Female; Humans; Indans; Isoindoles; Lactams; Male; Mice, Inbred C57BL; Microsomes, Liver; Oxazoles; Piperidines; Rats, Wistar; Receptor, Muscarinic M1; Scopolamine; Seizures; Structure-Activity Relationship; Sulfonamides; Thiadiazoles; Vomiting

Cannabidiol (CBD) is a phytocannabinoid that has demonstrated anticonvulsant efficacy in several animal models of seizure. The current experiment validated CBD's anticonvulsant effect using the acute pentylenetetrazol (PTZ) model. Furthermore, it tested whether CBD reduces seizure activity by interacting with either the serotonergic 5HT1A or 5HT2A receptor. 120 male adolescent Wistar-Kyoto rats were randomly assigned to 8 treatment groups in two consecutive experiments. In both experiments, subjects received either CBD (100mg/kg) or vehicle 60min prior to seizure testing. In Experiment 1, subjects received either WAY-100635 (1mg/kg), a 5HT1A antagonist, or saline vehicle injection 80min prior to seizure testing. In Experiment 2, subjects received either MDL-100907 (0.3mg/kg), a specific 5HT2A antagonist, or 40% DMSO vehicle 80min prior to seizure testing. 85mg/kg of PTZ was administered to induce seizure, and behavior was recorded for 30min. Seizure behaviors were subsequently coded using a 5-point scale of severity. Across both experiments, subjects in the vehicle control groups exhibited high levels of seizure activity and mortality. In both experiments, CBD treatment significantly attenuated seizure activity. Pre-treatment with either WAY-100635 or MDL-100907 did not block CBD's anticonvulsant effect. WAY-100635 administration, by itself, also led to a significant attenuation of seizure activity. These results do not support the hypothesis that CBD attenuates seizure activity through activation of the 5HT1A or 5HT2A receptor. While this work further confirms the anticonvulsant efficacy of CBD and supports its application in the treatment of human seizure disorders, additional research on CBD's mechanism of action must be conducted.

Topics: Animals; Anticonvulsants; Cannabidiol; Fluorobenzenes; Male; Pentylenetetrazole; Piperazines; Piperidines; Pyridines; Rats; Rats, Inbred WKY; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT2A; Seizures; Serotonin 5-HT1 Receptor Antagonists; Serotonin 5-HT2 Receptor Antagonists; Treatment Outcome

Mutations in the Cyclin-dependent kinase-like 5 (CDKL5) gene cause severe neurodevelopmental disorders accompanied by intractable epilepsies, i.e. West syndrome or atypical Rett syndrome. Here we report generation of the Cdkl5 knockout mouse and show that CDKL5 controls postsynaptic localization of GluN2B-containing N-methyl-d-aspartate (NMDA) receptors in the hippocampus and regulates seizure susceptibility. Cdkl5 -/Y mice showed normal sensitivity to kainic acid; however, they displayed significant hyperexcitability to NMDA. In concordance with this result, electrophysiological analysis in the hippocampal CA1 region disclosed an increased ratio of NMDA/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated excitatory postsynaptic currents (EPSCs) and a significantly larger decay time constant of NMDA receptor-mediated EPSCs (NMDA-EPSCs) as well as a stronger inhibition of the NMDA-EPSCs by the GluN2B-selective antagonist ifenprodil in Cdkl5 -/Y mice. Subcellular fractionation of the hippocampus from Cdkl5 -/Y mice revealed a significant increase of GluN2B and SAP102 in the PSD (postsynaptic density)-1T fraction, without changes in the S1 (post-nuclear) fraction or mRNA transcripts, indicating an intracellular distribution shift of these proteins to the PSD. Immunoelectron microscopic analysis of the hippocampal CA1 region further confirmed postsynaptic overaccumulation of GluN2B and SAP102 in Cdkl5 -/Y mice. Furthermore, ifenprodil abrogated the NMDA-induced hyperexcitability in Cdkl5 -/Y mice, suggesting that upregulation of GluN2B accounts for the enhanced seizure susceptibility. These data indicate that CDKL5 plays an important role in controlling postsynaptic localization of the GluN2B-SAP102 complex in the hippocampus and thereby regulates seizure susceptibility, and that aberrant NMDA receptor-mediated synaptic transmission underlies the pathological mechanisms of the CDKL5 loss-of-function.

Topics: Animals; Disease Models, Animal; Disease Susceptibility; Excitatory Amino Acid Antagonists; Guanylate Kinases; Hippocampus; Kainic Acid; Membrane Proteins; Mice, Inbred C57BL; Mice, Knockout; N-Methylaspartate; Piperidines; Post-Synaptic Density; Protein Serine-Threonine Kinases; Receptors, N-Methyl-D-Aspartate; RNA, Messenger; Seizures; Tissue Culture Techniques

Topics: Adrenergic alpha-2 Receptor Antagonists; Animals; Anticonvulsants; Axons; Body Temperature; Brain; Drug Evaluation, Preclinical; Epilepsy, Post-Traumatic; Imidazoles; Male; Motor Activity; Neuronal Plasticity; Neuroprotective Agents; Piperidines; Proof of Concept Study; Pyrazoles; Random Allocation; Rats, Sprague-Dawley; Recovery of Function; Rimonabant; Seizures; Spatial Memory

Seizure duration in electroconvulsive therapy (ECT) is positively related with patients' outcome. This study sought to investigate the impact of anesthetic management on seizure duration, and the impact of selected drugs (theophylline, remifentanil, S-ketamine) on seizure duration.. Retrospective analysis of all patients undergoing ECT at our institution from January 2011 to April 2012 was performed based on electronic medical chart and review of existing quality improvement data. Patient data (N = 78), including gender, age, height, weight, and administered drugs, energy levels, and electroencephalic seizure duration were analyzed. Statistical analysis was performed using a generalized linear model.. A total of 78 patients (male = 39, female = 39, age 51 ± 12 years) were included. Average number of session was 10 ± 6 (1-30). In our patient population, theophylline administration was the only parameter, which significantly prolonged seizure duration, whereas S-ketamine, remifentanil, thiopental, age, sex, session or energy level had no significant effect.. Theophylline can be a useful adjunct for patients with inadequate seizure duration. If there is a concomitant beneficial effect on patients' outcome needs to be investigated in further studies.

Topics: Anesthetics, Intravenous; Dose-Response Relationship, Drug; Drug Therapy, Combination; Electroconvulsive Therapy; Electroencephalography; Etomidate; Female; Humans; Ketamine; Male; Middle Aged; Piperidines; Remifentanil; Retrospective Studies; Seizures; Theophylline; Thiopental; Time Factors

Topics: Animals; Dose-Response Relationship, Drug; Dronabinol; Electroencephalography; Electromyography; Indoles; Locomotion; Mice; Naphthalenes; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Seizures

Epileptic seizures are short episodes of abnormal brain electrical activity. Many survivors of severe epilepsy display delayed neuronal death and permanent cognitive impairment. Donepezil is an acetylcholinesterase inhibitor and is an effective treatment agent for Alzheimer's disease. However, the role of donepezil in seizure-induced hippocampal injury remains untested. Temporal lobe epilepsy (TLE) was induced by intraperitoneal injection of pilocarpine (25 mg/kg). Donepezil (2.5 mg/kg/day) was administered by gavage in three different settings: (1) pretreatment for three days before the seizure; (2) for one week immediately after the seizure; and (3) for three weeks from three weeks after the seizure. We found that donepezil showed mixed effects on seizure-induced brain injury, which were dependent on the treatment schedule. Pretreatment with donepezil aggravated neuronal death, oxidative injury, and microglia activation. Early treatment with donepezil for one week showed neither adverse nor beneficial effects; however, a treatment duration of three weeks starting three weeks after the seizure showed a significant reduction in neuronal death, oxidative injury, and microglia activation. In conclusion, donepezil has therapeutic effects when injected for three weeks after seizure activity subsides. Therefore, the present study suggests that the therapeutic use of donepezil for epilepsy patients requires a well-conceived strategy for administration.

Topics: Animals; Cell Death; Cholinesterase Inhibitors; Disease Models, Animal; Donepezil; Drug Administration Schedule; Epilepsy, Temporal Lobe; Hippocampus; Indans; Male; Neurons; Nootropic Agents; Oxidative Stress; Pilocarpine; Piperidines; Rats, Sprague-Dawley; Seizures

A 24-year-old woman at 29 weeks' gestation, and with psychiatric symptoms, was admitted to hospital and diagnosed as having anti-N-methyl-D-aspartate receptor encephalitis. After 4 weeks of immunotherapy with little effect, an emergency cesarean section was performed at 33

Topics: Anesthesia, General; Anti-N-Methyl-D-Aspartate Receptor Encephalitis; Cesarean Section; Female; Humans; Infant, Newborn; Piperidines; Pregnancy; Remifentanil; Seizures; Young Adult

Topics: Bipolar Disorder; Electroconvulsive Therapy; Electroencephalography; Humans; Hypertension; Hypnotics and Sedatives; Male; Middle Aged; Piperidines; Remifentanil; Seizures

Cannabinoid CB1 antagonists have been investigated for possible treatment of e.g. obesity-related disorders. However, clinical application was halted due to their symptoms of anxiety and depression. In addition to these adverse effects, we have shown earlier that chronic treatment with the CB1 antagonist rimonabant may induce EEG-confirmed convulsive seizures. In a regulatory repeat-dose toxicity study violent episodes of "muscle spasms" were observed in Wistar rats, daily dosed with the CB1 receptor antagonist SLV326 during 5 months. The aim of the present follow-up study was to investigate whether these violent movements were of an epileptic origin. In selected SLV326-treated and control animals, EEG and behavior were monitored for 24 hours. 25% of SLV326 treated animals showed 1 to 21 EEG-confirmed generalized convulsive seizures, whereas controls were seizure-free. The behavioral seizures were typical for a limbic origin. Moreover, interictal spikes were found in 38% of treated animals. The frequency spectrum of the interictal EEG of the treated rats showed a lower theta peak frequency, as well as lower gamma power compared to the controls. These frequency changes were state-dependent: they were only found during high locomotor activity. It is concluded that long term blockade of the endogenous cannabinoid system can provoke limbic seizures in otherwise healthy rats. Additionally, SLV326 alters the frequency spectrum of the EEG when rats are highly active, suggesting effects on complex behavior and cognition.

Topics: Animals; Behavior, Animal; Brain; Cannabinoid Receptor Antagonists; Electroencephalography; Female; Male; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Rimonabant; Seizures

Changes in rhythmic activity can serve as early biomarkers of pathological alterations, but it remains unclear how different types of rhythmic activity are altered during neurodegenerative processes. Glutamatergic neurotoxicity, evoked by kainic acid (KA), causes hyperexcitation and acute seizures that result in delayed brain damage. We employed wide frequency range (0.1-300Hz) local field potential recordings in guinea pigs to study the oscillatory activity of the hippocampus, entorhinal cortex, medial septum, and amygdala in healthy animals for three months after KA introduction. To clarify whether the activation of endocannabinoid (eCB) system can influence toxic KA action, AM404, an eCB reuptake inhibitor, and URB597, an inhibitor of fatty acid amide hydrolase, were applied. The cannabinoid CB1 receptor antagonist AM251 was also tested. Coadministration of AM404 or URB597 with KA reduced acute behavioral seizures, but electrographic seizures were still registered. During the three months following KA injection, various trends in the oscillatory activities were observed, including an increase in activity power at all frequency bands in the hippocampus and a progressive long-term decrease in the medial septum. In the KA- and KA/AM251-treated animals, disturbances of the oscillatory activities were accompanied by cell loss in the dorsal hippocampus and mossy fiber sprouting in the dentate gyrus. Injections of AM404 or URB597 softened alterations in electrical activity of the brain and prevented hippocampal neuron loss and synaptic reorganization. Our results demonstrate the protective potential of the eCB system during excitotoxic influences.

Topics: Amygdala; Animals; Brain; Dentate Gyrus; Endocannabinoids; Guinea Pigs; Hippocampus; Kainic Acid; Neurons; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Seizures; Status Epilepticus

Objective To observe changes of serum neuron specific enolase (NSE) level in children patients with epilepsy by additional use of ilepcimide (piperine derivative). Methods Totally 107 epilepsy children patients were assigned to the test group (77 cases) and the control group (30 cases) ac- cording to random digit table. Children patients in the control group received anti-epileptic Western drugs only. Those in the test group additionally took ilepcimide, 5 mg/kg per day as initial dose, taken in two times. The dose was gradually added to those without control of epilepsy attack. Added dose within a week should not exceed 10 mg/kg per day. The therapeutic course for all was one year. Electoencephalo- gram (EEG) was performed before treatment, half a year after treatment, and one year after treatment, respectively. Serum NSE level was detected using electrochemiluminescence. Efficacy was assessed after 1-year treatment. Results The total effective rate was 65. 0% (50177) in the test group, with statistical difference as compared with that in the control group [30. 0% (9/30), P <0. 01 ]. Compared with before treatment, serum NES-level obviously decreased in the test group after 0. 5-year treatment and 1- year treatment respectively (P <0. 05, P <0. 01). Besides, serum NES level was lower after 1-year treatment than after 0. 5-year treatment (P <0. 05, P <0. 01). There was no statistical difference in serum NES level between the test group and the control group at each time point (P >0. 05). Results of EEG were obviously superior in the test group (3 with normal range EEG, 5 critically abnormal EEG, 69 abnormal EEG) to the control group (2 with normal range EEG and 75 abnormal EEG) after 1-year treatment, with statistical difference (Z= -2. 33, P <0. 05). There was no statistical difference in EEG results of the control group between before treatment (all abnormal EEG) and after 1-year treatment (3 critically abnormal EEG and 27 abnormal EEG) (Z = -1. 732, P > 0. 05). Conclusion Adding ilepcimide (piperine derivative) for epilepsy children patients could lower serum NSE level and the frequency of seizures, and improve results of EEG.

Topics: Child; Drugs, Chinese Herbal; Electroencephalography; Epilepsy; Humans; Phosphopyruvate Hydratase; Piperidines; Seizures

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

Dugesia tigrina is a non-parasitic platyhelminth, which has been recently utilized in pharmacological models, regarding the nervous system, as it presents a wide sensitivity to drugs. Our trials aimed to propose a model for an in vivo screening of substances with inhibitory activity of the enzyme acetylcholinesterase. Trials were performed with four drugs commercialized in Brazil: donepezil, tacrine, galantamine and rivastigmine, utilized in the control of Alzheimer's disease, to inhibit the activity of acetylcholinesterase. We tested five concentrations of the drugs, with an exposure of 24 h, and the mortality and the inhibition of acetylcholinesterase planarian seizure-like activity (pSLA) and planarian locomotor velocity (pLMV) were measured. Galantamine showed high anticholinesterasic activity when compared to the other drugs, with a reduction of 0.05 μmol·min(-1) and 63% of convulsant activity, presenting screw-like movement and hypokinesia, with pLMV of 65 crossed lines during 5 min. Our results showed for the first time the anticholinesterasic and convulsant effect, in addition to the decrease in locomotion induced by those drugs in a model of invertebrates. The experimental model proposed is simple and low cost and could be utilized in the screening of substances with anticholinesterasic action.

Topics: Animals; Cholinesterase Inhibitors; Convulsants; Donepezil; Galantamine; Indans; Locomotion; Models, Biological; Piperidines; Planarians; Rivastigmine; Seizures; Survival Rate; Tacrine

It remains unclear how infantile febrile seizures (FS) enhance adult seizure susceptibility. Here we showed that the transient increase of interleukin-1β (IL-1β) after prolonged FS promoted adult seizure susceptibility, which was blocked by interleukin-1 receptor antagonist (IL-1Ra) within a critical time window. Postnatal administered IL-1β alone mimicked the effect of FS on adult seizure susceptibility. IL-1R1 knockout mice were not susceptible to adult seizure after prolonged FS or IL-1β treatment. Prolonged FS or early-life IL-1β treatment increased the expression of cannabinoid type 1 receptor (CB1R) for over 50 days, which was blocked by IL-1Ra or was absent in IL-1R1 knockout mice. CB1R antagonist, knockdown and endocannabinoid synthesis inhibitor abolished FS or IL-1β-enhanced seizure susceptibility. Thus, this work identifies a pathogenic role of postnatal IL-1β/IL-1R1 pathway and subsequent prolonged prominent increase of endocannabinoid signaling in adult seizure susceptibility following prolonged FS, and highlights IL-1R1 as a potential therapeutic target for preventing the development of epilepsy after infantile FS.

Topics: Aging; Animals; Benzoxazines; Cannabinoid Receptor Antagonists; Cyclohexanones; Gene Expression Regulation; Hippocampus; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-1beta; Lipoprotein Lipase; Mice; Mice, Knockout; Morpholines; Naphthalenes; Piperidines; Pyrazoles; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Rimonabant; RNA, Small Interfering; Seizures; Seizures, Febrile; Signal Transduction; Tissue Culture Techniques

In order to optimise outcome to Electro Convulsive therapy (ECT), there has been a trend to utilise remifentanil as an adjunct to standard intravenous induction agents. This has allowed a reduction in the dose of anaesthetic agent, and usually an improved response to stimulation. However there have been no previous studies to ascertain whether this improvement is simply as a result of the reduced dose of anaesthetic agent or whether remifentanil itself might possess epileptogenic properties. This retrospective case-controlled study examined ECT outcomes, determined by EEG quality analysis, in patients who received ECT with or without remifentanil, where there was no dose reduction in the anaesthetic agent. There were no improvements seen in the measurements of any EEG parameter, including seizure duration. These observations suggest that remifentanil does not possess any intrinsic pro-convulsant activity and that any improvement in outcome seen with its use is as a result of dose reduction in the IV anaesthetic agent.

Topics: Adult; Aged; Case-Control Studies; Electroconvulsive Therapy; Electroencephalography; Female; Humans; Male; Middle Aged; Piperidines; Propofol; Remifentanil; Retrospective Studies; Seizures; Thiopental

Studies have reported that co-adjuvant remifentanil can enhance electroconvulsive therapy (ECT) seizure quality, putatively by allowing a reduction in the dosage of the main anaesthetic agents, as the latter have anticonvulsant properties. However, whether remifentanil also has direct effects on ECT seizure quality, and by implication, treatment efficacy, is unknown. This is the first study examining the effect of adjuvant remifentanil on ECT seizure quality when the dose of conventional anaesthesia remained unchanged. A total of 96 ECT sessions (from 36 patients) were retrospectively analysed. Subjects received ECT with and without remifentanil (1 µg/kg), while the dose of thiopentone (3-5 mg/kg) or propofol (1-2 mg/kg) was unchanged. Seizure quality indices (time to slow wave activity or TSLOW, amplitude, regularity, stereotypy, post-ictal suppression) and duration were assessed through a structured rating scale by a single trained blinded rater. Linear mixed-effects models with random subject effects analysed the effect of remifentanil on seizure parameters, controlling for other variables that can affect seizure quality or duration. Remifentanil was given in 47.9 % of the ECT sessions. Co-adjuvant remifentanil had no effects on any of the seizure quality parameters analysed [TSLOW (E = -0.21, p > 0.1), amplitude (E = 0.08, p > 0.5), regularity (E = -0.05, p > 0.5), stereotypy (E = -0.02, p > 0.5), suppression (E = -0.3, p > 0.05)] or on seizure duration (E = -0.25, p > 0.1). While adjuvant remifentanil may be a useful strategy for reducing anaesthetic dosage in ECT, present evidence suggests that remifentanil does not have intrinsic properties that enhance ECT seizures.

Topics: Adult; Aged; Cohort Studies; Electroconvulsive Therapy; Electroencephalography; Female; Humans; Hypnotics and Sedatives; Male; Middle Aged; Piperidines; Proportional Hazards Models; Reaction Time; Remifentanil; Seizures; Treatment Outcome; Young Adult

N-(2,6-Dichlorophenyl)-2-(4-methyl-1-piperidinyl)acetamide (LIA), a lidocaine analogue, has potential applications in treating neuropathic pain. The aim of this work was to characterize the pharmacological activity of LIA related with central nervous system and cardiovascular activity.. Anesthetic effect was tested in guinea pigs and mice. Ambulatory activity, anti-anxiety effect, sodium pentobarbital (PB)-induced hypnosis and pentylenetetrazol (PTZ)-induced seizures test were evaluated in mice to determine the possible central nervous system activity. The cardiovascular activities in vivo and ex vivo were analyzed in rats.. LIA (2%) presents, similar to lidocaine (2%), anesthetic activity on the corneal reflex, infiltration anesthesia and tail immersion test. LIA (1-100mg/kg, i.p.), similar to lidocaine (1-100mg/kg, i.p.), presents a dose-dependent sedative-hypnotic effect in mice. Both compounds did not produce anti-anxiety activity in mice. LIA did not prevent PTZ-induced seizures. However, LIA itself did not produce seizures at high doses in mice, as lidocaine does. LIA is a vasorelaxant compound for smooth muscle cells and presents hypotensive effect in vivo without increments to the heart rate significantly.. High doses of lidocaine produce seizures and vasoconstriction. In this study, we found that LIA shares a similar pharmacological profile as lidocaine's but without the primary adverse effects of seizures and vasoconstriction.

Topics: Anesthetics, Local; Animals; Anti-Anxiety Agents; Cardiovascular System; Guinea Pigs; Hypnotics and Sedatives; Lidocaine; Male; Mice; Piperidines; Rats; Rats, Wistar; Seizures

Both endocannabinoids and dynorphin are feedback messengers in nervous system that act at the presynaptic nerve terminal to inhibit transmitter release. Many studies showed the cannabinoid-opioid cross-modulation in antinociception, hypothermia, sedation and reward. The aim of this study was to assess the influence of early application of cannabinoid type 1 (CB1) receptor antagonism SR141716A after brain injury on dynorphin-κ opioid receptor (KOR) system and the expression of metabotropic glutamate receptors (mGluRs) in a rat model of fluid percussion injury (FPI). Firstly, seizure latency induced by pentylenetetrazole was significantly prolonged 6 weeks after brain injury in group of SR141716A treatment. Then, PCR and western blot showed that SR141716A inhibited the long-term up-regulation of CB1 receptors in hippocampus. However, SR141716A resulted in long-term potentiation of dynorphin release and did not influence the up-regulation of KOR in hippocampus after brain injury. Furthermore, SR141716A reverse the overexpression of mGluR5 in the late stage of brain injury. We propose that during the induction of epileptogenesis after brain injury, early application of CB1 receptor antagonism could prevent long-term hyperexcitability by up-regulation of dynorphin-KOR system and prevention of mGluR5 induced epileptogenesis in hippocampus.

Topics: Animals; Brain Injuries; Hippocampus; Male; Pentylenetetrazole; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Receptors, Opioid, kappa; Rimonabant; Seizures

AKB48 and its fluorinate derivate 5F-AKB48 are two novel synthetic cannabinoids belonging to a structural class with an indazole core structure. They are marketed as incense, herbal preparations or chemical supply for their psychoactive Cannabis-like effects.. The present study was aimed at investigating the in vitro and in vivo pharmacological activity of AKB48 and 5F-AKB48 in male CD-1 mice and comparing their in vivo effects with those caused by the administration of Δ. For the first time, the present study demonstrates the overall pharmacological effects induced by the administration of AKB48 and 5F-AKB48 in mice and suggests that the fluorination can increase the power and/or effectiveness of SCBs. Furthermore, this study outlines the potential detrimental effects of SCBs on human health.

Topics: Adamantane; Aggression; Animals; Behavior, Animal; Binding, Competitive; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Cannabis; Catalepsy; Dopamine; Dronabinol; Humans; In Vitro Techniques; Indazoles; Indoles; Male; Mice; Motor Activity; Naphthalenes; Nucleus Accumbens; Pain Threshold; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Reflex, Abnormal; Seizures

Ro 25-6981 maleate is a highly selective and activity-dependent antagonist of NMDA ionotropic glutamate receptors containing NR2B subunit (NR2B/NMDARs). The aim of our study was to investigate the influence of Ro 25-6981 administration in developing rats on physiological (single and paired pulse cortical interhemispheric evoked potentials) and epileptic brain activity (cortical afterdischarges (ADs)). Electrophysiological experiments were performed in animals with epidurally implanted electrodes at postnatal days (P) P12, P18, and P25. The drug was injected intraperitoneally at a dose of 1 or 3mg/kg. Control animals were injected with saline (1ml/kg). Single interhemispheric responses were evoked with 0.5-ms biphasic pulses with intensities increasing from 0.4 to 5mA, paired-pulse responses were elicited by twofold threshold intensity. The ADs were elicited by series of 15-s of 1-ms pulses at 8-Hz frequency. Firstly, six stimulations with stable suprathreshold intensity repeated at 30-min intervals were used to determine the time course of Ro 25-6981 effects against ADs in P12 animals. Secondly, similar experiment was performed in all age groups of animals but with 20-min intervals as well as a further experiment using stimulations with stepwise intensities increasing at 10-min intervals from 0.2 to 15 mA. Pretreatment with the 3-mg/kg (but not the lower) dose of Ro 25-9681 decreased significantly the amplitude of single responses evoked with higher stimulation intensities in P12 and P18 animals. Both doses affected responses in P25 animals, only the 1-mg/kg dose was more efficacious than the 3-mg/kg one. Paired pulse responses were not affected by either dose of Ro 25-6981 in any age group. Ro 25-9681 clearly influenced the duration of ADs only in P12 animals. The 1-mg/kg dose did not change the duration of ADs whereas the 3-mg/kg dose suppressed progressive prolongation of ADs with repeated stimulations. This effect was seen even 110-min after the drug injection. The modification of ADs, i.e. stimulations with stepwise increasing intensities (10 min intervals) was used to demonstrate possible dependence on activity. The Ro 25-6981 was administered immediately after the 4-mA stimulation (i.e. when rats experienced six ADs on the average). The 3-mg/kg dose resulted in shorter ADs after high stimulation intensities in P12. There were no significant effects in older animals, only a tendency to ADs shortening was observed in P25 rats. In conclusion, our resu

Topics: Age Factors; Animals; Anticonvulsants; Electric Stimulation; Male; Membrane Potentials; Phenols; Piperidines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures; Sensorimotor Cortex

Cannabinoid and PPAR receptors show well established interactions in a set of physiological effects. Regarding the seizure-modulating properties of both classes of receptors, the present study aimed to evaluate the roles of the PPAR-gamma, PPAR-alpha and CB1 receptors on the anticonvulsant effects of WIN 55,212-2 (WIN, a non selective cannabinoid agonist). The clonic seizure thresholds after intravenous administration of pentylenetetrazole (PTZ) were assessed in mice weighing 23-30 g. WIN increased the seizure threshold dose dependently. Pretreatment with pioglitazone, as a PPARγ agonist, potentiated the anticonvulsant effects of WIN, while PPARγ antagonist inhibited these anticonvulsant effects partially. On the other hand PPARα antagonist reduced the anticonvulsant effects of WIN significantly. Finally the combination of CB1 antagonist and PPARα antagonist could completely block the anticonvulsant properties of WIN. Taken together, these results show for the first time that a functional interaction exists between cannabinoid and PPAR receptors in the modulation of seizure susceptibility.

Topics: Anilides; Animals; Anticonvulsants; Benzoxazines; Cannabinoid Receptor Antagonists; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Male; Mice; Morpholines; Naphthalenes; Oxazoles; Pentylenetetrazole; Peroxisome Proliferator-Activated Receptors; Pioglitazone; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Seizures; Thiazolidinediones; Tyrosine

We report the case of an aborted awake craniotomy for a left frontotemporoinsular glioma due to ammonia encephalopathy on a patient taking Levetiracetam, valproic acid and clobazam. This awake mapping surgery was scheduled as a second-stage procedure following partial resection eight days earlier under general anesthesia. We planned to perform the surgery with local anesthesia and sedation with remifentanil and propofol. After removal of the bone flap all sedation was stopped and we noticed slow mentation and excessive drowsiness prompting us to stop and control the airway and proceed with general anesthesia. There were no post-operative complications but the patient continued to exhibit bradypsychia and hand tremor. His ammonia level was found to be elevated and was treated with an infusion of l-carnitine after discontinuation of the valproic acid with vast improvement. Ammonia encephalopathy should be considered in patients treated with valproic acid and mental status changes who require an awake craniotomy with patient collaboration.

Topics: Anesthesia, General; Anesthesia, Local; Anticonvulsants; Aphasia; Benzodiazepines; Brain Diseases; Brain Mapping; Brain Neoplasms; Carnitine; Clobazam; Conscious Sedation; Consciousness Disorders; Craniotomy; Dominance, Cerebral; Frontal Lobe; Glioma; Humans; Hyperammonemia; Hypnotics and Sedatives; Intraoperative Complications; Language; Levetiracetam; Male; Middle Aged; Piperidines; Piracetam; Propofol; Remifentanil; Seizures; Temporal Lobe; Valproic Acid

Monoacylglycerol lipase (MAGL) represents a primary degradation enzyme of the endogenous cannabinoid (eCB), 2-arachidonoyglycerol (2-AG). This study reports a potent covalent MAGL inhibitor, SAR127303. The compound behaves as a selective and competitive inhibitor of mouse and human MAGL, which potently elevates hippocampal levels of 2-AG in mice. In vivo, SAR127303 produces antinociceptive effects in assays of inflammatory and visceral pain. In addition, the drug alters learning performance in several assays related to episodic, working and spatial memory. Moreover, long term potentiation (LTP) of CA1 synaptic transmission and acetylcholine release in the hippocampus, two hallmarks of memory function, are both decreased by SAR127303. Although inactive in acute seizure tests, repeated administration of SAR127303 delays the acquisition and decreases kindled seizures in mice, indicating that the drug slows down epileptogenesis, a finding deserving further investigation to evaluate the potential of MAGL inhibitors as antiepileptics. However, the observation that 2-AG hydrolysis blockade alters learning and memory performance, suggests that such drugs may have limited value as therapeutic agents.

Topics: Acetylcholine; Administration, Oral; Analgesics; Animals; Arachidonic Acids; Binding Sites; Brain; Cannabinoid Receptor Antagonists; Carbamates; Chromatography, High Pressure Liquid; Crystallography, X-Ray; Disease Models, Animal; Electric Stimulation; Endocannabinoids; Enzyme Inhibitors; Glycerides; Hippocampus; Humans; Hydrolysis; In Vitro Techniques; Learning; Long-Term Potentiation; Mass Spectrometry; Memory, Short-Term; Mice; Mice, Inbred C57BL; Mice, SCID; Monoacylglycerol Lipases; Pain; Piperidines; Protein Structure, Tertiary; Pyrazoles; Rimonabant; Seizures; Sulfonamides

JWH-018 is a synthetic CB1 and CB2 agonist illegally marketed as products named "Spice" or "herbal blend" for its psychoactive effects which are much higher than those produced by cannabis. In the last year, the European Monitoring Centre for Drugs and Drug Addiction reported to the Italian National Early Warning System the seizure of plant material containing new halogenated derivatives of JWH-018 (JWH-018 Cl and JWH-018 Br). The present study aimed to investigate the in vitro and in vivo activity of these two new synthetic cannabinoids in mice. In vitro competition binding experiments performed on mouse and human CB1 receptors revealed a high affinity and potency of the halogenated compounds. Synthetic cannabinoids (0.01-6 mg/kg i.p.) impaired motor activity and induced catalepsy in mice and their effects were more severe with respect to those evoked by Δ(9)-THC. Moreover, they increased the mechanical and thermal pain threshold and induced a marked hypothermia. It is interesting to note that whereas high doses of JWH-018 cause seizures, myoclonia and hyperreflexia, the halogenated compounds, in particular JWH-018Br, were less effective. Behavioral and neurological changes were prevented by the selective CB1 receptor antagonist AM 251. These data demonstrate for the first time that JWH-018 Cl and JWH-018 Br act similarly to JWH-018 while inducing less convulsive episodes and myoclonias. These data support the hypothesis that the halogenated compounds may have been introduced onto market to produce similar intoxicating effects as JWH-018 while causing less side effects.

Topics: Animals; Binding, Competitive; Cannabinoid Receptor Agonists; Cannabinoids; Catalepsy; CHO Cells; Cricetulus; Halogenation; Humans; Hypothermia; Indoles; Male; Mice, Inbred ICR; Motor Activity; Naphthalenes; Pain Threshold; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Reflex, Abnormal; Seizures

Status epilepticus (SE) is a medical emergency associated with a high rate of mortality if not treated promptly. Exogenous and endogenous cannabinoids have been shown to possess anticonvulsant properties both in vivo and in vitro. Here we study the influence of endocannabinoid metabolism on the development of kainic acid-induced SE in guinea pigs. For this purpose, the inhibitors of endocannabinoid transport, AM404, and enzymatic (fatty acid amide hydrolase) degradation, URB597, were applied. Cannabinoid CB1 receptor antagonist, AM251, was also tested. Animal behavior as well as local electric field potentials in four structures: medial septum, hippocampus, entorhinal cortex and amygdala were analyzed when AM404 (120nmol), URB597 (4.8nmol) or AM251 (20nmol) were administrated alone or together with 0.4μg of kainic acid. All substances were injected i.c.v. AM404, URB597 or AM251 administered alone did not alter markedly local field potentials of all four studied structures in the long-term compared with their basal activity. AM404 and URB597 significantly alleviated kainic acid-induced SE, decreasing behavioral manifestations, duration of seizure events and SE in general without changing the amplitude of local field potentials. AM251 did not produce distinct effects on SE in terms of our experimental paradigm. There was no apparent change of the seizure initiation pattern when kainic acid was coadministrated with AM404, URB597 or AM251. The present study provides electrophysiologic and behavioral evidences that inhibition of endocannabinoid metabolism plays a protective role against kainic acid-induced SE and may be employed for therapeutic purposes. Further investigations of the influences of cannabinoid-related compounds on SE genesis and especially epileptogenesis are required.

Topics: Amidohydrolases; Animals; Anticonvulsants; Arachidonic Acids; Benzamides; Biological Transport; Brain; Cannabinoid Receptor Antagonists; Carbamates; Endocannabinoids; Guinea Pigs; Kainic Acid; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Seizures; Status Epilepticus

Temporal lobe epilepsy (TLE) is the most common form of drug resistant epilepsy. Current treatment is symptomatic, suppressing seizures, but has no disease modifying effect on epileptogenesis. We examined the effects of Z944, a potent T-type calcium channel antagonist, as an anti-seizure agent and against the progression of kindling in the amygdala kindling model of TLE. The anti-seizure efficacy of Z944 (5mg/kg, 10mg/kg, 30mg/kg and 100mg/kg) was assessed in fully kindled rats (5 class V seizures) as compared to vehicle, ethosuximide (ETX, 100mg/kg) and carbamazepine (30mg/kg). Each animal received the seven treatments in a randomised manner. Seizure class and duration elicited by six post-drug stimulations was determined. To investigate for effects in delaying the progression of kindling, naive animals received Z944 (30mg/kg), ETX (100mg/kg) or vehicle 30-minutes prior to each kindling stimulation up to a maximum of 30 stimulations, with seizure class and duration recorded after each stimulation. At the completion of drug treatment, CaV3.1, CaV3.2 and CaV3.3 mRNA expression levels were assessed in the hippocampus and amygdala using qPCR. Z944 was not effective at suppressing seizures in fully kindled rats compared to vehicle. Animals receiving Z944 required significantly more stimulations to evoke a class III (p<0.05), IV (p<0.01) or V (p<0.0001) seizure, and to reach a fully kindled state (p<0.01), than animals receiving vehicle. There was no significant difference in the mRNA expression of the T-type Ca2+ channels in the hippocampus or amygdala. Our results show that selectively targeting T-type Ca2+ channels with Z944 inhibits the progression of amygdala kindling. This could be a potential for a new therapeutic intervention to mitigate the development and progression of epilepsy.

Topics: Acetamides; Amygdala; Animals; Anticonvulsants; Benzamides; Calcium Channel Blockers; Disease Models, Animal; Kindling, Neurologic; Piperidines; Rats; Seizures

To elucidate the mechanisms that regulate p-glycoprotein (PGP) expression and function in pharmacoresistant epilepsy, we investigated the effect of an ETB receptor antagonist (BQ788) and a p38 mitogen-activated protein kinase (p38MAPK) inhibitor (SB202190) on intractable seizures in chronic epileptic rats.. Lithium-pilocarpine-induced chronic epileptic rats were used in the present study. Animals were given levetiracetam (LEV), LEV + SB202190, LEV + BQ788, SB202190 or BQ788 over a 3-day period using an osmotic pump. Seizure activity was recorded by video-EEG monitoring with 2h of recording per day at the same time of day. We also performed western blot after EEG analysis.. Compared to control animals, PGP, ETB receptor and p38MAPK expression was increased in the hippocampus of epileptic animals. Neither SB202190 nor BQ788 affected the spontaneous seizure activity in epileptic rats. Three of ten rats were responders and achieved complete seizure control or significant reduction in seizure activity by LEV. In four of ten rats, seizure frequency was unaltered by LEV (non-responders). LEV + SB202190 reduced seizure duration, but not seizure frequency, in both responders and non-responders. LEV + BQ788 alleviated seizure frequency and seizure duration in both responders and non-responders. Compared to responders, PGP and ETB receptor expression was enhanced in the hippocampus of non-responders.. To the best of our knowledge, these findings are the first indications of the role of ETB receptor in pharmacoresistant epilepsy. Therefore, the present data suggest that the regulation of the ETB receptor-mediated signaling pathway may be important for identification of new therapeutic strategies for improving antiepileptic drug efficacy.

Topics: Animals; Anticonvulsants; Brain; Chronic Disease; Disease Models, Animal; Endothelin B Receptor Antagonists; Enzyme Inhibitors; Epilepsy; Imidazoles; Levetiracetam; Male; Oligopeptides; p38 Mitogen-Activated Protein Kinases; Piperidines; Piracetam; Pyridines; Rats, Sprague-Dawley; Receptor, Endothelin B; Seizures; Treatment Outcome

An 80-year-old woman with Alzheimer's dementia presented with diarrhoea, vomiting and worsening confusion following an increase in donepezil dose from 5 to 10 mg. The ECG revealed prolongation of QTc interval. Soon after admission, she became unresponsive with polymorphic ventricular tachycardia (VT). Cardiopulmonary resuscitation with a 200 J shock was successful in establishing cardiac output. Following the discontinuation of donepezil, the QTc interval normalised and no further arrhythmias were recorded. Treatment with anticholinesterase inhibitors may result in life-threatening VT. Vigilance is required for the identification of this condition in patients presenting with presyncope, syncope or seizures.

Topics: Aged, 80 and over; Alzheimer Disease; Cardiopulmonary Resuscitation; Donepezil; Electrocardiography; Female; Humans; Indans; Long QT Syndrome; Nootropic Agents; Piperidines; Seizures; Syncope; Torsades de Pointes

Piperine, a natural compound isolated from the fruits of Piper, is known to modulate several neurotransmitter systems such as serotonin, norepinephrine, and GABA, all of which have been linked to the development of convulsions. Fruits of Piper species have been suggested as means for managing seizure disorders. The present study was designed to elucidate the anticonvulsant effect of piperine and its mechanisms of action using in-silico, in-vivo and in-vitro techniques.PASS software was used to determine its possible activity and mechanisms. Furthermore the latency for development of convulsions and mortality rate was recorded in different experimental mouse models of epilepsy (pentylenetetrazole, maximal electroshock, NMDA, picrotoxin, bicuculline, BAYK-8644, strychnine-induced convulsions) after administration of various doses of piperine (5, 10 and 20 mg/kg, i.p.). Finally, the effect of piperine on Na(+) and Ca(2+) channels were evaluated using the whole cell patch clamp techniqueOur results revealed that piperine decreased mortality in the MES-induced seizure model. Moreover, piperine (10 mg/kg) delayed the onset of tonic clonic convulsions in the pentylenetetrazole test and reduced associated mortality. Furthermore, an anticonvulsant dose of piperine also delayed the onset of tonic clonic seizures in strychnine, picrotoxin and BAY K-8644. Complete protection against mortality was observed in BAYK-8644 induced convulsions. Finally, whole cell patch clamp analysis suggested an inhibitory effect of piperine on Na(+) channels. Together, our data suggest Na(+) channel antagonist activity as a contributor to the complex anticonvulsant mechanisms of piperine.

Topics: Action Potentials; Alkaloids; Animals; Anticonvulsants; Benzodioxoles; Calcium; Cell Line; Humans; Mice; Piperidines; Polyunsaturated Alkamides; Seizures; Sodium; Sodium Channel Blockers

A patient with medication resistant schizophrenia underwent modified electroconvulsive therapy (12 sessions). Propofol was chosen as a hypnotic agent and the adjustment of its dose and stimulus intensity was attempted. However, despite using propofol of a dose minimally required for hypnosis, adequate seizures could not be induced even with the maximum stimulation. Assuming that propofol was preventing the induction of seizures, it was decided to reduce its dose and at the same time to combine it with remifentanil 100 μg starting from the fifth session. This allowed to reach the seizure adequacy during the next and the four subsequent sessions. Although from the tenth session on, adequate seizures could no longer be induced (possibly due to the development of resistance to propofol), the patient's symptoms showed improvement after completion of all 12 sessions.

Topics: Electroconvulsive Therapy; Humans; Male; Middle Aged; Piperidines; Propofol; Remifentanil; Seizures

T-type calcium channels play essential roles in regulating neuronal excitability and network oscillations in the brain. Mutations in the gene encoding Cav3.2 T-type Ca(2+) channels, CACNA1H, have been found in association with various forms of idiopathic generalized epilepsy. We and others have found that these mutations may influence neuronal excitability either by altering the biophysical properties of the channels or by increasing their surface expression. The goals of the present study were to investigate the excitability of neurons expressing Cav3.2 with the epilepsy mutation, C456S, and to elucidate the mechanisms by which it influences neuronal properties. We found that expression of the recombinant C456S channels substantially increased the excitability of cultured neurons by increasing the spontaneous firing rate and reducing the threshold for rebound burst firing. Additionally, we found that molecular determinants in the I-II loop (the region in which most childhood absence epilepsy-associated mutations are found) substantially increase the surface expression of T-channels but do not alter the relative distribution of channels into dendrites of cultured hippocampal neurons. Finally, we discovered that expression of C456S channels promoted dendritic growth and arborization. These effects were reversed to normal by either the absence epilepsy drug ethosuximide or a novel T-channel blocker, TTA-P2. As Ca(2+)-regulated transcription factors also increase dendritic development, we tested a transactivator trap assay and found that the C456S variant can induce changes in gene transcription. Taken together, our findings suggest that gain-of-function mutations in Cav3.2 T-type Ca(2+) channels increase seizure susceptibility by directly altering neuronal electrical properties and indirectly by changing gene expression.

Topics: Action Potentials; Animals; Anticonvulsants; Benzamides; Calcium Channel Blockers; Calcium Channels, T-Type; Cells, Cultured; Ethosuximide; Hippocampus; Humans; Mutation, Missense; Neurons; Piperidines; Protein Structure, Tertiary; Protein Transport; Rats; Rats, Sprague-Dawley; Seizures; Transcription, Genetic

Selective blockade of anandamide hydrolysis, through the inhibition of the FAAH enzyme, has anticonvulsant effects, which are mediated by CB1 receptors. Anandamide, however, also activates TRPV1 channels, generally with an opposite outcome on neuronal modulation. Thus, we suggested that the dual FAAH and TRPV1 blockade with N-arachidonoyl-serotonin (AA-5-HT) would be efficacious in inhibiting pentylenetetrazole (PTZ)-induced seizures in mice. We also investigated the contribution of CB1 activation and TRPV1 blockade to the overt effect of AA-5-HT. In the first experiment, injection of AA-5-HT (0.3-3.0 mg/kg) delayed the onset and reduced the duration of PTZ (60 mg)-induced seizures in mice. These effects were reversed by pre-treatment with the CB1 antagonist, AM251 (1.0-3.0 mg/kg). Finally, we observed that administration of the selective TRPV1 antagonist, SB366791 (0.1-1 mg/kg), did not entirely mimic AA-5-HT effects. In conclusion, AA-5-HT alleviates seizures in mice, an effect inhibited by CB1 antagonism, but not completely mimicked by TRPV1 blockage, indicating that the overall effect of AA-5-HT seems to depend mainly on CB1 receptors. This may represent a new strategy for the development of drugs against seizures, epilepsies and related syndromes.

Topics: Amidohydrolases; Anilides; Animals; Anticonvulsants; Arachidonic Acids; Cinnamates; Male; Mice; Pentylenetetrazole; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Seizures; Serotonin; TRPV Cation Channels

Recently, studies have shown that serotonin plays an important role in the control of seizure. However, the specific role of 5-HT receptor subtypes is not yet well described, in particular that of the 5-HT3 receptor. The present study was aimed to investigate the role of 5-HT3 receptor on the pentylenetetrazole (PTZ)-induced seizure in mice. Firstly, seizure latency was significantly prolonged by a 5-HT3 receptor agonist SR 57227 in a dose-dependent manner. Seizure score and mortality were also decreased by SR 57227 in PTZ-treated mice. Furthermore, these anticonvulsant effects of SR 57227 were inhibited by a 5-HT3 receptor antagonist ondansetron. However, ondansetron alone had no effect on seizure latency, seizure score or mortality at different doses. Immunohistochemical studies have also shown that c-Fos expression was significantly increased in hippocampus (dentate gyrus, CA1, CA3 and CA4) of PTZ-treated mice. Furthermore, c-Fos expression was significantly inhibited by ondansetron in mice treated with PTZ and SR 57227. An ELISA study showed that SR 57227 attenuated the PTZ-induced inhibitory effects of GABA levels in hippocampus and cortex, and the attenuated effects of SR 57227 were antagonized by ondansetron in hippocampus but not cortex. Our findings suggest that activation of 5-HT3 receptor by SR 57227, which plays an important role on the control of seizure induced by PTZ, may be related to GABA activity in hippocampus. Therefore, 5-HT3 receptor subtype is a potential target for the treatment of epilepsy.

Topics: Animals; Anticonvulsants; gamma-Aminobutyric Acid; Hippocampus; Male; Mice, Inbred ICR; Ondansetron; Pentylenetetrazole; Piperidines; Proto-Oncogene Proteins c-fos; Seizures; Survival Analysis

Ifenprodil, an antagonist of NMDA receptors containing the NR2B subunit, was expected to exhibit anticonvulsant action in rat pups up to the third postnatal week because of predominance of NR2B subunit at early development. Cortical epileptic afterdischarges (ADs) were used to study possible effects on threshold current intensities and duration of ADs in 12-, 15-, 18-, and 25-day-old rats. A series of 18 stimulation series with stepwise increasing current intensities (from 0.2 to 15 mA) was applied with 10-min intervals. The first experiment studied rats pretreated with ifenprodil (20 or 40 mg/kg), the second experiment studied an effect of ifenprodil on already present ADs-the dose of 20 mg/kg was administered after stimulation with the 3.5-mA current intensity. Pretreatment with ifenprodil resulted in an anticonvulsant effect in 15-day-old rats only, on the contrary, proconvulsant action was found in 18- and 25-day-old animals (decrease of thresholds especially for transition into the second, limbic type of ADs and increase in duration of ADs). Anticonvulsant effect was found in 12-, 15-, and 18-day-old rats in the second experiment-ADs were shortened. In contrast, no effect was observed in 25-day-old animals. An anticonvulsant action of ifenprodil is not only age-dependent but also activation-dependent.

Topics: Aging; Animals; Animals, Newborn; Anticonvulsants; Electric Stimulation; Male; Pentylenetetrazole; Piperidines; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures

Tetramethylenedisulfotetramine (TETS) is a potent convulsant poison for which there is currently no approved antidote. The convulsant action of TETS is thought to be mediated by inhibition of type A gamma-aminobutyric acid receptor (GABAAR) function. We, therefore, investigated the effects of post-exposure administration of diazepam, a GABAAR positive allosteric modulator, on seizure activity, death and neuroinflammation in adult male Swiss mice injected with a lethal dose of TETS (0.15mg/kg, ip). Administration of a high dose of diazepam (5mg/kg, ip) immediately following the second clonic seizure (approximately 20min post-TETS injection) effectively prevented progression to tonic seizures and death. However, this treatment did not prevent persistent reactive astrogliosis and microglial activation, as determined by GFAP and Iba-1 immunoreactivity and microglial cell morphology. Inhibition of soluble epoxide hydrolase (sEH) has been shown to exert potent anti-inflammatory effects and to increase survival in mice intoxicated with other GABAAR antagonists. The sEH inhibitor TUPS (1mg/kg, ip) administered immediately after the second clonic seizure did not protect TETS-intoxicated animals from tonic seizures or death. Combined administration of diazepam (5mg/kg, ip) and TUPS (1mg/kg, ip, starting 1h after diazepam and repeated every 24h) prevented TETS-induced lethality and influenced signs of neuroinflammation in some brain regions. Significantly decreased microglial activation and enhanced reactive astrogliosis were observed in the hippocampus, with no changes in the cortex. Combining an agent that targets specific anti-inflammatory mechanisms with a traditional antiseizure drug may enhance treatment outcome in TETS intoxication.

Topics: Animals; Anti-Inflammatory Agents; Anticonvulsants; Brain; Brain Waves; Bridged-Ring Compounds; Diazepam; Disease Models, Animal; Drug Administration Schedule; Drug Therapy, Combination; Electroencephalography; Encephalitis; Enzyme Inhibitors; Epoxide Hydrolases; GABA Modulators; Male; Mice; Phenylurea Compounds; Piperidines; Seizures; Time Factors

The present study was aimed to characterize the anticonvulsant effects of piperine in combination with well established antiepileptic drug (AED) phenytoin, in the mouse maximal electroshock (MES)-induced seizure model by using the type I isobolographic analysis for non-parallel dose-response relationship curves (DRRCs). Potential adverse-effect profiles of interactions of phenytoin with piperine at the fixed-ratio of 1:1 from the MES test with respect to long-term memory and skeletal muscular strength were evaluated along with free plasma concentration of piperine and phenytoin. Parameters of oxidative stress (glutathione, malondialdehyde), brain serotonin and serum calcium levels were also determined to probe the mechanism involved in the interaction. Test of parallelism revealed that 2 drugs were associated with non-parallel dose response effects, hence only one fixed ratio combination (1:1) was evaluated which displayed additive interaction between the 2 drugs with a slight tendency towards superadditivity. Free plasma concentrations of piperine and phenytoin revealed no significant changes in their concentrations when the drugs were combined at the fixed-ratio of 1:1. In combination, neither long-term memory nor skeletal muscular strength was impaired. Analysis of biochemical parameters showed that the piperine alone or in combination with phenytoin successfully reversed the parameters of oxidative stress and increased brain serotonin levels as compared to MES group. However, no significant alteration in the serum calcium levels was observed by any treatment. In conclusion, the combination displayed additive interaction and slight tendency towards synergistic potential with protection towards side effects associated with AED therapy and is worthy of consideration for further investigations.

Topics: Alkaloids; Animals; Anticonvulsants; Benzodioxoles; Calcium; Disease Models, Animal; Drug Therapy, Combination; Electroshock; Lipid Peroxidation; Male; Memory, Long-Term; Mice; Muscle Strength; Phenytoin; Piperidines; Polyunsaturated Alkamides; Seizures

Cannabinoid system plays a pivotal role in the seizure threshold modulation which is mainly mediated through activation of the cannabinoid CB₁ receptor. There is also several evidence of interaction between cannabinoid system and α₂-adrenoceptors in different paradigms. Using model of clonic seizure induced by intravenous pentylenetetrazole (PTZ) in male mice, we investigated whether α₂-adrenoceptors is involved in the effects of cannabinoids on the seizure threshold. Injection of the selective cannabinoid CB₁ agonist ACEA (2 mg/kg) significantly (P<0.01) increased the seizure threshold which was prevented by pretreatment with the selective CB1 antagonist AM251 (1 mg/kg, i.p.). The highest doses of clonidine, a α₂ receptor agonist, (1 and 5 mg/kg) showed anticonvulsant effects while yohimbine, a α₂ receptor antagonist, (0.01, 0.1, 1, and 10 mg/kg) did not induce any significant effect on PTZ seizure threshold. Pretreatment with clonidine (0.1 and 0.5 mg/kg) significantly reversed the anticonvulsant effect of ACEA (2 mg/kg). Yohimbine (0.1, 1, and 10 mg/kg) pretreatment of mice enhanced the clonic seizure threshold of ACEA (1 mg/kg), significantly. Combination of non-effective doses of AM251 (0.1 mg/kg) and clonidine (0.01 mg/kg) showed additive effect in blocking the anticonvulsant effect of ACEA (2 mg/kg). In conclusion, our findings demonstrated that α₂-adrenoceptors could be involved in the anticonvulsant properties of the specific cannabinoid CB₁ agonist ACEA, suggesting that CB₁ cannabinoid and α₂ receptors have functional interactions in modulation of clonic seizure threshold.

Topics: Animals; Anticonvulsants; Arachidonic Acids; Cannabinoids; Clonidine; Dose-Response Relationship, Drug; Drug Interactions; Male; Mice; Pentylenetetrazole; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, Adrenergic, alpha-2; Seizures; Yohimbine

Drugs that modulate the endocannabinoid system and endocannabinoids typically play an anticonvulsant role although some proconvulsant effects have been reported both in humans and animal models. Moreover, no evidence for a role of the cannabinoid system in human absence epilepsy has been found although limited evidence of efficacy in relevant experimental animal models has been documented. This study aims to characterize the role of cannabinoids in specific areas of the cortico-thalamic network involved in oscillations that underlie seizures in a genetic animal model of absence epilepsy, the WAG/Rij rat. We assessed the effects of focal injection of the endogenous cannabinoid, anandamide (AEA), a non-selective CB receptor agonist (WIN55,212) and a selective CB1 receptor antagonist/inverse agonist (SR141716A) into thalamic nuclei and primary somatosensory cortex (S1po) of the cortico-thalamic network. AEA and WIN both reduced absence seizures independently from the brain focal site of infusion while, conversely, rimonabant increased absence seizures but only when focally administered to the ventroposteromedial thalamic nucleus (VPM). These results, together with previous reports, support therapeutic potential for endocannabinoid system modulators in absence epilepsy and highlight that attenuated endocannabinergic function may contribute to the generation and maintenance of seizures. Furthermore, the entire cortico-thalamic network responds to cannabinoid treatment, indicating that in all areas considered, CB receptor activation inhibits the pathological synchronization that subserves absence seizures. In conclusion, our result might be useful for the identification of future drug therapies in absence epilepsy.

Topics: Animals; Anticonvulsants; Arachidonic Acids; Benzoxazines; Cannabinoid Receptor Agonists; Cerebral Cortex; Electroencephalography; Endocannabinoids; Epilepsy; Epilepsy, Absence; Injections, Intraventricular; Male; Morpholines; Naphthalenes; Neural Pathways; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Rimonabant; Seizures; Somatosensory Cortex; Thalamus

The mechanisms involved in the anti-seizure property of piperine (1-[5-(1,3-benzodioxol-5-yl)-1-oxo-2,4-pentadienyl]-(E,E)-piperidine, C17H19NO3) are still unclear. Piperine could activate transient receptor potential cation channel subfamily V member 1 (TRPV1) receptor, and the rapid activation of whole-cell currents is antagonized by the competitive TRPV1 antagonist capsazepine. Interestingly, recent studies have reported that TRPV1 may be a novel anti-epileptogenic target which led us to hypothesize that the anti-seizure property of piperine involves the TRPV1 receptor. To test this hypothesis, we examined the effect of piperine on seizures induced in mice and identified the receptors involved in the suppression of seizure caused by maximal electroshock (MES) and pentylenetetrazol (PTZ) models. Piperine, administered at doses of 40 and 80 mg/kg, significantly delayed the onset of myoclonic jerks and generalized clonic seizures, and decreased the seizure stage and mortality compared with the vehicle-treated animals. Piperine also significantly reduced the incidence of MES-induced tonic hindlimb extension (THE) and PTZ-induced Fos immunoreactivity in the dentate gyrus. The anti-seizure effects of piperine were blocked by a TRPV1-selective antagonist capsazepine. Taken together, these data support the further investigation of piperine as a TRPV1 agonist for anti-seizure therapy.

Topics: Alkaloids; Animals; Anticonvulsants; Behavior, Animal; Benzodioxoles; Electroshock; Gene Expression Regulation; Hippocampus; Male; Mice; Pentylenetetrazole; Piperidines; Polyunsaturated Alkamides; Proto-Oncogene Proteins c-fos; Seizures; TRPV Cation Channels

Topics: Aged; Anesthesia, Intravenous; Anesthetics, Intravenous; Consciousness Monitors; Electroencephalography; Epilepsy, Tonic-Clonic; Humans; Infusions, Intravenous; Male; Piperidines; Remifentanil; Seizures

Piperine, is the major active principal of black pepper. In traditional medicine, black pepper has been used as an analgesic, anti-inflammatory agent and in the treatment of epilepsy. This study was conducted to evaluate the in vivo analgesic and anticonvulsant effects of piperine in mice. The analgesic and anticonvulsant effects of piperine were studied in mice using acetic acid-induced writhing, tail flick assay, pentylenetetrazole (PTZ)- and picrotoxin (PIC)-induced seizures models. The intraperitoneal (i.p.) administration of piperine (30, 50 and 70 mg/kg) significantly inhibited (P<0.01) the acetic acid-induced writhing in mice, similar to the effect of indomethacin (20 mg/kg i.p.). In the tail flick assay, piperine (30 and 50 mg/kg, i.p.) and morphine (5 mg/kg, i.p.) caused a significant increase (P<0.01) in the reaction time of mice. Pre-treatment of animals with naloxone (5 mg/kg i.p.), reversed the analgesic effects of both piperine and morphine in the tail flick assay. Piperine (30, 50 and 70 mg/kg, i.p.) and standard drugs, valproic acid (200 mg/kg, i.p.), carbamazepine (30 mg/kg, i.p.) and diazepam (1 mg/kg, i.p.) significantly (P<0.01) delayed the onset of PTZ-and PIC-induced seizures in mice. These findings indicate that piperine exhibits analgesic and anticonvulsant effects possibly mediated via opioid and GABA-ergic pathways respectively. Moreover, piperine being the main constituent of black pepper, may be contributing factor in the medicinal uses of black pepper in pain and epilepsy.

Topics: Acetic Acid; Alkaloids; Analgesics; Animals; Anticonvulsants; Benzodioxoles; Hot Temperature; Male; Mice; Naloxone; Narcotic Antagonists; Pain; Pentylenetetrazole; Picrotoxin; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Seizures

Topics: 4-Aminopyridine; Donepezil; Follow-Up Studies; Humans; Indans; Middle Aged; Multiple Sclerosis; Piperidines; Potassium Channel Blockers; Risk Assessment; Seizures; Severity of Illness Index

Histamine H(3) receptor antagonists have been considered as potential drugs to treat central nervous system diseases. However, whether these drugs can inhibit epileptogenesis remains unclear. This study aimed to investigate the effects of thioperamide, a selective and potent histamine H(3) receptor antagonist, on the seizure development and memory impairment induced by pentylenetetrazole (PTZ)-kindling epilepsy in rats.. Chemical kindling was elicited by repeated intraperitoneal (ip) injections of a subconvulsant dose of PTZ (35 mg/kg) once every 48 hours for 12 times, and seizure activity of kindling was recorded for 30 minutes. Control rats were ip injected with saline instead of PTZ. Morris water maze was used to evaluate the spatial memory. Phosphorylated cyclic adenosine monophosphate response element binding protein (p-CREB) was tested by Western blotting in hippocampus.. Intracerebroventricular (icv) injections with thioperamide (10 µg, 20 µg) 30 minutes before every PTZ injections, significantly prolonged the onset of PTZ-kindling and inhibited the seizure stages. PTZ-kindling seizures led to the impairment of spatial memory in rats, and thioperamide ameliorated the impairment of spatial learning and memory. Compared to non-kindling rats, there was a significant decrease in p-CREB level in hippocampus of the PTZ-kindling rats, which was reversed by thioperamide.. Thioperamide plays a protective role in seizure development and cognitive impairment of PTZ-induced kindling in rats. The protection of thioperamide in cognitive impairment is possibly associated with the enhancement of CREB-dependent transcription.

Topics: Animals; Anticonvulsants; Cyclic AMP Response Element-Binding Protein; Histamine H3 Antagonists; Kindling, Neurologic; Male; Memory Disorders; Neuroprotective Agents; Pentylenetetrazole; Piperidines; Rats; Rats, Sprague-Dawley; Seizures; Synaptic Transmission

Piperine, an alkaloid present in the Piper genus, was shown to have an anticonvulsant activity, evaluated by the pilocarpine-induced model, in mice. Pilocarpine (350mg/kg, i.p.) was administered 30min after piperine (2.5, 5, 10 and 20mg/kg, i.p.) which significantly increased latencies to 1st convulsion and to death, and percentage of survivals. These parameters were also increased in the pilocarpine groups pretreated with atropine plus piperine (10 and 2.5mg/kg, respectively), as related to the pilocarpine group. However, they were not altered in the pilocarpine groups pretreated with memantine (a NMDA-type glutamate receptors blocker, 2mg/kg, p.o.) or nimodipine (a calcium channel blocker, 10mg/kg, p.o.), both associated with piperine (1 or 2.5mg/kg), as compared to the piperine plus pilocarpine group. Moreover, the pilocarpine group pretreated with diazepam (which binds to the GABAA receptor, 0.2 and 0.5mg/kg, i.p.) plus piperine (1 and 2.5mg/kg) significantly increased latency to the 1st convulsion, as related to the pilocarpine group, suggesting that the GABAergic system is involved with the piperine action. Furthermore, the piperine effect was blocked by flumazenil (2mg/kg, i.p.), a benzodiazepine antagonist. Untreated P350 animals showed decreased striatal DA and increased DOPAC and HVA levels that were not affected in the piperine plus pilocarpine groups. Piperine increased striatal levels of GABA, glycine and taurine, and reversed pilocarpine-induced increases in nitrite contents in sera and brain. Hippocampi from the untreated pilocarpine group showed an increased number of TNF-α immunostained cells in all areas, as opposed to the pilocarpine group pretreated with piperine. Taken together, piperine anticonvulsant effects are the result of its anti-inflammatory and antioxidant actions, as well as TNF-α reduction. In addition, piperine effects on inhibitory amino acids and on the GABAergic system may certainly contribute to the drug anticonvulsant activity.

Topics: Alkaloids; Amino Acids; Animals; Anticonvulsants; Antioxidants; Atropine; Benzodioxoles; Biogenic Monoamines; Brain; Diazepam; Disease Models, Animal; Epilepsy; Flumazenil; gamma-Aminobutyric Acid; Humans; Male; Memantine; Mice; Nimodipine; Nitrites; Pilocarpine; Piperidines; Polyunsaturated Alkamides; Seizures; Tumor Necrosis Factor-alpha

Use of a short-acting opiate to potentiate anesthetic induction agents has been shown to increase seizure duration in electroconvulsive therapy (ECT), but little is known of the effect of this combination on indices of seizure quality.. To determine whether anesthetic modality affects commonly provided indices of seizure quality.. Twenty-five subjects were given propofol 2 mg/kg body weight for their first ECT session, at which time seizure threshold was titrated. Subjects thereafter alternated between that anesthetic regimen or propofol 0.5 mg/kg plus remifentanil 1 mcg/kg. Linear mixed models with random subject effect, adjusting for electrode placement, electrical charge, and number of treatments, were fit to estimate effect of anesthesia on seizure duration and several standard seizure quality indices (average seizure energy, time to peak electroencephalography (EEG) power, maximum sustained power, interhemispheric coherence, early and midictal EEG amplitude, and maximum sustained interhemispheric EEG coherence).. Propofol-remifentanil anesthesia significantly lengthened seizure duration and was associated with longer time to reach maximal EEG power and coherence as well as maximal degree of interhemispheric EEG coherence. No effect was seen on early ictal amplitude or average seizure energy index.. Propofol-remifentanil anesthesia prolongs seizure duration and has a significant effect on some, but not all, measures of seizure quality. This effect may be of some benefit in cases where adequate seizures are otherwise difficult to elicit. Varying anesthetic technique may allow more precise investigation of the relationships between and relative impacts of commonly used seizure quality indices on clinical outcomes and ECT-related cognitive side effects.

Topics: Adult; Anesthetics, Intravenous; Drug Therapy, Combination; Electroconvulsive Therapy; Electroencephalography; Female; Humans; Male; Piperidines; Propofol; Remifentanil; Seizures; Treatment Outcome

The present Letter describes a one-pot multi-component method that allows the efficient and mild preparation of 3,5-diphenylpiperidin-2,6-dione and a new series of 3,5-diarylpiperidin-2,6-dione derivatives from ethyl 2-arylacetates, formaldehyde and ammonia/aliphatic/aromatic amines. The structures of the compounds were elucidated by IR, NMR spectroscopic data and microanalyses. The anticonvulsant activities of these compounds were evaluated by maximal electroshock seizure test and were also evaluated for motor impairment. Among the synthesized compounds, 5a, 5b, 5d, and 5e could be considered potentially the most useful and safe therapeutic compound and 5g, 5i, 5j, 5m, and 5o exhibit potent activities.

Topics: Animals; Anticonvulsants; Dose-Response Relationship, Drug; Drug Design; Drug Evaluation, Preclinical; Electroshock; Mice; Molecular Structure; Movement Disorders; Piperidines; Seizures; Stereoisomerism

Polyamines, including spermidine, facilitate seizures by positively modulating N-methyl-d-aspartate receptors (NMDAr). Although NMDAr antagonists decrease seizures, it remains to be determined whether traxoprodil, a selective antagonist at the NR2B subunit of the NMDAr, decreases seizures and whether spermidine facilitates pentylenetetrazol (PTZ)-induced seizures. Adult male Wistar rats were injected in the lateral ventricle with 0.9% NaCl (1μl, i.c.v.), spermidine (0.02, 0.2 or 2nmol/site, i.c.v.) or traxoprodil (0.2, 2 or 20nmol, i.c.v.) and with PTZ (35 or 70mg/kg, i.p.). The effect of orally administered traxoprodil (60mg/kg, p.o.) on seizures was also investigated. Latencies to clonic and generalized seizures, as well the total time spent in seizures were recorded by behavioral and electrographic methods (EEG). Spermidine (2nmol/site; i.c.v.) facilitated the seizures induced by a sub-threshold dose of PTZ (35mg/kg; i.p.), but did not alter seizure activity induced by a convulsant dose of PTZ (70mg/kg; i.p.). Traxoprodil (20nmol i.c.v.) increased the latency to generalized tonic-clonic seizures induced by PTZ (70mg/kg; i.p.). Traxoprodil (60mg/kg, p.o.) increased the latency to clonic and generalized seizures, and decreased the total time spent in seizures. These results support the role for the NR2B subunit in PTZ-induced seizures.

Topics: Animals; Male; Pentylenetetrazole; Piperidines; Rats; Rats, Wistar; Reaction Time; Receptors, N-Methyl-D-Aspartate; Seizures

Ghrelin is a pleiotropic neuropeptide that has been recently implicated in epilepsy. Animal studies performed to date indicate that ghrelin has anticonvulsant properties; however, its mechanism of anticonvulsant action is unknown. Here we show that the anticonvulsant effects of ghrelin are mediated via the growth hormone secretagogue receptor (GHSR). To our surprise, however, we found that the GHSR knockout mice had a higher seizure threshold than their wild-type littermates when treated with pilocarpine. Using both in vivo and in vitro models, we further discovered that inverse agonism and desensitization/internalization of the GHSR attenuate limbic seizures in rats and epileptiform activity in hippocampal slices. This constitutes a novel mechanism of anticonvulsant action, whereby an endogenous agonist reduces the activity of a constitutively active receptor.

Topics: Analysis of Variance; Animals; Anticonvulsants; Calcium; Disease Models, Animal; Disease Susceptibility; Dose-Response Relationship, Drug; Drug Interactions; Electric Stimulation; Excitatory Postsynaptic Potentials; gamma-Aminobutyric Acid; Ghrelin; Green Fluorescent Proteins; HEK293 Cells; Hippocampus; Humans; In Vitro Techniques; Limbic System; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microdialysis; Muscarinic Agonists; Neurons; Patch-Clamp Techniques; Pilocarpine; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptors, Ghrelin; Seizures; Severity of Illness Index; Species Specificity; Transfection

The depressant and anticonvulsant activities of iso-6-cassine (ISO) from Senna spectabilis (0.5, 1.0 and 1.5mg/kg) injected by oral route in mice caused a significant decrease in the motor activity of animals when compared with the control group, up to 30 days after the administration and at dose of 1.5mg/kg, it reduced the remaining time of animals on Rota-rod apparatus. Additionally, ISO at doses tested was also capable to promote an increase of latency for development of convulsions induced by pentylenetetrazole and picrotoxin. These results suggest possible depressant and anticonvulsant activities in mice that need further investigation.

Topics: Animals; Behavior, Animal; Central Nervous System; Dose-Response Relationship, Drug; Ketones; Male; Mice; Motor Activity; Pentylenetetrazole; Phytotherapy; Picrotoxin; Piperidines; Plant Extracts; Plant Leaves; Seizures; Senna Plant

Although a reduced dose of propofol combined with remifentanil is often used in anesthesia for electroconvulsive therapy (ECT), there have been few studies in which the optimal technique for injection of remifentanil was examined in detail. The aim of this study was to evaluate the effects of single and divided injection of remifentanil combined with propofol on seizure duration and hemodynamic responses during ECT.. Twenty-six ASA I-II patients were enrolled in this study and received a total of 78 ECTs. Each patient received propofol 1.2 mg/kg (group P), remifentanil 1 μg/kg followed by propofol 0.5 mg/kg (group R1), and remifentanil 1 μg/kg followed by propofol 0.5 mg/kg and thereafter remifentanil 2 μg/kg (group R2). Succinylcholine 1 mg/kg was used for muscle paralysis after loss of consciousness.. Although mean motor seizure durations were significantly longer in groups R1 and R2 than in group P (P < 0.05), they were similar in groups R1 and R2. Although the percentage increases in mean arterial pressure after ECT were significantly smaller in groups P (P < 0.01) and R2 (P < 0.05) than in group R1, they did not significantly differ between groups P and R2.. Divided use of remifentanil at 1 and 2 μg/kg combined with propofol 0.5 mg/kg produces an acceptable outcome in both seizure duration and hemodynamic stability during ECT compared with the standard hypnotic doses of propofol alone or remifentanil 1 μg/kg followed by propofol 0.5 mg/kg.

Topics: Adult; Aged; Anesthesia, Intravenous; Anesthetics, Intravenous; Depressive Disorder, Major; Dose-Response Relationship, Drug; Electroencephalography; Electroshock; Female; Hemodynamics; Humans; Male; Middle Aged; Piperidines; Preanesthetic Medication; Propofol; Remifentanil; Schizophrenia; Seizures

The aim of our study was to investigate the effects of ifenprodil and MK-801 on D,L-homocysteine thiolactone induced seizures in adult rats.Male Wistar rats were divided into following groups: 1. Saline-treated (C, n=10); 2. D,L-homocysteine thiolactone 8 mmol/kg, i.p. (H, n=7); 3. Ifenprodil 20 mg/kg i.p. (IF, n=8); 4. MK-801 0.5 mg/kg, i.p. (MK, n=8) and 5. Groups that received IF or MK 30 minutes prior to H (IFH, n=8 and MKH, n=8). Seizure behavior was assessed by incidence, latency, number and intensity of seizure episodes. Seizure severity was described by a descriptive scale with grades 0-4. Lethality in experimental group was recorded 90 min and 24 h upon D,L-homocysteine thiolactone administration.There were no behavioral signs of seizure activity in groups C, IF and MK.Pre-treatment with MK-801 (MKH) showed tendency to reduced incidence of convulsions, latency to the first seizure onset and the severity of seizure episodes, but statistical significance was not attained comparing to the H group. However, median number of seizure episodes was significantly decreased in MKH (p<0.05), comparing to the H group. On the other hand, ifenprodil (IFH) decreased the latency to the first seizure onset and increased the median number of seizure episodes (p<0.05). The majority of seizure episodes in IFH (72.1%, p<0.05) and MKH (73.1%, p<0.05) groups was grade 2 and significantly different comparing to the H (36.0%). Our findings suggest that MK-801 has a mild anticonvulsive effect on D,L-homocysteine thiolactone induced seizures in adult rats.

Topics: Animals; Dizocilpine Maleate; Homocysteine; Male; Piperidines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures

Sigma receptors represent a unique structural class of proteins and they have become increasingly studied as viable medication development targets for neurological and psychiatric disorders, including drug abuse. Earlier studies have shown that cocaine and many other abused substances interact with sigma receptors and that antagonism of these proteins can mitigate their actions.. In the present study, AC927 (1-(2-phenethyl)piperidine oxalate), a selective sigma receptor ligand, was tested against the behavioral and toxic effects of cocaine in laboratory animals.. Acute administration of AC927 in male, Swiss Webster mice significantly attenuated cocaine-induced convulsions, lethality, and locomotor activity, at doses that alone had no significant effects on behavior. Subchronic administration of AC927 also attenuated cocaine-induced conditioned place preference in mice, at doses that alone had no effects on place conditioning. In drug discrimination studies in male, Sprague-Dawley rats, AC927 partially substituted for the discriminative stimulus effects of cocaine. When it was administered with cocaine, AC927 shifted the cocaine dose-response curve to the left, suggesting an enhancement of the discriminative stimulus effects of cocaine. In non-human primates, AC927 was self-administered, maintaining responding that was intermediate between contingent saline and a maintenance dose of cocaine.. The ability of AC927 to elicit some cocaine-like appetitive properties and to also reduce many cocaine-induced behaviors suggests that it is a promising lead for the development of a medication to treat cocaine abuse.

Topics: Animals; Behavior, Animal; Cocaine; Conditioning, Operant; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Ligands; Macaca mulatta; Male; Mice; Models, Animal; Molecular Targeted Therapy; Motor Activity; Oxalates; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, sigma; Seizures; Self Administration

Post-ictal depression of consciousness occurs after generalized convulsive seizures, and includes analgesia, lasting for hours after electrically or chemically induced seizures in animals. The brain sites and mechanisms, mediating post-ictal analgesia, are unclear. The ventrolateral periaqueductal gray (PAG) is an important neuronal network site for mediating analgesia and also in generalized seizures, particularly in genetically epilepsy-prone rats (GEPRs). Endocannabinoids are implicated in mediating analgesia in several brain sites, including the PAG, and generalized seizures result in endocannabinoid release. This study evaluated if post-ictal analgesia occurs in GEPRs, following audiogenic seizures (AGS), and whether this analgesia involves endocannabinoid actions in PAG. Analgesia was evaluated, using thermal stimulation to evoke nociception, measuring changes in paw withdrawal latencies (PWLs) induced by AGS. Endocannabinoid involvement in post-ictal analgesia in GEPRs was evaluated, using focal bilateral microinjection of a cannabinoid (CB1) receptor antagonist (AM251) into PAG. AGS induced a significant increase in PWLs, lasting for ≥120min. Microinjection of AM251 (100 and 200, but not 50 pmol/side) into PAG significantly decreased post-ictal analgesia in GEPRs. Endocannabinoids are also known to activate transient receptor potential vanilloid (TRPV1) receptors, but PAG microinjection of a TRPV1 receptor antagonist (capsazepine) did not affect post-ictal analgesia in GEPRs. These results indicate that AGS in GEPRs induce post-ictal analgesia, which is the first observation of this phenomenon in a genetic epilepsy model. These findings suggest an important role of PAG in post-ictal analgesia. The results also suggest that CB1 receptors in PAG are critical for mediating post-ictal analgesia in GEPRs.

Topics: Amnesia, Anterograde; Analgesia; Animals; Epilepsy, Reflex; Female; Male; Pain Threshold; Periaqueductal Gray; Piperidines; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Seizures

Effects of the cannabinoid antagonist rimonabant on the EEG were investigated in healthy, non-epileptic rats. The drug was administered orally at 30 mg/kg/day for 3 weeks. The EEG was recorded continuously. In 3 out of 13 rats, limbic convulsive seizures, which were not related to the time of drug administration, were observed after 5-8 days. We hypothesize that an accumulation of micro-injuries in the brain is responsible for these "spontaneous" seizures.

Topics: Administration, Oral; Animals; Brain; Cannabinoid Receptor Modulators; Disease Models, Animal; Drug Administration Schedule; Electroencephalography; Endocannabinoids; Female; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Rimonabant; Seizures; Time Factors

Endocannabinoid system and its CB1 receptors are suggested to provide endogeneous protection against seizures. The present study examines whether CB1 receptors contribute to resistance to seizures and kindling epileptogenesis in a model of audiogenic epilepsy. Three groups of Wistar rats were used: rats unsusceptible to audiogenic seizures, rats with acquired resistance to audiogenic seizures and rats with reproducible audiogenic running seizures. Chronic treatment with the CB1 receptor antagonist SR141716 (5 daily dosing of 30mg/kg) did not change innate resistance to audiogenic seizures in non-epileptic rats but reverted acquired seizure resistance in rats which lost their epileptic sensitivity with repeated testing. In the latter rats, audiogenic running seizures reappeared for at least two weeks after the end of treatment. In rats with reproducible seizure response, acutely, SR lengthened audiogenic seizures due to prolongation or appearance, de novo, of post-running limbic clonus without any effect on running seizure per se. This limbic component mimicked audiogenic kindling and indicated propagation of sound-induced brainstem seizure to the limbic forebrain. After chronic SR administration the incidence of the limbic clonus remained to be increased for at least two weeks. The present study supports the hypothesis about a role of CB1 receptors in endogeneous anticonvulsive mechanisms of the brain.

Topics: Acoustic Stimulation; Acute Disease; Animals; Chronic Disease; Disease Models, Animal; Dose-Response Relationship, Drug; Epilepsy, Reflex; Kindling, Neurologic; Limbic System; Male; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Rimonabant; Seizures

There is some evidence that epileptic seizures could be induced or increased by 5-hydroxytryptamine (5-HT) attenuation, while augmentation of serotonin functions within the brain (e.g. by SSRIs) has been reported to be anticonvulsant. This study was performed to determine the effect of selective 5-HT(3) channel/receptor antagonist granisetron and agonist SR57227 hydrochloride on the pentylenetetrazole (PTZ)-induced seizure threshold in mice. The possible interaction of this effect with nitrergic system was also examined using the nitric oxide (NO) synthase inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME) and the NO precursor l-arginine. SR57227 (10mg/kg, i.p.) significantly increased the seizure threshold compared to control group, while high dose granisetron (10mg/kg, i.p.) proved proconvulsant. Co-administration of sub-effective doses of the 5-HT(3) agonist with l-NAME (5 and 60mg/kg, i.p., respectively) exerted a significant anticonvulsive effect, while sub-effective doses of granisetron (3mg/kg) was observed to have a proconvulsive action with the addition of l-arginine (75mg/kg, i.p.). Our data demonstrate that enhancement of 5-HT(3) receptor function results in as anticonvulsant effect in the PTZ-induced seizure model, and that selective antagonism at the 5-HT(3) receptor yields proconvulsive effects. Furthermore, the NO system may play a role in 5-HT(3) receptor function.

Topics: Animals; Anticonvulsants; Arginine; Disease Models, Animal; Disease Susceptibility; Dose-Response Relationship, Drug; Drug Combinations; Drug Interactions; Enzyme Inhibitors; Granisetron; Male; Mice; NG-Nitroarginine Methyl Ester; Nitric Oxide; Pentylenetetrazole; Piperidines; Receptors, Serotonin, 5-HT3; Seizures; Serotonin Antagonists

NR2B-subtype-selective antagonists differ from MK-801, a nonselective NMDA receptor antagonist. MK-801 antagonizes electrical seizures at doses as low as 0.1 to 0.18mg/kg and elicits popping at doses as low as 0.5mg/kg, whereas ifenprodil and Ro 8-4304 were unable to do so at the doses tested. Ro 25-6981, however, was able to antagonize electrically-precipitated tonic hindlimb extension at 100mg/kg, but was not able to elicit popping behavior at this dose.

Topics: Animals; Dose-Response Relationship, Drug; Electroshock; Male; Mice; Phenols; Piperidines; Receptors, N-Methyl-D-Aspartate; Seizures

Many patients with epilepsy are refractory to anticonvulsant drugs or do not tolerate side effects associated with the high doses required to fully prevent seizures. Antagonists of neurokinin-1 (NK1) receptors have the potential to reduce seizure severity, although this potential has not been fully explored in animals or humans. The present study was designed to evaluate the efficacy of the NK1-receptor antagonist, vofopitant, alone and in combination with different anticonvulsant drugs.. Studies were conducted in rats using a model of generalized seizure induced by electroshock. Drug concentrations in blood and brain were determined in parallel to distinguish pharmacodynamic from pharmacokinetic interactions.. The NK1-receptor antagonist, GR205171 (vofopitant) had no anticonvulsant efficacy by itself, but could potentiate the anticonvulsant efficacy of lamotrigine and other sodium channel blockers. However, GR205171 had no effect on the anticonvulsant potency of either valproate or gabapentin. GR205171 did not produce central nervous system (CNS) side effects at the doses tested, and it did not potentiate side effects induced by high doses of lamotrigine. The NK1-receptor inactive enantiomer of GR205171, GR226206 did not potentiate the efficacy of lamotrigine, suggesting that effects observed with GR205171 were mediated by NK1 receptors. Analysis of the dose-effect relationship for GR205171 indicated that a high (>99%) occupancy of NK1 receptors is required for effect, consistent with previous behavioral and human clinical studies with this pharmacologic class.. These results suggest that there may be benefit in adding treatment with a suitable NK1-receptor antagonist to treatment with a sodium channel blocker in patients with refractory epilepsy.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Electroshock; Male; Neurokinin-1 Receptor Antagonists; Piperidines; Rats; Rats, Sprague-Dawley; Seizures; Sodium Channels; Tetrazoles

A series of new 3-hydroxy-6-hydroxymethyl/methyl-2-substituted 4H-pyran-4-ones were synthesized and prepared by the reaction of kojic acid or allomaltol with piperidine derivatives and formaline as potential anticonvulsant compounds. The structure of the synthesized compounds was confirmed using the elemental analysis results and the spectroscopic techniques such as IR, 1H-NMR, and ESI-MS. Anticonvulsant activities were examined by maximal electroshock (MES) and subcutaneous Metrazol (scMet)-induced seizure tests. Neurotoxicity was determined by the rotorod toxicity test. All these tests were performed in accordance with the procedures of the Antiepileptic Drug Development (ADD) program. According to the activity studies and at all doses, 3-hydroxy-2-[(4-hydroxy-4-phenylpiperidin-1-yl)methyl]-6-methyl-4H-pyran-4-one (compound 1), 2-{[4-(4-chlorophenyl)-3,6-dihydropyridin-1(2H)-yl]methyl}-3-hydroxy-6-methyl-4H-pyran-4-one (compound 6), 2-[(4-acetyl-4-phenylpiperidin-1-yl)methyl]-3-hydroxy-6-(hydroxymethyl)-4H-pyran-4-one (compound 11), and 2-{[4-(4-chlorophenyl)-3,6-dihydropyridin-1(2H)-yl] methyl}-3-hydroxy-6-hydroxymethyl-4H-pyran-4-one (compound 12) were found to have anticonvulsant activity against MES-induced seizures at 4 h. Also, 2-{[4-(4-bromophenyl)-4-hydroxypiperidin-1-yl]methyl}-3-hydroxy-6-(hydroxymethyl)-4H-pyran-4-one (compound 8) was determined to be the most active compound against scMet-induced seizures at all doses at 0.5 and 4 h. In the rotorod neurotoxicity screening, all compounds showed no toxicity at all doses.

Topics: Animals; Anticonvulsants; Chemistry, Pharmaceutical; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Electroshock; Male; Mice; Pentylenetetrazole; Piperidines; Pyrones; Seizures; Structure-Activity Relationship

Brain inflammation is a major factor in epilepsy, but the impact of specific inflammatory mediators on neuronal excitability is incompletely understood. Using models of acute and chronic seizures in C57BL/6 mice, we discovered a proconvulsant pathway involving high-mobility group box-1 (HMGB1) release from neurons and glia and its interaction with Toll-like receptor 4 (TLR4), a key receptor of innate immunity. Antagonists of HMGB1 and TLR4 retard seizure precipitation and decrease acute and chronic seizure recurrence. TLR4-defective C3H/HeJ mice are resistant to kainate-induced seizures. The proconvulsant effects of HMGB1, like those of interleukin-1beta (IL-1beta), are partly mediated by ifenprodil-sensitive N-methyl-d-aspartate (NMDA) receptors. Increased expression of HMGB1 and TLR4 in human epileptogenic tissue, like that observed in the mouse model of chronic seizures, suggests a role for the HMGB1-TLR4 axis in human epilepsy. Thus, HMGB1-TLR4 signaling may contribute to generating and perpetuating seizures in humans and might be targeted to attain anticonvulsant effects in epilepsies that are currently resistant to drugs.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Epilepsy; Hippocampus; HMGB1 Protein; Humans; Interleukin-1beta; Kainic Acid; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Neurons; Piperidines; Receptors, N-Methyl-D-Aspartate; Seizures; Signal Transduction; Toll-Like Receptor 4

We showed previously that electrographic seizures involving dentate granule cells in organotypic hippocampal slice cultures were dramatically reduced following chronic treatment with the NR2B-selective antagonist, Ro25,6981, but were increased following chronic treatment with the high-affinity competitive antagonist, D(-)-2-amino-5-phosphonopentanoic acid (D-APV). To begin to investigate the potential mechanisms underlying the differential effects of N-methyl-D-aspartate receptor (NMDAR) antagonists on seizures, electrophysiologic experiments were conducted in dentate granule cells in hippocampal slice cultures treated for the entire 17-21 day culture period with vehicle, Ro25,6981 or D-APV. Initial experiments revealed a lack of an association between miniature excitatory postsynaptic current (mEPSC) measures and seizures suggesting that shifts in mEPSC were unlikely to account for the differential effects of D-APV and Ro25,6981 on seizures. However, the amplitude of tonic NMDAR-mediated currents was reduced in cultures treated chronically with D-APV and dramatically enhanced in cultures treated chronically with Ro25,6981. Because tonic NMDAR currents are mediated primarily by extrasynaptic NMDAR, these data show an inverse relationship between changes in extrasynaptic NMDAR function and alterations in seizure expression.

Topics: Animals; Dentate Gyrus; Disease Models, Animal; GABA-A Receptor Antagonists; Hippocampus; Phenols; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Seizures; Synaptic Transmission

Reversible acetylcholinesterase inhibitor donepezil displays prophylactic effects against intoxication with irreversible organophosphorous acetylcholinesterase inhibitors. We used behavioural observation of yawning and epileptic seizures, histochemical acetylcholinesterase staining, and in situ hybridization of the immediate early genes, c-fos and synaptotagmin 4 (Syt4) mRNAs in the brain, to evaluate whether donepezil could protect the brain against the effects of the organophosphate anticholinesterase, diisopropylfluorophosphate, in a rat model of intoxication. Diisopropylfluorophosphatetreated animals exhibited frequent yawning, significant inhibition of acetylcholinesterase staining and upregulation of c-fos mRNA, but not the epileptic seizures or significant change of Syt4 mRNA levels. In order to reduce the threshold for the induction of cholinergic seizures, additional groups of rats were pre-treated with LiCl 24 h before the treatment with diisopropylfluorophosphate. These rats exhibited the seizures, a significant inhibition of acetylcholinesterase staining and significant upregulation of c-fos and Syt4 mRNA levels. All the above-mentioned effects of diisopropylfluorophosphate were inhibited by donepezil pre-treatment. Donepezil pre-treatment by itself induced only a comparatively weaker inhibition of acetylcholinesterase staining and infrequent yawning. We conclude that donepezil protects the brain against diisopropylfluorophosphate-induced effects and that Syt4 mRNA upregulation may serve as a novel marker for organophosphate-induced seizures.

Topics: Acetylcholine; Acetylcholinesterase; Animals; Anticonvulsants; Brain; Cholinesterase Inhibitors; Donepezil; Genes, fos; Indans; Isoflurophate; Lithium Chloride; Male; Models, Animal; Piperidines; Rats; Rats, Wistar; Receptors, Cholinergic; RNA, Messenger; Seizures; Synaptotagmins; Up-Regulation; Yawning

Methionine-sulfoximine (MSO), a convulsant is known to increase the activity of histamine N-methyl transferase. The effect of a selective H3 receptor agonist R- (alpha) methylhistamine (RAMH) and antagonist (thioperamide, THP) and some antiepileptic drugs (gabapentin and sodium valproate) have been evaluated on MSO-induced convulsions in mice. The effect of THP was also evaluated in combination with these antiepileptic drugs. Sodium valproate (300 mg/kg, po) and gabapentin (400 mg/kg, po) offered protection against MSO-induced convulsions as evidenced by a significant prolongation of latency to abnormal dorsoflexion and complete protection against mortality within 6 h of administration. THP (15 mg/kg, ip) alone and in combination with sub-effective doses of gabapentin (75 mg/kg, po) and sodium valproate (75 mg/kg, po) revealed no significant differences from the control group or either drug alone. Hence, the convulsant action of MSO does not appear to be mediated via histaminergic mechanisms.

Topics: Amines; Animals; Anticonvulsants; Brain; Cyclohexanecarboxylic Acids; Drug Combinations; Gabapentin; gamma-Aminobutyric Acid; Male; Methionine Sulfoximine; Mice; Piperidines; Seizures; Valproic Acid

Typical N-methyl-D-aspartate (NMDA) receptor antagonists exhibit anticonvulsant action and unwanted effects, even in developing rats. Therefore, we studied the actions of the low-affinity, noncompetitive antagonist memantine and the NR2B-specific antagonist ifenprodil. Seizures (minimal clonic and generalized tonic-clonic) were elicited with pentylenetetrazol (100mg/kg subcutaneously) in rats 7, 12, 18, and 25 days old pretreated with memantine (2.5-40 mg/kg intraperitoneally) or ifenprodil (10-60 mg/kg intraperitoneally). The effects of both drugs were studied in open field and motor performance tests in 12-, 18-, and 25-day-old rats. Memantine suppressed generalized tonic-clonic seizures in all age groups; minimal seizures were potentiated. Ifenprodil abolished the tonic phase of generalized tonic-clonic seizures in 7-, 12-, and 18-day-old rats only; minimal seizures remained untouched. Memantine induced locomotor hyperactivity and compromised motor performance in all age groups. Ifenprodil exerted these effects only in 12-day-old rats; older animals were less active in open field tests. Memantine exhibits both anti- and pro-convulsant and behavioral effects typical of NMDA antagonists. Ifenprodil exerted the same effects in 12-day-old rats, but its anticonvulsant action in 18-day-old rats was accompanied by a decrease in locomotion.

Topics: Animals; Anticonvulsants; Behavior, Animal; Convulsants; Dose-Response Relationship, Drug; Epilepsy, Generalized; Excitatory Amino Acid Antagonists; Hand Strength; Learning; Memantine; Motor Activity; Orientation; Pentylenetetrazole; Piperidines; Postural Balance; Psychomotor Performance; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures

Cannabinoid system plays a pivotal role in the seizure threshold modulation which is mainly mediated through activation of the cannabinoid CB(1) receptor. There is also several evidence of interaction between cannabinoid system and other neurotransmitters including nitric oxide (NO) system. Using model of clonic seizure induced by pentylenetetrazole (PTZ) in male NMRI mice, we investigated whether NO is involved in the effects of cannabinoids on the seizure threshold. Injection of the selective cannabinoid CB(1) agonist ACEA (2mg/kg, i.p.) significantly (P<0.01) increased the seizure threshold which was prevented (P<0.001) by pretreatment with the selective CB(1) antagonist AM251 (1mg/kg, i.p.). The NO precursor l-arginine (50 and 100mg/kg, i.p.) potentiated the anticonvulsant effects of the sub-effective dose of ACEA (1mg/kg, i.p.). Pretreatment with non-effective doses of the non-specific NOS inhibitor l-NAME (15 and 30mg/kg, i.p.) and the specific neuronal NOS inhibitor 7-NI (40 and 80mg/kg, i.p.) but not the inducible NOS inhibitor aminoguanidine (10, 50 and 100mg/kg, i.p.) prevented the anticonvulsant effect of ACEA (2mg/kg, i.p.). Co-administration of non-effective dose of AM251 (0.5mg/kg) with both low and per se non-effective doses of l-NAME (1mg/kg, i.p.) and 7-NI (10mg/kg, i.p.) had significant (P<0.01) effect in preventing the anticonvulsant effect of ACEA (2mg/kg, i.p.). Our findings demonstrated that central NO system could be involved in the anticonvulsant properties of the specific cannabinoid CB(1) agonist ACEA, emphasizing on the interaction between two systems in the seizure modulation.

Topics: Analysis of Variance; Animals; Animals, Inbred Strains; Anticonvulsants; Arachidonic Acids; Arginine; Brain; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Male; Mice; NG-Nitroarginine Methyl Ester; Nitric Oxide; Pentylenetetrazole; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Seizures

Electrocorticography (ECoG) may be used to guide epilepsy surgery. However, anesthetics can suppress epileptiform activity or induce confounding burst-suppression patterns and the relationship between ECoG results and seizure outcome is controversial. In this study, we evaluated the ECoG activity under several different anesthetics and examined the relationship between ECoG and outcome.. We retrospectively studied 44 patients who had ECoG during epilepsy surgery. Anesthesia was with fentanyl and isoflurane (n = 19), fentanyl and sevoflurane (n = 9), remifentanil and sevoflurane (n = 5), remifentanil and propofol (n = 9), and fentanyl with propofol sedation during local anesthesia (n = 2). Pre-resection ECoG was considered satisfactory if epileptiform activity was present and there was no burst-suppression. Post-resection ECoG was graded according to residual epileptiform activity: A (none), B (mild), C (moderate). Seizure outcome was graded: I (seizure free without medication), II (seizure free with medication), III (> 50% seizure reduction) or IV (< 50% seizure reduction). Grades I-III were considered beneficial.. ECoG was satisfactory in 43 of the 44 surgeries, but one of the 11 recordings during propofol showed no epileptiform activity. Thirty-six of 37 patients (97%) with ECoG grade A or B and five of seven patients (71%) with ECoG grade C benefited from epilepsy surgery. Chi-squared, p > 0.05.. Satisfactory ECoG is possible using isoflurane or sevoflurane with nitrous oxide and fentanyl or remifentanil or using propofol and remifentanil. However, one of eleven ECoGs under propofol was negative for epileptiform activity. The amount of post-resection ECoG epileptiform activity does not significantly correlate with seizure outcome.

Topics: Adolescent; Adult; Anesthesia, General; Anesthetics; Child; Craniotomy; Electroencephalography; Epilepsy; Female; Fentanyl; Humans; Isoflurane; Jordan; Longitudinal Studies; Male; Methyl Ethers; Middle Aged; Piperidines; Propofol; Remifentanil; Retrospective Studies; Seizures; Sevoflurane; Treatment Outcome; Young Adult

Several results support the conclusion that the cannabinoid system has a role in generation and cessation of epileptic seizures. The aim of this study was to evaluate the effects of intracerebroventricular AM-251 [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide], a CB1-receptor antagonist, and ACEA (arachidonyl-2-chloroethylamide), a CB1-receptor agonist, on penicillin-induced epileptiform activity in rats.. In the first set of experiments, 30 min after penicillin injection, AM-251, at doses of 0.125, 0.25, 0.5, and 1 μg, was administered intracerebroventricularly (i.c.v.). In the second set of experiments, 30 min after penicillin injection, ACEA, at doses of 2.5, 5, 7.5, and 15 μg (i.c.v.), was administered. In the third set of experiments, AM-251, at doses of 0.125 and 0.25 μg (i.c.v.), was administered 10 min before ACEA (7.5 μg, i.c.v.) injection.. ACEA, at a dose of 7.5 μg, significantly decreased the frequency of penicillin-induced epileptiform activity without changing the amplitude. ACEA, at doses of 2.5, 5, and 15 μg, had no impact on either frequency or amplitude of epileptiform activity. AM-251, at doses of 0.25 and 0.50 μg, significantly increased the frequency of epileptiform activity. AM-251, at a dose of 0.25 μg (i.c.v.), was the most effective in changing the frequency of penicillin-induced epileptiform activity, and it also caused status epilepticus-like activity. AM-251, at doses of 0.125 and 0.25 μg, 10 min before ACEA (7.5 μg), reversed the anticonvulsant action of ACEA.. The results of the present study provide electrophysiologic evidence for the role of CB1 receptors in regulating the frequency of epileptiform activity in the model of penicillin-induced epilepsy. To elucidate the precise mechanism of cannabinoid action in the brain during seizure, more advanced electrophysiologic and neurochemical studies are required.

Topics: Animals; Anticonvulsants; Arachidonic Acids; Brain; Cannabinoids; Cerebral Cortex; Disease Models, Animal; Dose-Response Relationship, Drug; Electroencephalography; Epilepsy; Injections, Intraventricular; Male; Penicillins; Piperidines; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Seizures

Ifenprodil is a novel NMDA receptor antagonist that selectively inhibits receptors containing the NR2B subunit. Lindane, a widely used pesticide and scabicide, evokes seizures mainly through the blockade of the gamma-aminobutyric acid type A receptor complex. The aim of this study was to determine the effects of ifenprodil on the behavioral and electroencephalographic (EEG) manifestations of seizures in lindane-treated rats. Adult male Wistar rats with three electrodes implanted into the skull were treated intraperitoneally (i.p.) with lindane 8 mg/kg and observed for seizure behavior and EEG during the next 30 min. Seizure behavior was assessed by incidence, severity (determined by a descriptive rating scale ranging from 0 to 4) and duration of latency. Increasing doses of ifenprodil (5, 10, 20 mg/kg, i.p.) or vehicle were injected 30 min prior to lindane administration. Ifenprodil decreased the incidence and severity of lindane seizures and prolonged the latency to seizures in a dose-dependent manner. 20 mg/kg of ifenprodil significantly decreased the incidence (p < 0.05) and severity (p < 0.05) of seizures when compared to the vehicle treatment. Latency to seizures was significantly prolonged by 10 and 20 mg/kg of ifenprodil. The estimated ED(50) value of ifenprodil was 15.53 (5.48-15.20) mg/kg. The lindane-induced bursts of spiking activity in EEG were not completely suppressed by the applied doses of ifenprodil. These results indicate that ifenprodil alleviates behavioral seizures and modifies EEG characteristics of lindane seizures in rats, thus showing the involvement of NMDA receptors containing the NR2B subunit in the mechanisms of lindane convulsions.

Topics: Animals; Dose-Response Relationship, Drug; Drug Interactions; Electroencephalography; Excitatory Amino Acid Antagonists; Hexachlorocyclohexane; Male; Piperidines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures

This study examines electroencephalographic (EEG) and motor seizure duration and dynamic energy according to age and sex using remifentanil anesthesia in standard electroconvulsive therapy (ECT).. In an earlier study, we showed that remifentanil provides superior anesthesia for ECT in terms of providing adequate seizure duration with lower stimulus doses in patients refractory to maximal ECT settings with methohexital.. Patients, refractory to maximal ECT settings with methohexital, received remifentanil as the sole anesthetic agent. Stimulus dose was determined by the dose-titration method. Electroencephalographic seizure duration, motor seizure duration, and dynamic energy in joules (j) were compared between male and female subjects and among patients aged 40 years or younger, older than 40 years but aged 65 years or younger, and older than 65 years.. Seventy-two patients were included in the study. There was no significant difference in remifentanil doses between female and male subjects. There was no significant statistical difference between female and male subjects regarding motor seizure duration, EEG seizure duration, or dynamic energy (P > 0.05). There were significant statistical differences among different groups in terms of motor seizure duration, EEG seizure duration, and dynamic energy (P< 0.05). The younger age group had longer motor and EEG seizure durations and required lower dynamic energy.. There is no significant effect of sex on ECT with remifentanil anesthesia regarding EEG or motor seizure durations or dynamic energy; however, statistically significant differences were observed based upon age. Younger patients had both increased motor and EEG seizure duration compared with older patients who may require higher stimulus doses than younger patients for comparable motor and EEG seizure durations.

Topics: Adult; Age Factors; Aged; Anesthesia, General; Anesthetics, Intravenous; Dose-Response Relationship, Drug; Electroconvulsive Therapy; Electroencephalography; Female; Humans; Male; Middle Aged; Piperidines; Remifentanil; Retrospective Studies; Seizures; Sex Factors; Time Factors

Propofol is a widely used anesthetic agent for electroconvulsive therapy (ECT). However, there are concerns that its anticonvulsant effect may interfere with the efficacy of ECT. We aimed to investigate the effects on seizure activity of the addition of the opiate remifentanil to propofol anesthesia for ECT.. A retrospective analysis of 633 treatments in 73 patients was conducted. At each treatment, patients had received anesthesia with propofol alone or propofol plus remifentanil, depending on which anesthetist was providing anesthesia. Analysis of variance was performed to examine the effects of the anesthetic used, the electrode placement, the dose of electricity administered, and the stage in the course of treatment. Dependent variables were electroencephalogram seizure length and postictal suppression index (PSI).. Addition of remifentanil resulted in a small but significantly lower dose of propofol being used to induce unconsciousness. Addition of remifentanil affected seizure length, mainly related to an effect when placement was right unilateral (F = 5.70; P = 0.017). There was also a significantly increased PSI (F = 4.3; P = 0.039), which was not dependent on dose or on placement.. The data suggest that addition of remifentanil to propofol anesthesia significantly alters seizure indices. This may be secondary to a reduction in the amount of propofol required or to an independent effect of remifentanil. The increase in PSI in particular suggests that addition of remifentanil may improve clinical response. However, this can only be examined in a randomized controlled trial.

Topics: Analysis of Variance; Anesthesia; Anesthetics, Combined; Anesthetics, Intravenous; Dose-Response Relationship, Drug; Electroconvulsive Therapy; Electroencephalography; Humans; Piperidines; Propofol; Remifentanil; Retrospective Studies; Seizures

Several studies have reported that endogenous opioid and cannabinoid systems may be involved in some pathophysiological changes occurring in cholestatic liver disease. It is well known that endogenous opioids and cannabinoids alter the susceptibility of experimental animals to different models of seizure.. The alterations in pentylenetetrazole-induced clonic seizure thresholds were evaluated from 1 to 6 days after bile duct ligation in mice. Whether the pretreatment of cholestatic mice with different doses of opioid receptor antagonist naltrexone or cannabinoid CB(1) receptor antagonist AM251 (AM251) would have changed the clonic seizure threshold was also examined.. Although the clonic seizure threshold was similar between sham-operated and unoperated mice, there was a time-dependent increase in the threshold in cholestatic mice, reaching a peak on day 3 after bile duct ligation and declining partially after day 4. Chronic pretreatment with naltrexone (2, 5, and 10 mg/kg) reversed the increased threshold in cholestatic mice on day 3 after operation in a dose-dependent manner with the highest doses used restoring the threshold to that of the control animals. A similar reversal of the increased threshold was observed after acute (0.5, 0.75, and 1 mg/kg) or chronic (0.5 mg/kg for 4 days) pretreatment with AM251. Moreover, concurrent administration of doses of AM251 and naltrexone that each separately induced a partial reversal of increased seizure threshold in cholestasis caused a complete restoring of the threshold to the control level.. Both opioid and cannabinoid CB(1) receptors may be involved in the dramatic increase in pentylenetetrazole-induced seizure threshold in cholestasis.

Topics: Animals; Anticonvulsants; Bile Ducts; Cannabinoid Receptor Modulators; Cholestasis; Disease Models, Animal; Dose-Response Relationship, Drug; Ligation; Male; Mice; Naltrexone; Narcotic Antagonists; Opioid Peptides; Pentylenetetrazole; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, Opioid; Seizures; Time Factors

Excitotoxicity involves over activation of brain excitatory glutamate receptors and has been implicated in neurological, neurodegenerative and neuropsychiatric diseases. Metabolism of arachidonic acid (AA) through the phospholipase A(2) (PLA(2))/prostaglandin-endoperoxide synthase (PTGS) pathway is increased after excitotoxic stimulation. However, the individual roles of the PTGS isoforms in this process are not well established. We assessed the role of the PTGS isoforms in the process of excitotoxicity by exposing mice deficient in either PTGS-1 (PTGS-1(-/-)) or PTGS-2 (PTGS-2(-/-)) to the prototypic excitotoxin, kainic acid (KA). Seizure intensity and neuronal damage were significantly elevated in KA-exposed PTGS-2(-/-), but not in PTGS-1(-/-), mice. The increased susceptibility was not associated with an alteration in KA receptor binding activity or mediated through the CB1 endocannabinoid receptor. The frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) was decreased in the CA1 pyramidal neurons of PTGS-2(-/-) mice, suggesting an alteration of GABAergic function. In wild-type mice, six weeks treatment with the PTGS-2 selective inhibitor celecoxib recapitulated the increased susceptibility to KA-induced excitotoxicity observed in PTGS-2(-/-) mice, further supporting the role of PTGS-2 in the excitotoxic process. The increased susceptibility to KA was also associated with decreased brain levels of PGE(2), a biomarker of PTGS-2 activity. Our results suggest that PTGS-2 activity and its specific products may modulate neuronal excitability by affecting GABAergic neurotransmission. Further, inhibition of PTGS-2, but not PTGS-1, may increase the susceptibility to seizures.

Topics: Analysis of Variance; Animals; Autoradiography; Celecoxib; Chromatography, High Pressure Liquid; Cyclooxygenase 1; Cyclooxygenase 2; Enzyme-Linked Immunosorbent Assay; gamma-Aminobutyric Acid; Hippocampus; Kainic Acid; Male; Membrane Potentials; Membrane Proteins; Mice; Mice, Knockout; Neurons; Patch-Clamp Techniques; Piperidines; Pyrazoles; Seizures; Statistics, Nonparametric; Sulfonamides; Synaptic Transmission

Cannabinoid compounds are anticonvulsant since they have inhibitory effects at micromolar doses, which are mediated by activated receptors coupling to G(i/o) proteins. Surprisingly, both the analgesic and anticonvulsant effects of opioids are enhanced by ultra-low doses (nanomolar to picomolar) of the opioid antagonist naltrexone and as opioid and cannabinoid systems interact, it has been shown that ultra-low dose naltrexone also enhances cannabinoid-induced antinociception. Thus, concerning the seizure modulating properties of both classes of receptors this study investigated whether the ultra-low dose opioid antagonist naltrexone influences cannabinoid anticonvulsant effects. The clonic seizure threshold was tested in separate groups of male NMRI mice following injection of vehicle, the cannabinoid selective agonist arachidonyl-2-chloroethylamide (ACEA) and ultra-low doses of the opioid receptor antagonist naltrexone and a combination of ACEA and naltrexone doses in a model of clonic seizure induced by pentylenetetrazole (PTZ). Systemic injection of ultra-low doses of naltrexone (1pg/kg to 1ng/kg, i.p.) significantly potentiated the anticonvulsant effect of ACEA (1mg/kg, i.p.). Moreover, the very low dose of naltrexone (500pg/kg) unmasked a strong anticonvulsant effect for very low doses of ACEA (10 and 100microg/kg). A similar potentiation by naltrexone (500pg/kg) of anticonvulsant effects of non-effective dose of ACEA (1mg/kg) was also observed in the generalized tonic-clonic model of seizure. The present data indicate that the interaction between opioid and cannabinoid systems extends to ultra-low dose levels and ultra-low doses of opioid receptor antagonist in conjunction with very low doses of cannabinoids may provide a potent strategy to modulate seizure susceptibility.

Topics: Animals; Anticonvulsants; Arachidonic Acids; Cannabinoid Receptor Agonists; Cannabinoids; Convulsants; Dose-Response Relationship, Drug; Drug Synergism; Epilepsy, Generalized; Epilepsy, Tonic-Clonic; Injections, Intraperitoneal; Male; Mice; Naltrexone; Narcotic Antagonists; Pentylenetetrazole; Piperidines; Pyrazoles; Seizures

The delay in onset and treatment resistance of subpopulations of depressed patients to conventional serotonin reuptake inhibitors has lead to new drug development strategies to produce agents with improved antidepressant efficacy.. We report the in vivo characterization of the novel 5-HT(1A/1B) autoreceptor antagonist/5-HT transporter inhibitor (6-[(1-{2-[(2-methyl-5-quinolinyl)oxy]ethyl}-4-piperidinyl)methyl]-2H-1,4-benzoxazin-3(4H)-one), SB-649915-B.. Ex vivo binding was used to ascertain 5-HT(1A) receptor and serotonin transporter occupancy. 8-OH-DPAT-induced hyperlocomotion and SKF-99101-induced elevation of seizure threshold were used as markers of central blockade of 5-HT(1A) and 5-HT(1B) receptors, respectively. In vivo electrophysiology in the rat dorsal raphe and microdialysis in freely moving guinea pigs and rats were used to evaluate the functional outcome of SB-649915-B.. SB-649915-B (1-10 mg/kg p.o.) produced a dose-related inhibition of 5-HT(1A) receptor radioligand binding and inhibited ex vivo [(3)H]5-HT uptake in both guinea pig and rat cortex. SB-649915-B (0.1-10 mg/kg p.o.) reversed both 8-OH-DPAT-induced hyperlocomotor activity and SKF-99101-induced elevation of seizure threshold in the rat, demonstrating in vivo blockade of both 5-HT(1A) and 5-HT(1B) receptors, respectively. SB-649915-B (0.1-3 mg/kg i.v.) produced no change in raphe 5-HT neuronal cell firing per se but attenuated the inhibitory effect of 8-OH-DPAT. Acute administration of SB-649915-B resulted in increases (approximately two- to threefold) in extracellular 5-HT in the cortex of rats and the dentate gyrus and cortex of guinea pigs.. Based on these data, one may speculate that the 5-HT autoreceptor antagonist/5-HT transport inhibitor SB-649915-B will have therapeutic efficacy in the treatment of affective disorders with the potential for a faster onset of action compared to current selective serotonin reuptake inhibitors.

Topics: Animals; Benzoxazines; Dentate Gyrus; Dose-Response Relationship, Drug; Electrophysiology; Electroshock; Guinea Pigs; Locomotion; Male; Microdialysis; Mood Disorders; Neurons; Piperidines; Prefrontal Cortex; Quinolines; Radioligand Assay; Raphe Nuclei; Rats; Rats, Sprague-Dawley; Seizures; Selective Serotonin Reuptake Inhibitors; Serotonin; Serotonin 5-HT1 Receptor Antagonists; Serotonin Plasma Membrane Transport Proteins; Species Specificity

Current treatment of nerve agent poisoning consists of prophylactic administration of pyridostigmine and therapy using atropine, an oxime and a benzodiazepine. Pyridostigmine does however not readily penetrate the blood-brain barrier giving ineffective protection of the brain against centrally mediated seizure activity. In this study, we have evaluated donepezil hydrochloride, a partial reversible inhibitor of acetylcholinesterase (AChE) clinically used for treating Alzheimer's disease, in combination with procyclidine, used in treatment of Parkinson's disease and schizophrenia, as prophylaxis against intoxication by the nerve agent soman. The results demonstrated significant protective efficacy of donepezil (2.5 mg/kg) combined with procyclidine (3 or 6 mg/kg) when given prophylactically against a lethal dose of soman (1.6 x LD(50)) in Wistar rats. No neuropathological changes were found in rats treated with this combination 48 h after soman intoxication. Six hours after soman exposure cerebral AChE activity and acetylcholine (ACh) concentration was 5% and 188% of control, respectively. The ACh concentration had returned to basal levels 24 h after soman intoxication, while AChE activity had recovered to 20% of control. Loss of functioning muscarinic ACh receptors (17%) but not nicotinic receptors was evident at this time point. The recovery in brain AChE activity seen in our study may be due to the reversible binding of donepezil to the enzyme. Donepezil is well tolerated in humans, and a combination of donepezil and procyclidine may prove useful as an alternative to the currently used prophylaxis against nerve agent intoxication.

Topics: Acetylcholine; Acetylcholinesterase; Animals; Body Temperature; Brain; Convulsants; Donepezil; Electroencephalography; Indans; Male; Muscarinic Antagonists; Nootropic Agents; Piperidines; Procyclidine; Rats; Rats, Wistar; Receptors, Cholinergic; Seizures; Soman

We showed that dextromethorphan (DM) provides neuroprotective/anticonvulsant effects and that DM and its major metabolite, dextrorphan, have a high-affinity for sigma(1) receptors, but a low affinity for sigma(2) receptors. In addition, we found that DM has a higher affinity than DX for sigma(1) sites, whereas DX has a higher affinity than DM for PCP sites. We extend our earlier findings by showing that DM attenuated trimethyltin (TMT)-induced neurotoxicity (convulsions, hippocampal degeneration and spatial memory impairment) in rats. This attenuation was reversed by the sigma(1) receptor antagonist BD 1047, but not by the sigma(2) receptor antagonist ifenprodil. DM attenuates TMT-induced reduction in the sigma(1) receptor-like immunoreactivity of the rat hippocampus, this attenuation was blocked by the treatment with BD 1047, but not by ifenprodil. These results suggest that DM prevents TMT-induced neurotoxicity, at least in part, via sigma(1) receptor stimulation.

Topics: Adrenergic alpha-Antagonists; Animals; Avoidance Learning; Behavior, Animal; Dextromethorphan; Ethylenediamines; Immunohistochemistry; Learning Disabilities; Maze Learning; Memory; Nerve Degeneration; Neurotoxicity Syndromes; Piperidines; Radioligand Assay; Rats; Rats, Inbred F344; Receptors, Phencyclidine; Receptors, sigma; Seizures; Sigma-1 Receptor; Trimethyltin Compounds

Bis-Mannich bases, bis(3-aryl-3-oxopropyl)ethylamine hydrochlorides 1-4, and their corresponding structural and non-classical isomers, 4-aryl-3-arylcarbonyl-1-ethyl-4-piperidinol hydrochlorides 5-8, were synthesized. The aryl part was phenyl in 1 and 5, p-methylphenyl in 2 and 6, p-chlorophenyl in 3 and 7, and 2-thienyl in 4 and 8. The chemical stuructures of the compounds were confirmed by 1H-NMR, 13C-NMR, UV, IR and elemental analyses. Anticonvulsant activities of the compounds were evaluated by the maximum electroshock (MES) and subcutaneous pentylenetetrazole (scMet) tests in the dose range of 30-300 mg/kg. Alterations in biological activity depending on modifications in chemical structure were also followed. Compounds 1-4, 6, and 8 were toxic and caused death of the animals 20 min after the injection. Compounds 2, 3 and 6 were also neurotoxic at the 100 mg/kg dose level. While only compound 7 was active in the scMet test at 300 mg/kg within 4 h, all the compounds showed activity in the MES test at different dose levels and time periods. In conclusion, compounds 5 and 7, which were not toxic and did not show neurotoxicity, seemed to be candidate compounds to develop new anticonvulsant compounds useful in the treatment of the grand mal (compounds 5, 7) and petit mal (compound 7) epilepsies.

Topics: Animals; Anticonvulsants; Convulsants; Electroshock; Elements; Ethylamines; Indicators and Reagents; Magnetic Resonance Spectroscopy; Male; Mannich Bases; Mice; Neurotoxicity Syndromes; Pentylenetetrazole; Piperidines; Postural Balance; Seizures; Spectrophotometry, Infrared

The cleft-type cyclophanes (ACCn, DNCn and TsDCn) were found to strongly inhibit macroscopic currents at heteromeric NMDA receptors (NR1/NR2) but not AMPA receptors expressed in Xenopus oocytes at voltage-clamp recording. The inhibition by cleft-type cyclophanes was voltage-dependent, because the inhibition was larger at -100 mV than at -20 mV. Mutations at NR1 N650, located in the vestibule of the channel pore, reduced the inhibition by DNCn and TsDCn, suggesting that the residue (N650) interacts with these cleft-type cyclophanes. Cell toxicity of TsDCn on SH-SY5Y cells was slightly weaker than that of memantine. The neuroprotective effects of cleft-type cyclophanes against cell damage caused by NMDA were investigated in cultured rat hippocampal neurons. Addition of 10 microM DNCn or TsDCn into the medium ablated the neurotoxicity induced by NMDA, and a similar effect was also observed with memantine. The neuroprotective effects of cleft-type cyclophanes were then assayed on NMDA-induced seizures in mice. Intracerebroventricular injection of TsDCn (5 mg/mouse) decreased the seizure induced by intraperitoneal injection of NMDA (115 mg/kg) in mice. The results demonstrate that these cleft-type cyclophanes interact directly with the extracellular mouth of the NMDA channel pore and exhibit neuroprotective effects on NMDA-induced excitatory toxicity in primary cultured neurons and mice.

Topics: Animals; Cell Line, Tumor; Ethers, Cyclic; Female; Hippocampus; Larva; Mice; N-Methylaspartate; Neuroblastoma; Neurons; Neuroprotective Agents; Neurotoxins; Piperidines; Rats; Receptors, N-Methyl-D-Aspartate; Seizures; Xenopus

Several lines of evidence suggest that cannabinoid compounds are anticonvulsant since they have inhibitory effects at micromolar doses, which are mediated by activated receptors coupling to Gi/o proteins. Surprisingly, both the analgesic and anticonvulsant effects of opioids are enhanced by ultra-low doses (nanomolar to picomolar) of the opioid antagonist naltrexone and as opioid and cannabinoid systems interact, it has been shown that ultra-low dose naltrexone also enhances cannabinoid-induced antinociception. However, regarding the seizure modulating properties of both classes of receptors this study investigated whether ultra-low dose cannabinoid antagonist AM251 influences cannabinoid anticonvulsant effects. The clonic seizure threshold (CST) was tested in separate groups of male NMRI mice following injection of vehicle, the cannabinoid selective agonist arachidonyl-2-chloroethylamide (ACEA) and ultra-low doses of the cannabinoid CB1 antagonist AM251 and a combination of ACEA and AM251 doses in a model of clonic seizure induced by pentylenetetrazole (PTZ). Systemic administration of ultra-low doses of AM251 (10 fg/kg-100 ng/kg) significantly potentiated the anticonvulsant effect of ACEA at 0.5 and 1 mg/kg. Moreover, inhibition of cannabinoid induced excitatory signaling by AM251 (100 pg/kg) unmasked a strong anticonvulsant effect for very low doses of ACEA (100 ng/kg-100 microg/kg), suggesting that a presumed inhibitory component of cannabinoid receptor signaling can exert strong seizure-protective effects even at very low levels of cannabinoid receptor activation. A similar potentiation by AM251 (100 pg/kg and 1 ng/kg) of anticonvulsant effects of non-effective dose of ACEA (0.5 and 1 mg/kg) was also observed in the generalized tonic-clonic model of seizure. The present data suggest that ultra-low doses of cannabinoid receptor antagonists may provide a potent strategy to modulate seizure susceptibility, especially in conjunction with very low doses of cannabinoids.

Topics: Animals; Anticonvulsants; Arachidonic Acids; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Convulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Male; Mice; Pentylenetetrazole; Piperidines; Pyrazoles; Seizures

New series of imidazolones and pyrrolones were synthesized. The compounds were tested regarding their anxiolytic properties due to modulation of the GABAA receptor response. Several derivatives exhibit considerable pharmacological activity while lacking the typical side effects of benzodiazepine receptor agonists. 1-(4-chlorophenyl)-4-morpholin-1-yl-1,5-dihydro-imidazol-2-one (2) and 1-(4-chlorophenyl)-4-piperidin-1-yl-1,5-dihydro-imidazol-2-one (3) were protective in the pentylenetetrazole test in rats with oral ED50 of 27.4 and 12.8 mg/kg and TD50 (rotarod) of >500 and 265 mg/kg, respectively. The minimum effective dose in the Vogel conflict test was 3 mg/kg for both compounds. Common structure-activity relationship and comparative molecular field analysis models of the various series of derivatives could be established which are in accordance with a GABAA mediated pharmacological action. The findings fit well into an established pharmacophore model. This model is refined by an additional steric restriction feature.

Topics: Administration, Oral; Animals; Anti-Anxiety Agents; Anticonvulsants; Binding Sites; Brain; GABA Antagonists; GABA-A Receptor Agonists; Imidazoles; Male; Mice; Models, Molecular; Morpholines; Pentylenetetrazole; Piperidines; Pyrroles; Quantitative Structure-Activity Relationship; Radioligand Assay; Rats; Rats, Wistar; Rotarod Performance Test; Seizures

In our studies on the development of new anticonvulsants, we planned the synthesis of N-substituted 1,2,3,4-tetrahydroisoquinolines to explore the structure-activity relationships. All derivatives were evaluated against audiogenic seizures in DBA/2 mice, and the 1-(4'-bromophenyl)-6,7-dimethoxy-2-(piperidin-1-ylacetyl) derivative (26) showed the highest activity with a potency comparable to that of talampanel, the only noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonist in clinical trials as an anticonvulsant agent. Electrophysiological experiments indicated that 26 acts as noncompetitive AMPA receptor modulator.

Topics: Acoustic Stimulation; Animals; Anticonvulsants; In Vitro Techniques; Isoquinolines; Male; Mice; Mice, Inbred DBA; Olfactory Pathways; Piperidines; Rats; Rats, Wistar; Receptors, AMPA; Seizures; Structure-Activity Relationship; Tetrahydroisoquinolines

Freeze-lesion-induced focal cortical dysplasia in rats closely resembles human microgyria, a neuronal migration disorder associated with drug-resistant epilepsy. Alterations in expression of N-methyl-D-aspartate receptors (NMDARs) containing NR2B subunits have been suggested to play a role in the hyperexcitability seen in this model. We examined the effect of NMDAR antagonists selective for NR2B subunits (Ro 25-6981 and ifenprodil) on activity evoked by intracortical stimulation in brain slices from freeze-lesioned rat neocortex. Whole-cell voltage-clamp recordings showed that Ro 25-6981 (1 microM) significantly reduced the response area of evoked postsynaptic currents in pyramidal cells from the paramicrogyral area whereas responses were unaffected in slices from control (sham operated) animals. Voltage-sensitive dye imaging was used to examine spatiotemporal spread of evoked activity in lesioned and control cortices. The imaging experiments revealed that peak amplitude, duration, and lateral spread of evoked activity in the paramicrogyral area was reduced by bath application of Ro 25-6981 (1 microM) and ifenprodil (10 microM). Ro 25-6981 had no effect on evoked activity in neocortical slices from control animals. The non-selective NMDAR antagonist d-2-amino-5-phosphonvaleric acid (APV, 20 microM) reduced activity evoked in presence of 50 microM 4-aminopyridine (known to increase excitability by enhancing neurotransmitter release) in neocortical slices from control animals whereas Ro 25-6981 (1 microM) did not. These results suggest that NR2B subunit-containing NMDARs contribute significantly to the enhanced spatiotemporal spread of paroxysmal activity observed in vitro in the rat freeze-lesion model of focal cortical dysplasia.

Topics: Adrenergic alpha-Antagonists; Animals; Disease Models, Animal; Evoked Potentials; Neocortex; Patch-Clamp Techniques; Peptide Fragments; Phenols; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Seizures

3D QSAR studies on the title compounds led to the development of a model with three biophoric sites and six secondary sites viz. H-acceptor (ACC), H-donor (DON), heteroatom (presence), hydrophobic (hydrophobicity), steric (refractivity), and a ring (presence) along with total hydrophobicity and total refractivity as global properties. The model predicted the test set of compounds reasonably well. Three of the five newly synthesized 2-substituted octahydropyrazinopyridoindoles have shown potent antihistaminic H(1) activity with less toxicity and sedation potential.

Topics: Animals; Diphenhydramine; Guinea Pigs; Histamine Antagonists; Ileum; Indoles; Male; Mice; Molecular Structure; Piperazines; Piperidines; Quantitative Structure-Activity Relationship; Seizures

Exposure to the organophosphate nerve agent soman produces seizures that in turn lead to neuropathology. This study describes the temporal and spatial evolution of brain pathology following soman-induced convulsions and the attenuation of these alterations after neuroprotective intervention with magnetic resonance imaging (MRI). Neuroimaging 12 h after soman exposure, the hippocampus and thalamus exhibited significant decreases (23%) in apparent diffusion coefficients (ADC). These acute effects were resolved by 7 days. In addition, T2 measurements declined significantly at 12 h (37%) returning to near normal values by 24 h. Histopathological analyses confirmed moderate cell loss within the hippocampus and piriform cortex. Together these findings suggest that initial cell death was resolved through regional cellular remodeling. Pharmacological countermeasures were administered in the form of diazepam, a benzodiazepine anticonvulsant, or gacyclidine (GK-11), an anti-glutamatergic compound. Diazepam therapy applied immediately after soman exposure prevented acute ADC changes. However the presence of edema, using T2 measurements, was detected at 3 h within the retrosplenial, amygdala and piriform cortices and at 12 h in the thalamus (34% below normal). GK-11 therapy appeared to prevent most of these changes. However at 7 days after soman, a decrease (17%) in ADC was observed in the piriform cortex. Pathology was confined to the piriform cortex suggesting that this region is more difficult to protect. This is the first report that provides temporal and spatial resolution using MRI with histological correlation of pharmacological interventions against soman-mediated seizure-induced neuropathology.

Topics: Animals; Anticonvulsants; Brain; Cell Death; Cyclohexanes; Cyclohexenes; Diazepam; Diffusion Magnetic Resonance Imaging; Magnetic Resonance Imaging; Male; Neuroprotective Agents; Piperidines; Rats; Rats, Sprague-Dawley; Seizures; Soman; Status Epilepticus

Dyskinesias and seizures are both medically refractory disorders for which cannabinoid-based treatments have shown early promise as primary or adjunctive therapy. Using the Borna disease (BD) virus rat, an animal model of viral encephalopathy with spontaneous hyperkinetic movements and seizure susceptibility, we identified a key role for endocannabinoids in the maintenance of a balanced tone of activity in extrapyramidal and limbic circuits. BD rats showed significant elevations of the endocannabinoid anandamide in subthalamic nucleus, a relay nucleus compromised in hyperkinetic disorders. While direct and indirect cannabinoid agonists had limited motor effects in BD rats, abrupt reductions of endocannabinoid tone by the CB1 antagonist SR141716A (0.3 mg/kg, i.p.) caused seizures characterized by myoclonic jerks time-locked to periodic spike/sharp wave discharges on hippocampal electroencephalography. The general opiate antagonist naloxone (NLX) (1 mg/kg, s.c.), another pharmacologic treatment with potential efficacy in dyskinesias or L-DOPA motor complications, produced similar seizures. No changes in anandamide levels in hippocampus and amygdala were found in convulsing NLX-treated BD rats. In contrast, NLX significantly increased anandamide levels in the same areas of normal uninfected animals, possibly protecting against seizures. Pretreatment with the anandamide transport blocker AM404 (20 mg/kg, i.p.) prevented NLX-induced seizures. These findings are consistent with an anticonvulsant role for endocannabinoids, counteracting aberrant firing produced by convulsive agents, and with a functional or reciprocal relation between opioid and cannabinoid tone with respect to limbic convulsive phenomena.

Topics: Animals; Anticonvulsants; Arachidonic Acids; Basal Ganglia; Borna Disease; Cannabinoid Receptor Modulators; Convulsants; Disease Models, Animal; Endocannabinoids; Limbic System; Male; Movement Disorders; Naloxone; Narcotic Antagonists; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Inbred Lew; Receptor, Cannabinoid, CB1; Rimonabant; Seizures

Electroconvulsive therapy (ECT) is standard treatment of severe depression. The induction of a seizure is a core event in successful ECT. Although propofol is a frequently used anesthetic agent, one of its limitations is a reduction of seizure duration. No such effects have been reported regarding remifentanil, an ultrarapid-acting opioid that is used to induce and maintain anesthesia. The simultaneous administration of propofol and remifentanil may have similar safety and efficacy in terms of induction of anesthesia during ECT as propofol alone and significantly increase seizure duration.. Twenty-one ECT patients (10 men, 11 women, aged 24 to 81 years) were recruited. Muscle paralysis was achieved with succinylcholine (0.5-0.75 mg/kg intravenously [IV]). Unconsciousness was induced by either propofol (1 mg/kg IV) or propofol (0.5 mg/kg IV) + remifentanil (1 microg/kg) in a crossover format. ECT was administered according to established clinical protocols at the Sheba Medical Center, Israel. No changes in ECT current were permitted in the 2 protocols of each patient. Statistical analysis was based on paired t tests.. In all but 2 cases, seizure duration was significantly longer in the remifentanil group than in the control group (motor seizure 53.7 +/- 28.3 seconds vs. 29.5 +/- 10.9 seconds, t = 4.017, P = 0.0007; Electroencephalographic (EEG) seizures 60.8 +/- 25.1 seconds vs. 40.1 +/- 17.0 seconds, t = 3.971, P = 0.001). No significant differences were found in mean recovery time, post-treatment elevation in blood pressure, heart-beat, or oxygen saturation.. During anesthesia, the addition of remifentanil to propofol appears to be as effective as propofol alone with regard to anesthesia efficacy and cardiovascular function while significantly increasing seizure duration. Whether this discovery is of relevance to the clinical efficacy of ECT remains to be tested.

Topics: Adult; Aged; Aged, 80 and over; Anesthetics, Intravenous; Depressive Disorder, Major; Electroconvulsive Therapy; Female; Hemodynamics; Humans; Male; Middle Aged; Piperidines; Propofol; Remifentanil; Schizophrenia; Seizures; Time Factors

Rapid administration of large doses of ammonia leads to death of animals, which is largely prevented by pretreatment with N-methyl-D-aspartate (NMDA) receptor antagonists. The present study focuses on a subunit(s) of NMDA receptor involved in ammonia-induced death by use of NMDA receptor GluRepsilon subunit-deficient (GluRepsilon(-/-)) mice and the selective GluRepsilon2 antagonist CP-101,606. Acute ammonia intoxication was induced in mice (eight per group) by a single intraperitoneal (i.p.) injection of ammonium chloride. Appearance of neurological deteriorations depended on the doses of ammonium chloride injected. While wild-type, GluRepsilon1(-/-), GluRepsilon4(-/-), and GluRepsilon1(-/-)/epsilon4(-/-) mice all died by ammonium chloride at 12 mmol/kg during the first tonic convulsions, two of eight GluRepsilon3(-/-) mice survived. Pretreatment of wild-type mice with CP-101,606 prevented two mice from ammonia-induced death. Pretreatment of GluRepsilon3(-/-) mice with CP-101,606 prevented the death of three mice and prolonged the time of death of non-survivors. Similarly, the neuronal form of nitric oxide synthase (NOS) inhibitor 7-nitroindazole (7-NI) as well as the nonselective NOS inhibitor L-NMMA, but not the inducible NOS inhibitor 1400W, partially prevented the death of mice and prolonged the period of death. Furthermore, ammonium chloride prolonged the increase in intracellular free Ca2+ concentration ([Ca2+]i) and subsequent NO production induced by NMDA in the cerebellum. These results suggest that activation of NMDA receptor containing GluRepsilon2 and GluRepsilon3 subunits and following activation of neuronal NOS are involved in acute ammonia intoxication which leads to death of animals.

Topics: Ammonia; Animals; Calcium; Cerebellum; Coma; Dizocilpine Maleate; Dose-Response Relationship, Drug; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Injections, Intraperitoneal; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Piperidines; Receptors, N-Methyl-D-Aspartate; Seizures

Topics: Anesthetics, Intravenous; Bipolar Disorder; Drug Resistance; Drug Therapy, Combination; Electroconvulsive Therapy; Female; Humans; Methohexital; Middle Aged; Piperidines; Remifentanil; Seizures; Treatment Outcome

Cannabinoid and opioid receptor agonists show functional interactions in a number of their physiological effects. Regarding the seizure-modulating properties of both classes of receptors, the present study examined the possibility of a functional interaction between these receptors. We used acute systemic administration of cannabinoid selective CB(1) receptor agonist (ACPA) and antagonist (AM251) and opioid receptor agonist (morphine) and antagonists (naltrexone and norbinaltorphimine) in a model of clonic seizure induced by pentylenetetrazole (PTZ). Acute administration of ACPA (1.5-2 mg/kg) increased the PTZ-induced seizure threshold. In contrast, AM251 (0.5-2 mg/kg) dose-dependently decreased the seizure threshold. Low dose of AM251 (0.5 mg/kg), which did not alter seizure threshold by itself, reversed the anticonvulsant effect of ACPA (2 mg/kg), showing a CB(1) receptor-mediated mechanism. Naltrexone (1 or 10 mg/kg) but not specific kappa-opioid receptor antagonist norbinaltorphimine (5 mg/kg) completely reversed the anticonvulsant effect of ACPA (2 mg/kg). Moreover, the combination of the lower doses of AM251 (0.5 mg/kg) and naltrexone (0.3 mg/kg) had an additive effect in blocking the anticonvulsant effect of ACPA. In accordance with previous reports, morphine exerted biphasic effects on clonic seizure threshold with anticonvulsant effect at lower (0.5-1 mg/kg) and proconvulsant effect at a higher (30 mg/kg) doses. The pretreatment with AM251 blocked the anticonvulsant effect of morphine at 1 mg/kg, while pretreatment with ACPA (1 mg/kg) potentiated the anticonvulsant effect of morphine at 0.5 mg/kg. The proconvulsant effect of morphine at 30 mg/kg was also inhibited by AM251 (2 mg/kg). A similar interaction between cannabinoids and opioids was also detected on their anticonvulsant effects against the generalized tonic-clonic model of seizure. In conclusion, cannabinoids and opioids show functional interactions on modulation of seizure susceptibility.

Topics: Analysis of Variance; Animals; Arachidonic Acids; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Cannabinoids; Differential Threshold; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Male; Mice; Mice, Inbred Strains; Morphine; Naltrexone; Narcotic Antagonists; Narcotics; Pentylenetetrazole; Piperidines; Pyrazoles; Reaction Time; Receptor, Cannabinoid, CB1; Receptors, Opioid; Seizures; Statistics, Nonparametric; Time Factors

The effects of histamine H3 antagonists on amygdaloid kindled and maximal electroshock seizures in rats were studied to determine their potential as new antiepileptic drugs. Under pentobarbital anesthesia, rats were fixed to a stereotaxic apparatus and a stainless steel guide cannula for drug administration was implanted into the lateral ventricle. In amygdaloid kindled seizures, electrodes were implanted into the right amygdala and electroencephalogram was recorded bipolarly; stimulation was applied bipolarly every day by a constant current stimulator and continued until a generalized convulsion was obtained. In the maximal electroshock (MES) seizure test, electroconvulsion was induced by stimulating animals through ear-clip electrodes, and the durations of tonic and clonic seizures were measured. Thioperamide, clobenpropit, iodophenpropit, VUF5514, VUF5515 and VUF4929 caused a dose-dependent inhibition of both seizure stage and afterdischarge (AD) duration of amygdaloid kindled seizures. The duration of tonic seizure induced by MES was also inhibited by H3 antagonists, but the duration of clonic seizures were unchanged. Among the H3 antagonists tested, clobenpropit and iodophenpropit were somewhat more potent than the other drugs on amygdaloid kindled seizures and MES seizures, respectively. These results indicate that some H3 antagonists may be useful as antiepileptic drugs, especially for secondary generalized seizures and/or tonic-clonic seizures in humans.

Topics: Amygdala; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Electroencephalography; Electroshock; Epilepsy, Tonic-Clonic; Histamine Agonists; Histamine Antagonists; Imidazoles; Injections, Intraventricular; Isothiuronium; Kindling, Neurologic; Lateral Ventricles; Male; Methylhistamines; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3; Seizures; Thiourea

Topics: Anesthetics, Intravenous; Drug Therapy, Combination; Electroconvulsive Therapy; Humans; Methohexital; Piperidines; Remifentanil; Seizures; Treatment Outcome

Renal failure has been viewed as a state of cellular calcium toxicity due to the retention of small fast-acting molecules. We have tested this hypothesis and identified potentially neuroexcitatory compounds among a number of putative uremic neurotoxins by examining the acute in vitro effects of these compounds on cultured central neurons. The in vitro neuroexcitatory and synergistic effects of guanidinosuccinate and spermine were also examined in vivo.. The acute effects of 17 candidate uremic neurotoxins on murine spinal cord neurons in primary dissociated cell culture were investigated using the tight-seal whole-cell recording technique. The compounds studied comprised low-molecular-weight solutes like urea, indoles, guanidino compounds, polyamines, purines and phenoles, homocysteine, orotate, and myoinositol. Currents evoked by these compounds were further examined using various ligand- and voltage-gated ion channel blockers. The acute in vivo effects of guanidinosuccinate and spermine were behaviorally assessed following their injection in mice.. It was shown that 3-indoxyl sulfate, guanidinosuccinate, spermine, and phenol evoked significant whole-cell currents. Inward whole-cell current evoked by 3-indoxyl sulfate was not blocked by any of the applied ligand- or voltage-gated ion channel blockers, and the compound appeared to influence miscellaneous membrane ionic conductances, probably involving voltage-gated Ca2+ channels as well. Phenol-evoked outward whole-cell currents were at least partly due to the activation of voltage-gated K+ channels, but may also involve a variety of other ionic conductances. On the other hand, inward whole-cell currents evoked by guanidinosuccinate and spermine were shown to be due to specific interaction with voltage- and ligand-gated Ca2+ channels. Guanidinosuccinate-evoked current was caused by activation of N-methyl-d-aspartate (NMDA) receptor-associated ion channels. Low (micromol/L) concentrations of spermine potentiated guanidinosuccinate-evoked current through the action of spermine on the polyamine binding site of the NMDA receptor complex, whereas current evoked by high (mmol/L) concentrations of spermine alone involved direct activation of voltage-gated Ca2+ channels. Finally, intracerebroventricular administration of 0.25 micromol/L spermine potentiated clonic convulsions induced by guanidinosuccinate. These neuroexcitatory and synergistic effects of guanidinosuccinate and spermine could take place at pathophysiologic concentrations.. The observed in vitro and in vivo effects of uremic retention solutes suggest that the identified compounds could play a significant role in uremic pathophysiology. Some of the compounds tested displayed in vitro and in vivo neuroexcitatory effects that were mediated by ligand- and voltage-gated Ca2+ channels. The findings suggest a mechanism for the involvement of calcium toxicity in the central nervous system complications in renal failure with particular reference to guanidinosuccinate and spermine.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Bicuculline; Calcium Channels; Cells, Cultured; Drug Synergism; Excitatory Amino Acid Antagonists; GABA Antagonists; Guanidines; Membrane Potentials; Mice; Neurons; Nickel; Piperidines; Potassium Channel Blockers; Seizures; Spermine; Spinal Cord; Succinates; Synapses; Tetraethylammonium; Tetrodotoxin; Uremia

Several studies have demonstrated the importance of nicotinic mechanisms in the pathophysiology of neurodegenerative and cognitive disorders, warranting the search and development of novel nicotinic ligands as potential therapeutic agents. The present study was designed to assess whether the subtype-selective nicotinic acetylcholine receptor (nAChR) ligand SIB-1553A [(+/-)-4-([2-(1-methyl-2-pyrrolidinyl)ethyl]thio)phenol hydrochloride], with predominant agonist activity at beta4 subunit-containing human nAChRs, and no activity at muscle nAChR subtypes, could enhance cognitive performance in rodents with a more desirable safety/tolerability profile as compared to the nonselective prototypic nAChR ligand nicotine. SIB-1553A was equi-efficacious to nicotine in improving working memory performance in scopolamine-treated mice as measured by increased alternation in a T-maze, and was more efficacious than nicotine in improving the baseline cognitive performance of aged mice. This effect on working memory was confirmed in a delayed nonmatching to place task using the eight-arm radial maze. SIB-1553A produced dose-dependent side effects (ie motor deficits and seizures), although these effects were observed at doses 12 to 640-fold above those required to increase cognitive performance. Overall, SIB-1553A was significantly less potent than nicotine in eliciting these undesirable effects. Thus, the subtype-selective profile of SIB-1553A appears to translate into a more efficacious and better tolerated nAChR ligand as compared to nicotine. In the present studies, cognitive enhancement induced by SIB-1553A was similar in magnitude to that produced by the clinically efficacious acetylcholinesterase inhibitor donepezil. Taken together, the present data confirm the importance of nAChR subtypes in modulating cognitive processes, and suggest that activation of nAChR subtypes by selective nAChR ligands may be a viable approach to enhance cognitive performance.

Topics: Age Factors; Animals; Attention; Behavior, Animal; Choice Behavior; Cholinesterase Inhibitors; Cognition; Discrimination Learning; Donepezil; Dose-Response Relationship, Drug; Drug Interactions; Drug Tolerance; Indans; Lethal Dose 50; Male; Mecamylamine; Memory, Short-Term; Mice; Mice, Inbred C57BL; Motor Activity; Muscarinic Antagonists; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Phenols; Piperidines; Psychomotor Performance; Pyrrolidines; Reaction Time; Receptors, Nicotinic; Scopolamine; Seizures

[(18)F]1-(Fluoropropyl)-4-[(4-cyanophenoxy)methyl]piperidine ([(18)F]FPS) is a novel high affinity (KD = 0.5 nM) sigma receptor radioligand that exhibits saturable and selective in vivo binding to sigma receptors in rats, mice and non-human primates. In order to support an IND application for the characterization of [(18)F]FPS through PET imaging studies in humans, single organ and whole body radiation adsorbed doses associated with [(18)F]FPS injection were estimated from distribution data obtained in rats. In addition, acute toxicity studies were conducted in rats and rabbits and limited toxicity analyses were performed in dogs. Radiation dosimetry estimates obtained using rat biodistribution analysis of [(18)F]FPS suggest that most organs would receive around 0.012-0.015 mGy/MBq. The adrenal glands, brain, kidneys, lungs, and spleen would receive slightly higher doses (0.02-0.03 mGy/MBq). The adrenal glands were identified as the organs receiving the greatest adsorbed radiation dose. The total exposure resulting from a 5 mCi administration of [(18)F]FPS is well below the FDA defined limits for yearly cumulative and per study exposures to research participants. Extended acute toxicity studies in rats and rabbits, and limited acute toxicity studies in beagle dogs suggest at least a 175-fold safety margin in humans at a mass dose limit of 2.8 microg per intravenous injection. This estimate is based on the measured no observable effect doses (in mg/m(2)) in these species. These data support the expectation that [(18)F]FPS will be safe for use in human PET imaging studies at a maximum administration of 5 mCi and a mass dose equal to or less than 2.8 microg FPS per injection.

Topics: Animals; Dogs; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Female; Humans; In Vitro Techniques; Leukocyte Count; Organ Specificity; Piperidines; Rabbits; Radiation Dosage; Radiometry; Radiopharmaceuticals; Rats; Seizures; Species Specificity; Tissue Distribution; Toxicity Tests

This study was performed to investigate whether or not endogenous histamine can protect seizure development of pentylenetetrazole (PTZ)-induced kindling in rats. An intracerebroventricular (i.c.v.) injection with clobenpropit (5 and 10 microg), a representative H(3)-antagonist, significantly prolonged the onset of kindling and inhibited the seizure stages in a dose-dependent manner. Its action was significantly reversed by both immepip (2 microg, i.c.v.), an H(3)-agonist, and alpha-fluoromethylhistidine (alpha-FMH, 10 microg, i.c.v.), a selective histidine decarboxylase inhibitor. alpha-FMH (20 microg, i.c.v.) and pyrilamine (1 and 5 mg/kg i.p.), a classical H(1)-antagonist, markedly augmented the severity of seizure development of PTZ-induced kindling. Therefore, these results indicate that brain endogenous histamine plays a certain protective role on seizure development of PTZ-induced kindling in rats, and that its protective roles are mediated by H(1)-receptors.

Topics: Animals; Dose-Response Relationship, Drug; Drug Synergism; Histamine; Histamine Release; Histidine; Imidazoles; Injections, Intraventricular; Kindling, Neurologic; Male; Methylhistidines; Pentylenetetrazole; Piperidines; Pyrilamine; Rats; Rats, Sprague-Dawley; Seizures; Thiourea

Excitotoxic neuronal injury by action of the glutamate receptors of the N-methyl-d-aspartate (NMDA) subtype have been implicated in the pathogenesis of brain damage as a consequence of bacterial meningitis. The most potent and selective blocker of NMDA receptors containing the NR2B subunit is (R,S)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperid inepropanol (RO 25-6981). Here we evaluated the effect of RO 25-6981 on hippocampal neuronal apoptosis in an infant rat model of meningitis due to Streptococcus pneumoniae. Animals were randomized for treatment with RO 25-6981 at a dosage of either 0.375 mg (15 mg/kg; n = 28) or 3.75 mg (150 mg/kg; n = 15) every 3 h or an equal volume of sterile saline (250 microl; n = 40) starting at 12 h after infection. Eighteen hours after infection, animals were assessed clinically and seizures were observed for a period of 2 h. At 24 h after infection animals were sacrificed and brains were examined for apoptotic injury to the dentate granule cell layer of the hippocampus.. Treatment with RO 25-6981 had no effect on clinical scores, but the incidence of seizures was reduced (P < 0.05 for all RO 25-6981 treated animals combined). The extent of apoptosis was not affected by low or high doses of RO 25-6981. Number of apoptotic cells (median [range]) was 12.76 [3.16-25.3] in animals treated with low dose RO 25-6981 (control animals 13.8 [2.60-31.8]; (P = NS) and 9.8 [1.7-27.3] (controls: 10.5 [2.4-21.75]) in animals treated with high dose RO 25-6981 (P = NS).. Treatment with a highly selective blocker of NMDA receptors containing the NR2B subunit failed to protect hippocampal neurons from injury in this model of pneumococcal meningitis, while it had some beneficial effect on the incidence of seizures.

Topics: Animals; Animals, Suckling; Apoptosis; Cell Count; Cerebrospinal Fluid; Dentate Gyrus; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Excitatory Amino Acid Antagonists; Meningitis, Pneumococcal; Neurons; Phenols; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Seizures; Survival Rate; Treatment Outcome

Activation of polyamine catabolism in transgenic mice through an overexpression of spermidine/spermine N(1)-acetyltransferase (SSAT) results in a massive overaccumulation of the diamine putrescine in most tissues including brain. Putrescine pool in transgenic animals was strikingly expanded in every six brain regions analyzed at present. Pons (23-fold), cerebellum (37-fold), cerebrum (34-fold), and hippocampus (16-fold) showed the greatest increases in putrescine levels. Moreover, the molar ratio of putrescine to spermidine was increased in the different brain regions of the transgenic animals on an average of nearly 40-fold. Upon an exposure of the animals to pentylenetetrazol (PTZ) infusions, a compound known to induce epilepsy-like seizure activity, the SSAT transgenic mice showed significantly elevated seizure threshold to both clonic and tonic convulsions in comparison with their syngenic littermates. This difference, however, disappeared when the animals were treated with ifenprodil prior to PTZ infusions. The latter compound acts as an antagonist of N-methyl-D-aspartate receptor by binding to the polyamine site of the receptor. Overexpression of SSAT likewise appeared to protect the transgenic animals from PTZ-induced neuron loss in the hippocampus. As putrescine is known to serve as a precursor to gamma-aminobutyric acid (GABA), we carried out (1)H NMR analyses the results of which revealed that the levels of the inhibitory amino acid GABA and its excitatory counterpart glutamate were indistinguishable in syngenic and transgenic animals in all brain regions analyzed. The present results suggest that the frequently observed enhanced accumulation of putrescine in response to brain insults belongs to neuroprotective measures rather than being a cause of the subsequent injury.

Topics: Acetyltransferases; Animals; Biogenic Polyamines; Brain; Cell Count; Crosses, Genetic; Dose-Response Relationship, Drug; Drug Resistance; Excitatory Amino Acid Antagonists; gamma-Aminobutyric Acid; Glutamic Acid; Mice; Mice, Inbred BALB C; Mice, Inbred DBA; Mice, Transgenic; Neurons; Pentylenetetrazole; Piperidines; Putrescine; Seizures

Ro 63-1908, 1-[2-(4-hydroxy-phenoxy)-ethyl]-4-(4-methyl-benzyl)-piperidin-4-ol, is a novel subtype-selective N-methyl-D-aspartate (NMDA) antagonist that has been characterized in vitro and in vivo. Ro 63-1908 inhibited [(3)H]dizocilpine ((3)H-MK-801) binding in a biphasic manner with IC(50) values of 0.002 and 97 microM for the high- and low-affinity sites, respectively. Ro 63-1908 selectively blocked recombinant receptors expressed in Xenopus oocytes containing NR1C + NR2B subunits with an IC(50) of 0.003 microM and those containing NR1C + NR2A subunits with an IC(50) of >100 microM, thus demonstrating greater than 20,000-fold selectivity for the recombinant receptors expressing NR1C + NR2B. Ro 63-1908 blocked these NMDA NR2B-subtype receptors in an activity-dependent manner. Ro 63-1908 was neuroprotective against glutamate-induced toxicity and against oxygen/glucose deprivation-induced toxicity in vitro with IC(50) values of 0.68 and 0.06 microM, respectively. Thus, the in vitro pharmacological characterization demonstrated that Ro 63-1908 was a potent and highly selective antagonist of the NR2B subtype of NMDA receptors. Ro 63-1908 was active against sound-induced seizures (ED(50) = 4.5 mg/kg i.p. when administered 30 min beforehand) in DBA/2 mice. The dose required to give a full anticonvulsant effect did not produce a deficit in the Rotarod test. NMDA-induced seizures were also inhibited by Ro 63-1908 with an ED(50) of 2.31 mg/kg i.v. when administered 15 min before testing. Ro 63-1908 gave a dose-related neuroprotective effect against cortical damage in a model of permanent focal ischemia. Maximum protection of 39% was seen at a plasma concentration of 450 ng/ml. There were, however, no adverse cardiovascular or CNS side-effects seen at this dosing level.

Topics: Acoustic Stimulation; Algorithms; Animals; Anticonvulsants; Brain; Cerebral Cortex; Electrophysiology; Excitatory Amino Acid Antagonists; In Vitro Techniques; Infarction, Middle Cerebral Artery; Macaca fascicularis; Male; Mice; Motor Activity; Neurons; Neuroprotective Agents; Oocytes; Phenols; Piperidines; Psychomotor Performance; Rats; Receptors, N-Methyl-D-Aspartate; Seizures; Vacuoles; Xenopus

The anticonvulsant effect of cannabinoids has been shown to be mediated through activation of the cannabinoid CB(1) receptor. This study was initiated to evaluate the effects of endogenously occurring cannabinoids (endocannabinoids) on seizure severity and threshold. The anticonvulsant effect of the endocannabinoid, arachidonylethanolamine (anandamide), was evaluated in the maximal electroshock seizure model using male CF-1 mice and was found to be a fully efficacious anticonvulsant (ED(50)=50 mg/kg i.p.). The metabolically stable analog of anandamide, (R)-(20-cyano-16,16-dimetyldocosa-cis-5,8,11,14-tetraenoyl)-1'-hydroxy-2'-propylamine (O-1812), was also determined to be a potent anticonvulsant in the maximal electroshock model (ED(50)=1.5 mg/kg i.p.). Furthermore, pretreatment with the cannabinoid CB(1) receptor specific antagonist N-(piperidin-1-yl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride (SR141716A) completely abolished the anticonvulsant effect of anandamide as well as O-1812 (P< or =0.01, Fisher exact test), indicating a cannabinoid CB(1) receptor-mediated anticonvulsant mechanism for both endocannabinoid compounds. Additionally, the influence of cannabinoid CB(1) receptor endogenous tone on maximal seizure threshold was assessed using SR141716A alone. Our data show that SR141716A (10 mg/kg i.p.) significantly reduced maximal seizure threshold (CC(50)=14.27 mA) compared to vehicle-treated animals (CC(50)=17.57 mA) (potency ratio=1.23, lower confidence limit=1.06, upper confidence limit=1.43), indicating the presence of an endogenous cannabinoid tone that modulates seizure activity. These data demonstrate that anandamide and its analog, O-1812, are anticonvulsant in a whole animal model and further implicate the cannabinoid CB(1) receptor as a major endogenous site of seizure modulation.

Topics: Animals; Anticonvulsants; Arachidonic Acids; Cannabinoid Receptor Modulators; Endocannabinoids; Fatty Acids, Unsaturated; Male; Mice; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Seizures

The neuropeptide nociceptin/orphanin FQ (N/OFQ) has been shown to modulate neuronal excitability and neurotransmitter release. Previous studies indicate that the mRNA levels for the N/OFQ precursor (proN/OFQ) are increased after seizures. However, it is unclear whether N/OFQ plays a role in seizure expression. Therefore, (1) we analyzed proN/OFQ mRNA levels and NOP (the N/OFQ receptor) mRNA levels and receptor density in the kainate model of epilepsy, using Northern blot analysis, in situ hybridization, and receptor binding assay, and (2) we examined susceptibility to kainate seizure in mice treated with 1-[(3R, 4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1, 3-dihydro-benzimidazol-2-one (J-113397), a selective NOP receptor antagonist, and in proN/OFQ knock-out mice. After kainate administration, increased proN/OFQ gene expression was observed in the reticular nucleus of the thalamus and in the medial nucleus of the amygdala. In contrast, NOP mRNA levels and receptor density decreased in the amygdala, hippocampus, thalamus, and cortex. Mice treated with the NOP receptor antagonist J-113397 displayed reduced susceptibility to kainate-induced seizures (i.e., significant reduction of behavioral seizure scores). N/OFQ knock-out mice were less susceptible to kainate seizures compared with their wild-type littermates, in that lethality was reduced, latency to generalized seizure onset was prolonged, and behavioral seizure scores decreased. Intracerebroventricular administration of N/OFQ prevented reduced susceptibility to kainate seizures in N/OFQ knock-out mice. These data indicate that acute limbic seizures are associated with increased N/OFQ release in selected areas, causing downregulation of NOP receptors and activation of N/OFQ biosynthesis, and support the notion that the N/OFQ-NOP system plays a facilitatory role in kainate seizure expression.

Topics: Animals; Benzimidazoles; Binding, Competitive; Brain; Cell Membrane; Disease Models, Animal; Hippocampus; Homozygote; Injections, Intraventricular; Kainic Acid; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Narcotic Antagonists; Nociceptin; Nociceptin Receptor; Opioid Peptides; Organ Specificity; Piperidines; Prosencephalon; Rats; Rats, Sprague-Dawley; Receptors, Opioid; RNA, Messenger; Seizures; Thalamus

A series of novel 4-arylpiperidines and 4-aryl-4-piperidinols (2a-f, 3a-f and 4a-f) was synthesized and evaluated for blocking effects on both neuronal Na(+) and T-type Ca(2+) channels and binding affinity for dopamine D(2) receptors. Most of the compounds blockaded both ion channels with potency greater than or equal to flunarizine 1a which was adopted as a reference standard. In addition, these compounds had significantly reduced affinity for dopamine D(2) receptors which is common in this class of structure. Compounds 2a-f, 3a-f and 4a-f exhibited potent anticonvulsant effects following systemic (ip) administration on audiogenic seizures in DBA/2 mice, indicating their excellent brain permeability. The neuroprotective activity of 2a, 3a and 4a was also assessed in a transient middle cerebral artery occlusion (MCAO) model. These compounds significantly reduced neuronal damage without affecting ischemic hyperthemia, while flunarizine 1a produced only minor reductions. In particular, 4a had 1.7-fold the potency in this MCAO model but only 1/20 the affinity for dopamine D(2) receptors of 1a. The superposition of 2a, 3a and 4a on the basis of analyses of systematic conformation and similar structure has revealed that the cinnamyl, phenacyl and phenoxypropanol groups are likely to be structurally and biologically equivalent. Moreover, the superposition of 2a and 2f shows that diphenyl ether and biphenyl groups occupy a similar space, suggesting that both groups act as a bioisostere for the blockade of ion channels; however, this is not the case for dopamine D(2) receptors since only biphenyl compounds such as 2f had high affinity similar to flunarizine 1a. Compound 4a (SUN N5030) has a good pharmacological profile and may be useful in the alleviation and treatment of ischemic diseases.

Topics: Animals; Biochemistry; Calcium Channel Blockers; Cerebral Cortex; Drug Evaluation, Preclinical; Female; Flunarizine; Ischemia; Male; Mice; Mice, Inbred DBA; Neuroprotective Agents; Phenyl Ethers; Piperidines; Rats; Rats, Wistar; Receptors, Dopamine D2; Seizures; Sodium Channel Blockers; Structure-Activity Relationship

1. Several neuroleptics inhibited the 3 microM gamma-aminobutyric acid induced-chloride current (GABA-current) on dissociated rat dorsal root ganglion neurons in whole-cell patch-clamp investigations. 2. The IC(50) for clozapine, zotepine, olanzapine, risperidone and chlorpromazine were 6.95, 18.26, 20.30, 106.01 and 114.56 microM, respectively. The values for the inhibitory effects of neuroleptics on the GABA (3 microM)-current, which were calculated by the fitting Hill's equations where the concentrations represent the mean therapeutic blood concentrations, were ranked clozapine>zotepine>chlorpromazine>olanzapine>risperidone. These inhibitory effects, weighted with the therapeutic concentrations of neuroleptics, were correlated with the clinical incidences of seizure during treatment with neuroleptics. 3. Clozapine reduced the picrotoxin-inhibiton, and may compete with a ligand of the t-butylbicyclophosphorothionate (TBPS) binding site. 4. Haloperidol and quetiapine did not affect the peak amplitude of the GABA (3 microM)-current. However, haloperidol reduced the clozapine-inhibition, and may antagonize ligand binding to TBPS binding site. 5. Neuroleptics including haloperidol and quetiapine enhanced the desensitization of the GABA (3 microM)-current. However, haloperidol and quetiapine at 100 microM inhibited the desensitization at the beginning of application. 6. Blonanserin (AD-5423) at 30 and 50 microM potentiated the GABA (3 microM)-current to 170.1+/-6.9 and 192.0+/-10.6% of the control current, respectively. Blonanserin shifted GABA concentration-response curve leftward. Blonanserin only partly negatively interacted with diazepam. The blonanserin-potentiation was not reversed by flumazenil. Blonanserin is not a benzodiazepine receptor agonist. 7. The various effects of neuroleptics on the GABA-current may be related to the clinical effects including modifying the seizure threshold.

Topics: Animals; Antipsychotic Agents; Cells, Cultured; Chloride Channel Agonists; Chloride Channels; Clozapine; Dibenzothiazepines; Dose-Response Relationship, Drug; Drug Synergism; gamma-Aminobutyric Acid; Ganglia, Spinal; Haloperidol; Incidence; Membrane Potentials; Piperazines; Piperidines; Quetiapine Fumarate; Rats; Rats, Wistar; Seizures

2-Methyl-4-oxo-3H-quinazoline-3-acetyl piperidine (Q5), a selective inhibitor of the fast-desensitising component of transmembrane Ca2+ ion influx to (S)-alpha-amino-3-hydroxy-5-methyliso-xazole-4-propionate ((S)-AMPA) was tested for possible anticonvulsant effects in the low-[Mg2+] model of experimental epilepsy. Evolutionary analysis of burst parameters such as half-width, decay time constant, burst multiplicity, instantaneous frequency and amplitude disclosed an approximate doubling of half-width within periods of interictal activity, being predictive for the onset of seizure-like events (SLEs). We found that SLEs observed in the CA3 region of rat hippocampal slices were suppressed by the application of 50 microM Q5. These results suggest an AMPA receptor function shaping the dynamics of spontaneous epileptiform activity.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Anticonvulsants; Electrophysiology; Excitatory Amino Acid Antagonists; In Vitro Techniques; Magnesium; Male; Membrane Potentials; Piperidines; Quinazolines; Rats; Rats, Wistar; Receptors, AMPA; Receptors, Glutamate; Seizures

The purification, characterization, and synthesis of conantokin-R (Con-R), an N-methyl-D-aspartate (NMDA) receptor peptide antagonist from the venom of Conus radiatus, are described. With the use of well defined animal seizure models, Con-R was found to possess an anticonvulsant profile superior to that of ifenprodil and dizocilpine (MK-801). With voltage-clamp recording of Xenopus oocytes expressing heteromeric NMDA receptors from cloned NR1 and NR2 subunit RNAs, Con-R exhibited the following order of preference for NR2 subunits: NR2B approximately NR2A > NR2C >> NR2D. Con-R was without effect on oocytes expressing the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor subunit GluR1 or the kainate receptor subunit GluR6. In mouse cortical neurons voltage-clamped at -60 mV, Con-R application produced a slowly developing block of inward currents evoked by 10 microM NMDA and 1 microM glycine (IC(50) = 350 nM). At 3 microM, Con-R did not affect gamma-aminobutyric acid- or kainate-evoked currents. Con-R prevented sound-induced tonic extension seizures in the Frings audiogenic seizure-susceptible mice at i.c.v. doses below toxic levels. It was also effective at nontoxic doses in CF#1 mice against tonic extension seizures induced by threshold (15 mA) and maximal (50 mA) stimulation, and it partially blocked clonic seizures induced by s.c. pentylenetetrazol. In contrast, MK-801 and ifenprodil were effective only at doses approaching (audiogenic seizures) or exceeding (electrical and pentylenetetrazol seizures) those required to produce significant behavioral impairment. These results indicate that the subtype selectivity and other properties of Con-R afford a distinct advantage over the noncompetitive NMDA antagonists MK-801 and ifenprodil. Con-R is a useful new pharmacological agent for differentiation between the anticonvulsant and toxic effects of NMDA antagonists.

Topics: Animals; Anticonvulsants; Behavior, Animal; Binding, Competitive; Cerebral Cortex; Conotoxins; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Electroshock; Evoked Potentials; Female; gamma-Aminobutyric Acid; Glutamic Acid; In Vitro Techniques; Kainic Acid; Male; Mice; Mollusk Venoms; Oocytes; Pentylenetetrazole; Piperidines; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Recombinant Proteins; Seizures; Sound; Xenopus

Antagonists at the 1A/2B subtype of the NMDA receptor (NR1A/2B) are typically small molecules that consist of a 4-benzyl- or a 4-phenylpiperidine with an omega-phenylalkyl substituent on the heterocyclic nitrogen. Many of these antagonists, for example ifenprodil (1), incorporate a 4-hydroxy substituent on the omega-phenyl group. In this study, the position of this 4-hydroxy substituent was transferred from the omega-phenyl group to the benzyl or phenyl group located on the 4-position of the piperidine ring. Analogues incorporating pyrrolidine in lieu of piperidine were also prepared. Electrical recordings using cloned receptors expressed in Xenopus oocytes show that high-potency antagonists at the NR1A/2B subtype are obtained employing N-(omega-phenylalkyl)-substituted 4-(4-hydroxyphenyl)piperidine, 4-(4-hydroxybenzyl)piperidine, and (+/-)-3-(4-hydroxyphenyl)pyrrolidine as exemplified by 21 (IC(50) = 0.022 microM), 33 (IC(50) = 0.059 microM), and 40 (IC(50) = 0.017 microM), respectively. These high-potency antagonists are >1000 times more potent at the NR1A/2B subtype than at either the NR1A/2A or NR1A/2C subtypes. The binding affinities of 21 at alpha(1)-adrenergic receptors ([(3)H]prazosin, IC(50) = 0.54 microM) and dopamine D2 receptors ([(3)H]raclopride, IC(50) = 1.2 microM) are reduced by incorporating a hydroxy group onto the 4-position of the piperidine ring and the beta-carbon of the N-alkyl spacer to give (+/-)-27: IC(50) NR1A/2B, 0.026; alpha(1), 14; D2, 105 microM. The high-potency phenolic antagonist 21 and its low-potency O-methylated analogue 18 are both potent anticonvulsants in a mouse maximal electroshock-induced seizure (MES) study (ED(50) (iv) = 0.23 and 0.56 mg/kg, respectively). These data indicate that such compounds penetrate the blood-brain barrier but their MES activity may not be related to NMDA receptor antagonism.

Topics: Animals; Anticonvulsants; Cerebral Cortex; Corpus Striatum; Electroshock; Excitatory Amino Acid Antagonists; In Vitro Techniques; Male; Mice; Oocytes; Piperidines; Pyrrolidines; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-1; Receptors, Dopamine; Receptors, N-Methyl-D-Aspartate; Seizures; Xenopus laevis

The effect of selective histamine H3-receptor antagonist thioperamide was studied on PTZ-induced seizures in mice. Thioperamide significantly protected clonic seizures induced by PTZ in a dose-dependent manner. The effect of thioperamide was completely countered by pretreatment with R (alpha)-methylhistamine (RAMH), a selective H3-receptor agonist suggesting that the observed effect of thioperamide was elicited by histamine H3-receptors. RAMH alone did not significantly modify PTZ seizures. The findings are consistent with a role for the histaminergic neuronal system in seizures and suggest that H3-receptors may play an important role in modulating clonic seizures induced by PTZ in mice.

Topics: Animals; Dose-Response Relationship, Drug; Histamine Antagonists; Male; Methylhistamines; Mice; Pentylenetetrazole; Piperidines; Protective Agents; Receptors, Histamine H3; Seizures

In this study, we assessed the effects of the acute administration of various 5-HT receptor antagonists on hippocampal partial seizures generated by low-frequency electrical stimulation in male Wistar rats. The seizure threshold and severity were determined by measuring the pulse number threshold and primary and secondary afterdischarges, respectively, and the latency of secondary discharge was also determined. The administration of either the selective 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazineyl]ethyl]-N-(pyridinyl)-c yclohe xanecarboximimde 3 HCl (WAY 100635, 0.1-1 mg/kg i.p.), the selective 5-HT(3) receptor antagonist granisetron (0.3-3 mg/kg i.p.), the selective 5-HT(2A) receptor antagonist R-(+)-a-(2, 3-dimethoxyphenyl)-1-[2-(4-fluorophenyl) ethyl]-4-piperidine-methanol (MDL 100907, 0.3-3 mg/kg i.p.) or the 5-HT(2B,C) receptor antagonist antagonist N-(1-methyl-5-indolyl)-N'-(3-pyridyl) urea HCl (SKB 200646A, 5-50 mg/kg i.p.) did not alter the pulse number threshold compared to vehicle-treated animals. However, the acute administration of WAY 100635 (0.3 mg/kg) and M100907 (1 mg/kg) significantly increased, whereas granisetron (1 mg/kg) decreased, the primary afterdischarge duration compared to vehicle-treated animals. The latency of secondary after discharge was significantly decreased by WAY 100635 (1 mg/kg) and granisetron (3 mg/kg) compared to vehicle-treated animals. These results suggest that in this model, the antagonism of 5-HT(1A), 5-HT(2A), 5-HT(3) or 5-HT(2B,C) receptors do not lower or raise seizure threshold. However, the antagonism of 5-HT(1A) receptors may increase or augment seizure severity.

Topics: Animals; Dose-Response Relationship, Drug; Electroencephalography; Fluorobenzenes; Granisetron; Hippocampus; Indoles; Locomotion; Male; Piperazines; Piperidines; Pyridines; Rats; Rats, Wistar; Receptors, Serotonin; Seizures; Serotonin Antagonists; Severity of Illness Index; Urea

We investigated whether some histamine H(3)-antagonists would attenuate amygdaloid kindled seizures in rats. Thioperamide, a standard H(3)-antagonist, did not significantly reduce either seizure ranks or afterdischarge duration (ADD). Betahistine which has both H(3)-antagonistic activity and H(1)-agonistic activity significantly reduced ADD, albeit mild at a toxic dose, though seizure ranks were not affected. In addition, L-histidine, the precursor of histamine, affected neither seizure ranks, nor ADD. It was shown that H(3)-antagonists have no significant inhibitory action against amygdaloid kindled seizures, probably because released histamine was unable to inhibit those seizures.

Topics: Amygdala; Animals; Betahistine; Histamine Agonists; Histamine Antagonists; Kindling, Neurologic; Male; Piperidines; Rats; Rats, Wistar; Seizures

Rats become susceptible to audiogenic seizures (AS) when they are exposed to intense noise during a certain critical period of development (priming). Antagonism of N-methyl-D-aspartate (NMDA) receptor NR2B subunit by injecting an antagonist ifenprodil at priming enhanced the later susceptibility to AS. An weak NR2A antagonist, dextromethorphan, did not show such effects while it significantly suppressed the manifestation of AS in already susceptible post-weaning (primed) rats. These results indicate that NR2B plays an important role in the developmental regulation of the auditory system involved in AS but this subunit has a minor relevance to the manifestation of AS in the later life.

Topics: Animals; Dextromethorphan; Disease Susceptibility; Epilepsy, Reflex; Excitatory Amino Acid Antagonists; Female; Male; Piperidines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures

The present study examines the effect of tiagabine (a selective inhibitor of GABA transporter 1, GAT-1), SNAP-5114 (a semi-selective inhibitor of rat GAT-3/mouse GAT4) and NNC 05-2045 (a non-selective GABA uptake inhibitor) in modulating GABA levels in the hippocampus and thalamus. Anticonvulsant effects of the same compounds were assessed (after intranigral administration) after maximal electroshock (MES) in juvenile rats. Anticonvulsant effects were also tested after intraperitoneal (i.p.) administration against audiogenic seizures in DBA/2 mice and against pentylentetrazole (PTZ)-induced tonic convulsions or MES in NMRI mice. Tiagabine (30 microM, perfused through the microdialysis probe in halothane anaesthetized rats) increased GABA levels to (% basal+/-SEM) 645+/-69 in the hippocampus and 409+/-61 in the thalamus. SNAP-5114 (100 microM) increased GABA levels in the thalamus (% basal+/-SEM) to 247+/-27 but had no effect on hippocampal GABA-levels. NNC 05-2045 (100 microM) increased GABA levels both in the hippocampus (% basal+/-SEM, 251+/-51) and in the thalamus (298+/-27). All compounds protected against tonic hindlimb extension (THE) in juvenile male rats after intranigral administration. Sound induced convulsions in DBA/2 mice were dose-dependently inhibited by all compounds (administered intraperitoneal, i.p.) with ED(50) values of 1, 6 and 110 micromol/kg, for tiagabine, NNC 05-2045 and SNAP-5114, respectively. Tiagabine and NNC 05-2045 but not SNAP-5114 protected against PTZ-induced tonic convulsions whereas only NNC 05-2045 protected against MES-induced tonic convulsions in NMRI mice. However, tiagabine and NNC 05-2045 exerted a synergistic effect in the MES model. These findings substantiate and extend previous findings of different effects of selective versus non-selective GABA uptake inhibitors in animal models of epilepsy.

Topics: Acoustic Stimulation; Anesthesia; Animals; Anisoles; Anticonvulsants; Carbazoles; Chromatography, High Pressure Liquid; Convulsants; Electroshock; Female; GABA Agonists; GABA Antagonists; gamma-Aminobutyric Acid; Hippocampus; Male; Mice; Mice, Inbred DBA; Microdialysis; Neurotransmitter Uptake Inhibitors; Nipecotic Acids; Pentylenetetrazole; Piperidines; Seizures; Substantia Nigra; Thalamus; Tiagabine

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Male; Piperidines; Seizures

Topics: Acoustic Stimulation; Animals; Anticonvulsants; Benzothiazoles; Convulsants; Dimaprit; Female; Histamine Agonists; Histamine Antagonists; Male; Mice; Mice, Inbred DBA; Pentylenetetrazole; Phenoxypropanolamines; Piperidines; Receptors, Histamine H2; Seizures; Thiazoles

Organophosphorus (OP) nerve agents are still used as warfare and terrorism compounds. Classical delayed treatment of victims of organophosphate poisoning includes combined i.v. administration of a cholinesterase reactivator (an oxime), a muscarinic cholinergic receptor antagonist (atropine) and a benzodiazepine anticonvulsant (diazepam). The objective of this study was to evaluate, in a realistic setting, the therapeutic benefit of administration of GK-11 (gacyclidine), an antiglutamatergic compound, as a complement to the above therapy against organophosphate poisoning. Gacyclidine was injected (i.v.) in combination with atropine/diazepam/pralidoxime at man-equivalent doses after a 45- or 30-min latency period to intoxicated primates (2 LD50). The effects of gacyclidine on the animals' survival, electroencephalographic (EEG) activity, signs of toxicity, recovery after challenge and central nervous system histology were examined. The present data demonstrated that atropine/diazepam/pralidoxime alone or combined with gacyclidine did not prevent signs of soman toxicity when treatment was delayed 45 min after poisoning. Atropine/diazepam/pralidoxime also did not control seizures or prevent neuropathology in primates exhibiting severe signs of poisoning when treatment was commenced 30 min after intoxication. However, in this latter case, EEG recordings revealed that additional treatment with gacyclidine was able to stop soman-induced seizures and restore normal EEG activity. This drug also totally prevented the neuropathology observed 5 weeks after soman exposure in animals treated with atropine/diazepam/pralidoxime alone. Overall, in the case of severe OP-poisoning, gacyclidine represents a promising adjuvant therapy to the currently available polymedication to ensure optimal management of organophosphate poisoning in man. This drug is presently being evaluated in a human clinical trial for a different neuroprotective indication. However, it should always be kept in mind that, in the case of severe OP-poisoning, medical intervention must be conducted as early as possible.

Topics: Animals; Anticonvulsants; Antidotes; Atropine; Brain; Cerebellum; Cerebral Cortex; Chemical Warfare Agents; Cholinesterase Reactivators; Cyclohexanes; Cyclohexenes; Diazepam; Drug Therapy, Combination; Electrocardiography; Excitatory Amino Acid Antagonists; Haplorhini; Macaca fascicularis; Male; Piperidines; Poisoning; Pralidoxime Compounds; Seizures; Soman; Time Factors

The NMDA receptor complex is thought to be altered in kindling, an animal model for complex partial epilepsy. This receptor complex has several modulatory sites including those for glutamate, glycine and polyamines with activation resulting in altered cation channel opening. Two NMDA receptor effectors, ifenprodil and arcaine, were evaluated for effects on the acquisition of electrical kindling of the amygdala. Rats were administered 0, 3.2, 10, 32 and 100 microg of ifenprodil or 0, 32 or 100 microg of arcaine, intracerebroventricularly, 10 min before a daily kindling stimulus. Ifenprodil, at low doses, enhanced kindling acquisition, while the highest dose, 100 microg, inhibited kindling. Arcaine increased the number of trials required to reach fully generalized (stage 5) seizures at the 100 microg dose. Since these agents had mixed actions on kindling development, it is unclear whether these or similar NMDA effectors would be useful in the modulation of complex partial seizures.

Topics: Amygdala; Animals; Anticonvulsants; Biguanides; Brain; Dose-Response Relationship, Drug; Electric Stimulation; Injections, Intraventricular; Kindling, Neurologic; Male; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Seizures

The aim of the present study was to examine the influence of ifenprodil (a non-competitive NMDA receptor antagonist which also blocks 5-HT3 receptors and alpha1-adrenoceptors) on the effects of ethanol in the mouse in vivo and to elucidate the role of various receptors in these actions. The ethanol (4 g/kg i.p.)-induced sleeping time was shortened by ifenprodil 1 mg/kg but was not affected by ifenprodil 0.3 mg/kg, the 5-HT3 receptor antagonist ondansetron 0.03 mg/kg and the non-competitive NMDA receptor antagonist MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cycloheptan-5,10-imine maleate) 0.01 mg/kg. Ifenprodil 10 mg/kg mimicked the alpha1-adrenoceptor antagonist prazosin 1 mg/kg in that it prolonged the hypnotic response to ethanol (no additive effect when both drugs were given in combination); this is compatible with an involvement of alpha1-adrenoceptors in this effect of ifenprodil. Chronic exposure to ethanol (7%) induced physical dependence. The severity of ethanol withdrawal was suppressed by ifenprodil 1 and 10 mg/kg. In conclusion, ifenprodil influences ethanol-related changes in mouse behaviour and may prove to be useful in the treatment of alcoholism.

Topics: Animals; Behavior, Animal; Brain; Central Nervous System Depressants; Dose-Response Relationship, Drug; Ethanol; Excitatory Amino Acid Antagonists; Male; Mice; Piperidines; Prazosin; Seizures; Sleep; Substance Withdrawal Syndrome

The role of endothelin receptor subtypes, i.e., ET(A) and ET(B) receptors, in the behavioral effects of the intracerebroventricular (ICV) administration of endothelin-1 were examined in conscious rats. ICV administration of endothelin-1 (1-9 pmol/rat) dose dependently produced barrel rolling and other convulsive behaviors including bodily twitching, rigidity, back crawling, fore/hindlimb dystonia, fore/hindlimb clonus, tail extension, and facial clonus. Moreover, a marked increase in spontaneous locomotor activity was observed in animals that were treated with a low dose of endothelin-1 (1 pmol/rat, ICV). Endothelin-1 (9 pmol/rat, ICV)-induced barrel rolling and other convulsive behaviors were completely suppressed by the coadministration of BQ-123 (15 nmol, ICV), a specific endothelin ET(A) receptor antagonist, but not of BQ-788 (15 nmol/rat, ICV), a specific endothelin ET(B) receptor antagonist. In contrast, increased locomotor activity produced by treatment with a low dose of endothelin-1 (1 pmol/rat, ICV) was antagonized by coadministration of BQ-788, but not of BQ123. These results indicate that endothelin-1, which has affinity for both endothelin ET(A) and ET(B) receptors, most likely acts on central ET(A) receptors to evoke barrel rolling and other convulsive behaviors. In addition, activation of central ET(B) receptors may be involved in the increase in spontaneous locomotor activity. These results suggest that brain endothelin receptor subtypes may be involved in the regulation of various physiological functions.

Topics: Animals; Behavior, Animal; Endothelin Receptor Antagonists; Endothelin-1; Injections, Intraventricular; Male; Motor Activity; Oligopeptides; Peptides, Cyclic; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Seizures

Some 3,3-disubstituted 2-pyrrolidinones and 2-piperidinones (five- and six-membered ring lactams, respectively) possess potent in vivo anticonvulsant activity. In vitro these lactams potentiate GABA(A) receptor-mediated chloride currents, which is thought to be the mechanism by which they exert their therapeutic effects. However, the apparent affinity for these GABA(A) interactions is low: EC50s range from hundreds of micromolar to low millimolar values. In order to more completely characterize the activities of these compounds, it was necessary to know the concentrations required to curtail epileptiform activity in an intact neural network, and the mechanism by which this occurs. To address these questions, we used two methods of inducing ictal activity in hippocampal-entorhinal cortical slices: 4-aminopyridine (4-AP) and low Mg2+. We found that 3,3-diethyl-2-pyrrolidinone (diethyl-lactam) prevents seizure-like discharges with IC50s of 1.1 and 2.1 mM in the two models, respectively. These values are nearly identical to the EC50 value obtained in whole-cell studies of diethyl-lactam's GABA(A) receptor modulation. The addition of the GABA(A) antagonist picrotoxin to the low Mg2+ ACSF produced seizures which persisted during diethyl-lactam application. Neither 3-benzyl-3-ethyl-2-piperidinone (3-BEP) nor alpha-ethyl-alpha-methyl-gamma-thiobutyrolactone (alpha-EMTBL), two compounds which are similar to diethyl-lactam, but demonstrate picrotoxin-insensitive inhibition of voltage-dependent currents, diminished low Mg2+/picrotoxin seizure activity. Our results support the hypothesis that diethyllactam and related compounds exert their anticonvulsant activity primarily, if not exclusively, by modulating the GABA(A) receptor.

Topics: 4-Butyrolactone; Animals; Anticonvulsants; Calcium Channel Blockers; Electrophysiology; gamma-Aminobutyric Acid; Hippocampus; In Vitro Techniques; Lactams; Mice; Phenytoin; Piperidines; Potassium Channel Blockers; Receptors, GABA-A; Seizures; Sodium Channel Blockers; Synaptic Transmission

In this article, the rationale for the design, synthesis, and biological evaluation of a series of N-type voltage-sensitive calcium channel (VSCC) blockers is described. N-Type VSCC blockers, such as ziconotide, have shown utility in several models of stroke and pain. Modification of the previously reported lead, 1a, led to several 4-(4-benzyloxylphenyl)piperidine structures with potent in vitro and in vivo activities. In this series, the most interesting compound, (S)-2-amino-1-{4-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-p iperidin-1-yl}-4-methyl-pentan-1-one (11), blocked N-type calcium channels (IC(50) = 0.67 microM in the IMR32 assay) and was efficacious in the audiogenic DBA/2 seizure mouse model (ED(50) = 6 mg/kg, iv) as well as the antiwrithing model (ED(50) = 6 mg/kg, iv). Whole-cell voltage-clamp electrophysiology experiments demonstrated that compound 11 blocked N-type Ca(2+) channels and Na(+) channels in superior cervical ganglion neurons at similar concentrations. Compound 11, which showed superior in vivo efficacy, stands out as an interesting lead for further development of neurotherapeutic agents in this series.

Topics: Acoustic Stimulation; Analgesics, Non-Narcotic; Animals; Anticonvulsants; Blood Pressure; Calcium Channel Blockers; Cell Line; Heart Rate; Humans; In Vitro Techniques; Ion Channel Gating; Male; Mice; Mice, Inbred DBA; Microsomes, Liver; Neurons; Pain Measurement; Patch-Clamp Techniques; Piperidines; Rats; Rats, Sprague-Dawley; Rats, Wistar; Seizures

Organophosphorus nerve agents are still in use today in warfare and as terrorism compounds. Classical emergency treatment of organophosphate poisoning includes the combined administration of a cholinesterase reactivator (an oxime), a muscarinic cholinergic receptor antagonist (atropine) and a benzodiazepine anticonvulsant (diazepam). However, recent experiments with primates have demonstrated that such treatment, even when administered immediately after organophosphate exposure, does not rapidly restore normal electroencephalographic (EEG) activity and fails to totally prevent neuronal brain damage. The objective of this study was to evaluate, in a realistic setting, the therapeutic benefit of administration of GK-11 (gacyclidine), an antiglutamatergic compound, as a complement to the available emergency therapy against organophosphate poisoning. GK-11 was injected at a dose of 0.1 mg/kg (i.v) after a 45-min latency period to heavily intoxicated (8 LD50) primates. Just after intoxication, man-equivalent doses of one autoinjector containing atropine/pralidoxime/diazepam were administered. The effects of GK-11 were examined on survival, EEG activity, signs of toxicity, recovery after challenge and central nervous system histology. The present data demonstrate that treatment with GK-11 prevents the mortality observed after early administration of classical emergency medication alone. EEG recordings and clinical observations also revealed that GK-11 prevented soman-induced seizures and motor convulsions. EEG analysis within the classical frequency bands (beta, theta, alpha, delta) demonstrated that central activity was totally restored to normal after GK-11 treatment, but remained profoundly altered in animals receiving atropine/pralidoxime/diazepam alone. GK-11 also markedly accelerated clinical recovery of soman-challenged primates. Lastly, this drug totally prevented the neuropathology observed 3 weeks after soman exposure in animals treated with classical emergency treatment alone. GK-11 represents a promising adjuvant therapy to the currently available emergency polymedication to ensure optimal management of organophosphate poisoning in man. This drug is presently being evaluated in a human clinical trial for a different neuroprotective indication.

Topics: Animals; Anticonvulsants; Atropine; Brain; Chemical Warfare Agents; Cholinesterase Inhibitors; Cholinesterase Reactivators; Cyclohexanes; Cyclohexenes; Diazepam; Drug Combinations; Excitatory Amino Acid Antagonists; Injections, Intravenous; Macaca fascicularis; Male; Muscarinic Antagonists; Neuroprotective Agents; Piperidines; Pralidoxime Compounds; Seizures; Soman; Staining and Labeling; Time Factors

The effects of histamine H3-receptor antagonists, thioperamide, and clobenpropit on amygdaloid kindled seizures were investigated in rats. Both intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) injections of H3-antagonists resulted in a dose-related inhibition of amygdaloid kindled seizures. An inhibition induced by thioperamide was antagonized by an H3-agonist [(R)-alpha-methylhistamine] and H1-antagonists (diphenhydramine and chlorpheniramine). On the other hand, an H2-antagonist (cimetidine and ranitidine) caused no antagonistic effect. Metoprine, an inhibitor of N-methyltransferase was also effective in inhibiting amygdaloid kindled seizure, and this effect was augmented by thioperamide treatment.

Topics: Amygdala; Animals; Brain Chemistry; Enzyme Inhibitors; Histamine Antagonists; Histamine N-Methyltransferase; Imidazoles; Injections, Intraventricular; Kindling, Neurologic; Male; Piperidines; Pyrimethamine; Rats; Rats, Wistar; Receptors, Histamine H3; Seizures; Thiourea

Substance P (SP) can play an important role in neuronal survival. To analyze the role of SP in excitotoxicity, kainic acid (KA) was administered to rats and in situ hybridization was used to analyze the levels of the SP encoding preprotachykinin-A (PPT-A) mRNA in striatal and hippocampal subregions 1, 4, and 24 h and 7 days after KA. In striatum and piriform cortex, PPT-A mRNA peaked 4 h after KA while in hippocampus, levels peaked after 24 h. KA caused seizures and neuronal toxicity as indicated by a reduction of the number of neurons in the hippocampal CA1 subregion after 7 days. KA was later administered alone or following pretreatment with the tachykinin NK1 receptor antagonist CP-122,721-1 (0.3 mg/kg). The pretreatment decreased seizure activity and a negative correlation was found between seizure activity and survival of CA1 neurons. Conclusively, treatment with CP-122,721-1 has a seizure inhibiting property and may possibly counteract KA-induced nerve cell death in CA1.

Topics: Animals; Cell Survival; Corpus Striatum; Hippocampus; Kainic Acid; Kinetics; Male; Neurokinin-1 Receptor Antagonists; Piperidines; Protein Precursors; Rats; Rats, Sprague-Dawley; RNA, Messenger; Seizures; Substance P; Tachykinins; Time Factors; Transcription, Genetic

We investigated the role of the NMDA receptor complex in DMCM (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate)-induced seizures in mice. The seizure threshold of DMCM was evaluated using an i.v. infusion technique. Pretreatment with the non-competitive NMDA receptor antagonist MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d) cycloheptan-5,10-imine maleate) or phencyclidine (PCP) significantly increased the seizure threshold for DMCM. Furthermore, the seizure threshold of DMCM was increased by intracerebroventricular (i.c.v.), but not intrathecal (i.t.), pretreatment with MK-801. Moreover, 7-chlorokynurenic acid, a glycine site antagonist, also increased the seizure threshold of DMCM, whereas ifenprodil, a non-competitive polyamine site antagonist, did not. These findings indicate that the ion-channel binding site and the glycine binding site on the NMDA receptor complex in the brain may be involved in the expression of seizures induced by DMCM.

Topics: Animals; Carbolines; Cerebral Ventricles; Convulsants; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Infusions, Intravenous; Injections, Intraventricular; Injections, Spinal; Kynurenic Acid; Male; Mice; Mice, Inbred Strains; Phencyclidine; Piperidines; Receptors, N-Methyl-D-Aspartate; Seizures; Spinal Cord

The effects of several NMDA receptor antagonists on pentylenetetrazole-induced diazepam-withdrawal seizure were examined in mice. The decrease in the seizure threshold for pentylenetetrazole during diazepam withdrawal was inhibited by pretreatment with MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cycloheptan-5,10-imine maleate), 7-chlorokynurenic acid and ifenprodil. Furthermore, MK-801 and ifenprodil, at doses which did not affect the threshold of pentylenetetrazole-induced seizure in control mice, also significantly suppressed the decrease in the seizure threshold during diazepam withdrawal, whereas 7-chlorokynurenic acid did not. These findings suggest that overactivity of an ion channel site and an ifenprodil binding site on the NMDA receptor may play an important role in the hypersensitivity of pentylenetetrazole-induced seizure in diazepam-withdrawn mice.

Topics: Animals; Anticonvulsants; Convulsants; Diazepam; Disease Models, Animal; Dizocilpine Maleate; Drug Interactions; Excitatory Amino Acid Antagonists; Infusions, Intravenous; Injections, Intraperitoneal; Injections, Subcutaneous; Kynurenic Acid; Male; Mice; Neuroprotective Agents; Pentylenetetrazole; Piperidines; Receptors, N-Methyl-D-Aspartate; Seizures; Substance Withdrawal Syndrome

2-Aroyl-4-(omega-aminoacyl)- (4) and 4-aroyl-2-(omega-aminoacyl)pyrroles (9) represent a new, structurally novel class of anticonvulsant agents. Compounds of type 4 were prepared by Friedel-Crafts acylation of a 2-aroylpyrrole with an omega-chloroacyl chloride followed by displacement of the chloro group by a primary or secondary amine. Compounds of type 9 were prepared by Friedel-Crafts aroylation of a 2-(omega-chloroacyl)pyrrole followed by displacement by an amine. These compounds were active in the mouse and rat maximal electroshock tests but not in the mouse metrazole test. The lead compound, RWJ-37868, 2-(4-chlorobenzoyl)-4-(1-piperidinyl-acetyl)-1,3,5-trimethylpyrrole++ + (4d), showed potency and therapeutic index comparable to those of phenytoin and carbamazepine and greater than those of sodium valproate. This compound blocked bicuculline induced seizures, did not elevate seizure threshold following iv infusion of metrazole, and blocked influx of Ca2+ ions into cerebellar granule cells induced by K+ or veratridine.

Topics: Anesthesia; Animals; Anticonvulsants; Bicuculline; Calcium; Cerebellum; Electroshock; Mice; Models, Molecular; Molecular Structure; Pentylenetetrazole; Piperidines; Potassium; Pyrroles; Rats; Seizures; Structure-Activity Relationship; Veratridine

1. The involvement of the N-methyl-D-aspartate (NMDA) receptor macrocomplex in the development of spermine-induced CNS excitation in vivo was investigated. 2. Injection of 100 micrograms of spermine into the left lateral cerebral ventricle of female Laca mice (20-25 g) resulted in the development of two distinct phases of CNS excitatory effects which were quantified by a scoring system. 3. The first phase effects occurred within minutes of injection and generally lasted for about 1 h. Most mice showed scratching of the upper body, frequent face washing and some mice developed clonic convulsions. By about 2 h after injection, the second phase of effects began to develop in the form of body tremor which worsened with time and culminated in fatal tonic convulsions, generally within 8 h of injection. 4. Pretreatment of the mice with dizocilpine (0.3 mg kg-1, i.p.) resulted in antagonism of the first phase of spermine-induced effects, but a higher dose (0.3 mg kg-1, (x2), i.p.) was necessary to inhibit the second phase effects. 5. Whereas the glutamate antagonist, 3-((R)-2-carboxypiperazin-4-yl) propyl-1-phosphonic acid (D-CPP) (10, 20 mg kg-1, i.p.), the glycine antagonist 7-chlorokynurenate (10, 30, 50 nmol, i.c.v.), or the polyamine antagonist ifenprodil (30, 60 mg kg-1, i.p.) antagonized the first phase of effects produced by spermine, these agents given as monotherapy, were ineffective against the development of the second phase of effects. 6. Co-administration of ifenprodil with either D-CPP or 7-chlorokynurenate resulted in a dose-dependent antagonism of the development of the second phase of spermine-induced effects. 7. It is concluded that the development of the two temporally distinct phases of spermine-induced effects may be mediated by pharmacologically distinct mechanisms, although the results suggest that the NMDA receptor macrocomplex may be involved in both phases of effects. Furthermore, a moderate dose of D-CPP or 7-chlorokynurenate appears to enhance the inhibitory potential of ifenprodil in vivo.

Topics: Animals; Brain; Cerebral Ventricles; Dizocilpine Maleate; Female; Kynurenic Acid; Mice; Neuroprotective Agents; Piperazines; Piperidines; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Seizures; Spermine; Tremor

In traditional Chinese medicine, a mixture of radish and pepper is used to treat epilepsy. The presumptive effectiveness of this prescription might be due to the anticonvulsant actions of the principal component of pepper, the alkaloid piperine (CAS 94-62-2). The effects of piperine on convulsions induced in mice by agonists at different excitatory amino acid receptor subtypes were studied. Piperine was shown to significantly block convulsions induced by intracerebroventricular injection of threshold doses of kainate, but to have no or only slight effects on convulsions induced by L-glutamate, N-methyl-D-aspartate or guanidinosuccinate. Piperine suspensions, injected intraperitoneally, 1 h before injection of the threshold intracerebroventricular dose of kainate for the induction of clonic convulsions (1 nmol), blocked these convulsions with an ED50 (and 95% confidence interval) of 46 (25-86) mg/kg. Although piperine did block convulsions, induced by kainate, the compound does not appear to act as a kainate receptor antagonist. Whole-cell currents induced by the application of kainate to spinal cord cells in primary dissociated cultures were not affected by co-application of piperine.

Topics: Alkaloids; Animals; Anticonvulsants; Benzodioxoles; Excitatory Amino Acid Agonists; Female; Injections, Intraventricular; Kainic Acid; Male; Mice; Patch-Clamp Techniques; Piperidines; Polyunsaturated Alkamides; Seizures; Spinal Cord

Budipine is a novel antiparkinsonian drug which is particularly beneficial in the treatment of parkinsonian tremor. The mechanism of action of budipine is not fully understood. To study whether budipine has dopaminergic activity in vivo, we used the 6-hydroxydopamine rotational model of Parkinson's disease. Budipine (0.78-12.5 mg/kg i.p.) did not induce ipsilateral or contralateral rotations, suggesting that it does not possess direct or indirect dopaminergic activity. This conclusion is further supported by the observation that budipine (10 mg/kg) i.v. did not facilitate striatal dopamine release measured in vivo by brain microdialysis. To investigatate possible antimuscarinic and N-methyl-D-aspartic acid (NMDA) antagonistic properties of budipine, we compared budipine with the antimuscarinic antiparkinsonian drug biperiden and the NMDA receptor antagonist 3-[(+/-)-2-carboxypiperazine-4-yl]-propyl-1-phosphonic acid (CPP). In receptor-binding assays, budipine inhibited thienylcyclohexylpiperidyl-3,4-[3H](n) ([I3H]TCP) (2.5 nM)-binding with an IC50 of 36 microM and [3H]3-quinuclidinol benzilate-binding with an IC50 of 1.1 microM. The respective values for biperiden were 170 and 0.053 microM. In line with these findings, budipine and CPP increased the threshold for NMDA-induced seizures in mice with an ED50 of 10.2 and 4.4 mg/kg, respectively, whereas biperiden was not effective. In 6-hydroxydopamine-lesioned rats, budipine (3.13-12.5 mg/kg) and CPP (0.1-0.39 mg/kg) increased the number of contralateral rotations induced by apomorphine, whereas biperiden was not effective. The present data suggest that budipine acts by blocking muscarinic and NMDA transmission while facilitation of dopaminergic transmission does not appear to contribute to its in vivo action. In comparison to biperiden, which has also antimuscarinic and NMDA receptor antagonistic properties, the anti-NMDA action of budipine is more prominent.

Topics: Animals; Antiparkinson Agents; Biperiden; Central Nervous System; Dopamine; Excitatory Amino Acid Antagonists; Male; Mice; Microdialysis; Muscarinic Antagonists; N-Methylaspartate; Neostriatum; Neurotransmitter Agents; Oxidopamine; Piperazines; Piperidines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Rotation; Seizures; Stereotyped Behavior; Sympatholytics

Cessation of chronic administration of orally administered large amounts of ethanol for 7 days resulted in a markedly increased frequency of audiogenic seizures in Sprague-Dawley rats. Oral administration of the novel glycine receptor antagonist, L-701,324, produced a dose-dependent (2.5 and 5.0 mg/kg; -30 min) inhibition of ethanol withdrawal signs when measured about 12 h after withdrawal of the ethanol treatment. Similarly, using the same experimental paradigm, oral administration of the specific polyamine receptor antagonist, eliprodil, caused a dose-related (2.0 and 5.0 mg/kg; -30 min) inhibition of ethanol withdrawal-induced audiogenic seizure activity. The inhibition of ethanol withdrawal seizures produced by L-701,324 and eliprodil, respectively, was obtained at doses which by themselves did not change the locomotor activity in naive Sprague-Dawley rats. The findings that L-701,324 and eliprodil are potent inhibitors of seizure activity induced by cessation of chronic ethanol administration and the fact that they, in contrast to currently available NMDA receptor antagonists, do not produce psychotomimetic and/or sedative effects, suggest that these drugs may represent a new class of therapeutically useful pharmacological agents for the treatment of ethanol withdrawal seizures. Furthermore, since there is evidence that eliprodil produces its pharmacological actions through a specific inhibition of NMDAR1 and/or NMDAR2B subunits, these data may indicate that certain NMDA receptor subunits may be of particular importance for the mediation of seizure activity following the discontinuation of chronic ethanol exposure.

Topics: Acoustic Stimulation; Administration, Oral; Animals; Anticonvulsants; Central Nervous System Depressants; Dizocilpine Maleate; Ethanol; Excitatory Amino Acid Antagonists; Male; Motor Activity; Piperidines; Quinolones; Rats; Rats, Sprague-Dawley; Seizures; Substance Withdrawal Syndrome

The behavioural and convulsant effects of imipenem (Imi), a carbapenem derivative, were studied after intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures. The anticonvulsant effects of some excitatory amino acid antagonists and muscimol (Msc), a GABAA agonist, against seizures induced by i.p. or i.c.v. administration of Imi were also evaluated. The present study demonstrated that the order of anticonvulsant activity in our epileptic model, after i.p. administration, was (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)-cyclohepten-5,10-imine maleate (MK-801) > (+/-)(E)-2-amino-4-methyl-5-phosphono-3-pentenoate ethyl ester (CGP 39551) > 3-((+/-)-2-carboxypiperazin-4-yl)propenyl-1-phosphonic acid (CPPene) > 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CCP) > 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)-quinoxaline (NBQX). Ifenprodil, a compound acting on the polyamine site of NMDA receptor complex was unable to protect against seizures induced by Imi, suggesting that the poliamine site did not exert a principal role in the genesis of seizures induced by Imi. In addition, the order of anticonvulsant potency in our epileptic model, after i.c.v. administration, was CPPene > MK-801 > Msc > (-)-2-amino-7-phosphonic acid (AP7) > gamma-D-glutamylaminomethylsulphonate (gamma-D-GAMS) > NBQX > kynurenic acid (KYNA) > 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX). The relationship between the different site of action and the anticonvulsant activity of these derivatives was discussed. Although the main mechanism of Imi induced seizures cannot be easily determined, potential interactions with the receptors of the excitatory amino acid neurotransmitters exists. In fact, antagonists of excitatory amino acids are able to increase the threshold for the seizures or to prevent the seizures induced by Imi. In addition, Imi acts on the central nervous system by inhibition of GABA neurotransmission and Msc, a selective GABAA agonist, was able to protect against seizures induced by Imi.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Amino Acids; Animals; Anticonvulsants; Dizocilpine Maleate; Excitatory Amino Acids; Glutamine; Imipenem; Kynurenic Acid; Mice; Mice, Inbred DBA; Muscimol; Piperazines; Piperidines; Quinoxalines; Seizures

1. The behaviour and EEG effects of the dopamine and sigma (sigma) ligands (+) 3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)3-PPP) were studied in mice. 2. (+) 3-PPP dose-dependently (60-100 mg/kg i.p.) produced behavioural and electrical tonic-clonic seizures. 3. The incidence of the tonic seizures elicited by 100 mg/kg of the drug was significantly (P < 0.05) prevented by spiperone (0.5 mg/kg i.p.) and haloperidol (0.5 mg/kg i.p.). 4. The results show an influence on the behavioural and electrical threshold of convulsions by (+) 3-PPP depending on a prevalent interference on dopamine receptors.

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Convulsants; Dopamine Agonists; Dopamine Antagonists; Electric Stimulation; Electroencephalography; Male; Mice; Piperidines; Receptors, sigma; Seizures; Stereoisomerism

To assess the involvement of intra-amygdala kinase activity in aversively motivated learning, rats received intracranial injections of polymixin B sulfate (PMXB)--a protein kinase C (PKC) and calcium/calmodulin-dependent kinase II inhibitor--immediately after inhibitory avoidance training. When tested 48 h later, retention was significantly impaired relative to vehicle-injected controls. Delayed injections (2 h posttraining) and injections made dorsal to the amygdala were ineffective. Immediate posttraining injections of the more selective PKC inhibitor, NPC 15437, also impaired retention. These results suggest that intra-amygdala protein phosphorylation must occur soon after training for learned avoidance responses to be successfully retained.

Topics: Amygdala; Animals; Anti-Inflammatory Agents, Non-Steroidal; Avoidance Learning; Electroencephalography; Injections; Male; Memory; Piperidines; Polymyxin B; Protein Kinase Inhibitors; Rats; Rats, Sprague-Dawley; Seizures

Procyclidine (up to 20 mg/kg i.p.) did not influence the electroconvulsive threshold per se, but when given in a dose of 10 mg/kg, it potentiated the protective activity of carbamazepine, diphenylhydantoin, phenobarbital and valproate, and in a dose of 20 mg/kg, that of diazepam against maximal electroshock-induced convulsions in mice. Ifenprodil increased the threshold for electroconvulsions when applied at 20 and 40 mg/kg (i.p.), but surprisingly, when combined with all antiepileptics tested, it did not influence their anticonvulsant actions. The chimney test in mice revealed, that application of procyclidine at 10 mg/kg together with phenobarbital and valproate, and procyclidine at 20 mg/kg with diazepam resulted in motor impairment. However, when procyclidine was applied at 10 mg/kg together with carbamazepine or diphenylhydantoin, no motor impairment was noted. The combined treatment of procyclidine (10 mg/kg) with carbamazepine, diphenylhydantoin, phenobarbital or valproate, as well as procyclidine (20 mg/kg) with diazepam caused significant worsening of long-term memory. Finally, procyclidine did not alter the total plasma levels of carbamazepine, diazepam, diphenylhydantoin, phenobarbital and valproate. It may be concluded that not all agents interfering with NMDA receptor complex-mediated events lead to the potentiation of the anticonvulsant activity of antiepileptic drugs.

Topics: Animals; Anticonvulsants; Avoidance Learning; Drug Synergism; Electroshock; Male; Memory; Mice; Movement; Piperidines; Procyclidine; Receptors, N-Methyl-D-Aspartate; Seizures

Several new bioanalogues of (+/-)-N-methyl-N-(1-[3-(4-fluorophenoxy)-2-hydroxy-propyl]piperidin++ +-4-yl) benzothiazol-2-amine (1, sabeluzole, CAS 104383-17-7) were prepared by reacting 1,2-epoxy-3-aryloxypropanes with 4-arylaminopiperidines. Some of these derivatives showed enhanced activity in the potassium cyanide hypoxia test and in the pentetrazol convulsion test in mice compared to 1.

Topics: Animals; Anticonvulsants; Cell Survival; Cyanides; Hypoxia; Male; Mice; Mice, Inbred Strains; Pentylenetetrazole; Piperidines; Seizures; Thiazoles

We have used the pilocarpine-induced seizure model in mice and i.c.v. injection of subtype-specific receptor antagonists to investigate the muscarinic receptor subtype specificity of cholinergically-activated seizures. The rank order potencies of antagonists for inhibition of pilocarpine-induced seizures are atropine = telenzepine > 4-diphenylacetoxy-N-(2-chloroethyl)-piperidine (4-DAMP) > pirenzepine with ID50's of 8.6, 12.0, 29.9, and 83.0 nmol/mouse, respectively. The M3-specific antagonists hexahydrosila-difenidol and its p-fluoro analog showed no effect on pilocarpine-induced seizures. The M2-specific antagonists gallamine and methoctramine cause seizures in mice in the absence of a pilocarpine injection. These seizures could be inhibited by coinjection of methoctramine with the M1-specific antagonist, pirenzepine. These data suggest a role of muscarinic M1 receptors in mediating pilocarpine-induced seizures and a role of the muscarinic M2 receptors in modulating neuronal activity.

Topics: Animals; Atropine; Cerebral Ventricles; Injections, Intraventricular; Male; Mice; Parasympatholytics; Pilocarpine; Piperidines; Pirenzepine; Receptors, Muscarinic; Seizures

Budipine (1-t-butyl-4,4-diphenylpiperidine) is a novel antiparkinsonian agent. Its clinical efficacy has been proven in double-blind placebo-controlled trials. The mechanism of action of budipine, however, is unknown. Budipine selectively increased the threshold of N-methyl-D-aspartate (NMDA)-induced seizures in mice. Similar to known specific NMDA antagonist, budipine depressed polysynaptic spinal reflexes in mice, but had no consistent effect on spinal monosynaptic reflexes. In receptor binding experiments, budipine displaced thienylcyclohexylpiperidyl-3,4-[3H]-(n) ([3H]-TCP) from its binding site with an IC50 of 36 microM suggesting that budopine acts as a non-competitive NMDA antagonist with moderate receptor affinity. It is concluded that the newly discovered NMDA antagonistic action of budipine is at least partly responsible for its antiparkinsonian activity. Our findings are additional evidence for the hypothesis that NMDA antagonists may be useful in the treatment of Parkinson's disease (PD).

Topics: Amino Acids; Anesthesia; Animals; Antiparkinson Agents; Binding, Competitive; Brain Chemistry; H-Reflex; In Vitro Techniques; Male; Mice; N-Methylaspartate; Phencyclidine; Piperidines; Rats; Receptors, N-Methyl-D-Aspartate; Reflex; Reflex, Monosynaptic; Seizures; Spinal Cord

Certain sigma receptor ligands have been shown to block locomotor stimulation produced by cocaine at doses that do not have significant behavioral activity when given alone. Using a potent and selective ligand of sigma binding sites, 6-[6-(4-hydroxypiperidinyl)hexyloxy]-3-methylflavone (NPC 16377), we further investigated the influence of sigma ligands on additional behavioral and toxic effects of cocaine in mice. A behaviorally inactive dose of NPC 16377 shifted the dose-effect function for the locomotor stimulant effects of cocaine to the right by a factor of 2.5. A higher dose of NPC 16377 produced an insurmountable blockade of this stimulant effect of cocaine. Prior exposure to cocaine enhances the locomotor stimulant effects of cocaine (sensitization). NPC 16377 prevented the development of cocaine sensitization without producing behavioral effects of its own. However, NPC 16377 was unable to block the expression of sensitization in mice previously exposed to cocaine. NPC 16377 also did not consistently alter the discriminative stimulus effects of cocaine or methamphetamine in rats discriminating either 3 or 10 mg/kg of cocaine, or 1 mg/kg of methamphetamine from saline. The potential phencyclidine-like behavioral effects of NPC 16377 were also evaluated. Unlike the NMDA channel ligand, dizocilpine, NPC 16377 did not increase responding under a fixed-interval schedule of food presentation in rats nor did it substitute for the discriminative stimulus effects of either 1.5 mg/kg of phencyclidine or 0.2 mg/kg of dizocilpine in rats discriminating these drugs from saline. NPC 16377 displayed limited but significant anticonvulsant activity against diazepam-sensitive cocaine convulsions. The lethal effects of higher doses of cocaine were neither significantly blocked nor enhanced in rats or mice with NPC 16377. These findings extend earlier observations on the cocaine-blocking effects of sigma ligands to a novel structure with exceptional selectivity for sigma sites. These data indicate that some sigma ligands may be capable of altering certain behavioral and toxic actions of cocaine without notable behavioral side effects as evidenced in preclinical tests. As such, these compounds may ultimately be useful in the treatment of cocaine abuse.

Topics: Animals; Cocaine; Conditioning, Psychological; Discrimination Learning; Flavonoids; Male; Methamphetamine; Mice; Motor Activity; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, sigma; Seizures

The effect of thioperamide, a histamine H3 receptor antagonist, on electrically induced convulsions was studied in mice. Thioperamide significantly and dose dependently decreased the duration of each phase of convulsion and raised the electroconvulsive threshold. Its anticonvulsant effects were prevented by pretreatment with (R)-alpha-methylhistamine, a histamine H3 receptor agonist. These findings suggest that the effect of thioperamide on electrically induced convulsions is due to an increase in endogenous histamine release in the brain, an effect mediated by histamine H3 receptors. The anticonvulsant effect of thioperamide was antagonized strongly by mepyramine (or pyrilamine), a centrally acting histamine H1 receptor antagonist, but not by zolantidine, a centrally acting histamine H2 receptor antagonist. Thus, the blockade by mepyramine of the thioperamide-induced decrease in seizure susceptibility indicates that histamine released by thioperamide from the histaminergic nerve terminals interacts with the histamine H1 receptors of postsynaptic neurons. These findings support the hypothesis that the central histaminergic system is involved in the inhibition of seizures.

Topics: Animals; Anticonvulsants; Electroshock; Histamine Antagonists; Male; Mice; Mice, Inbred Strains; Piperidines; Receptors, Histamine; Receptors, Histamine H3; Seizures

1. A pair of benzamide analogues containing a pyrrolidinyl or piperidinyl group was examined for their anticonvulsant activity against the electroshock-induced seizures in mice and the ability to block the voltage-gated Na channel in N1E-115 cells, in comparison with the prototype compound, U-54494A, (+/-)-cis-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-ben zam ide , a potent anticonvulsant and a Na channel blocker. 2. The pyrrolidinyl benzamide (U-49524E) was found to be effective against the electroshock-induced seizures (ED50 = 35 mg kg-1, i.p.) whereas the benzamide with a piperidinyl moiety (U-49132E) was inactive (ED50 greater than 100 mg kg-1). 3. Using whole-cell patch clamp techniques we found that U-49132E was several times less potent, with an IC50 of 396 microM as compared to 118 microM for U-49524E at the holding potential of -80 mV, and was much slower in blocking Na channels with a half-time of 10.7 +/- 1.1 min vs. 2.2 +/- 0.4 min for its counterpart. 4. Qualitatively, their general modes of interaction with Na channels were similar to each other and to that of U-54494A in that they interacted with the resting and slowly-inactivated states of the channels and exhibited a use-dependent inhibition because of a slow recovery from the inactivated state in the presence of the drugs. 5. Comparison of their physicochemical properties, shows the less potent and slowly acting U-49132E is more hydrophobic and bulkier than U-49524E, but has the same pKa. This suggests that the drugs approach the Na channel through a narrow and hydrophilic pathway.6. Overall, this study underscores the importance of inhibiting the Na channel to the anticonvulsant activity of the benzamide compounds.

Topics: Animals; Anticonvulsants; Cyclohexanes; Injections, Intraperitoneal; Male; Mice; Neuroblastoma; Piperidines; Pyrrolidines; Seizures; Sodium; Sodium Channels; Tumor Cells, Cultured

Topics: Antidepressive Agents, Tricyclic; Depressive Disorder; Humans; Incidence; Neurotransmitter Uptake Inhibitors; Paroxetine; Piperidines; Seizures; Serotonin; Suicide

The recent finding that ifenprodil binds with high affinity to sigma sites suggests that other sigma agents may have ifenprodil-like cerebroprotectant and functional N-methyl-D-aspartate (NMDA) antagonist effects. The present study, compared the in vivo effects of ifenprodil and the sigma agents, BMY 14802, caramiphen and haloperidol, in three tests sensitive to NMDA antagonists and purported cerebroprotectant drugs. When administered at or below the rotorod TD50 dose, all four compounds significantly increased survival time in an hypoxic environment (4% O2 in nitrogen). Caramiphen and ifenprodil (ED50 = 52 and 61 mg/kg, respectively) also blocked maximal electroshock-induced seizures, whereas BMY 14802 and haloperidol were ineffective. Finally, caramiphen (ED50 = 95 mg/kg) antagonized seizures and lethality induced by administration of NMDA (250 mg/kg, IP). BMY 14802, haloperidol and ifenprodil only partially antagonized NMDA-induced seizures, but did enhance the anticonvulsant potency of the noncompetitive NMDA antagonist, MK-801. Together, these findings suggest that sigma agents may have cerebroprotective effects.

Topics: Animals; Anticonvulsants; Brain Diseases; Electroshock; Haloperidol; Hypoxia; Male; Mice; Mice, Inbred Strains; N-Methylaspartate; Nimodipine; Piperidines; Postural Balance; Pyrimidines; Receptors, Opioid; Receptors, sigma; Seizures

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

The functional significance of the interaction between serotonergic and dopaminergic neurotransmission is still uncertain. To document this interaction further, specific behavioral responses of rats to tryptamine and apomorphine were studied. The sequential injection of these agonists, at time intervals with minimal direct behavioral interference, was used to observe response changes with respect to a single challenge. The antagonists haloperidol, ritanserin and risperidone, with known actions on serotonin-S2 (5-HT2) and dopamine-D2 (D2) receptors were used to evaluate effective antagonism of single and sequential challenges. When tryptamine was preceded by an apomorphine challenge the effective doses of the 5-HT2 antagonists ritanserin and risperidone for 50% inhibition of the seizures increased by a factor of 2.5. The dose-response curve of haloperidol remained virtually unchanged, apparently because of the potent dopamine-D2 antagonism associated with these doses which may block the potentiating effect of apomorphine. When apomorphine was preceded by a tryptamine challenge, the total agitation score of the control animals increased by 59% on the average. Haloperidol was equally effective against the enhanced as against the unenhanced apomorphine response. Ritanserin reduced agitation only by the part corresponding to the tryptamine enhancement. Risperidone's activity against the enhanced agitation started at very low doses and was complete at a dose still about 2.5 times lower than that required against the single apomorphine challenge. Mutual enhancement of tryptamine and apomorphine appears to occur even at a time when the behavioral effects of the first agonist are no longer manifest. The enhanced agitation remains largely dopamine-D2-specific and the enhanced seizures serotonin 5-HT2-specific.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antipsychotic Agents; Apomorphine; Dopamine; Dose-Response Relationship, Drug; Drug Interactions; Haloperidol; Injections, Intravenous; Isoxazoles; Male; Piperidines; Rats; Rats, Inbred Strains; Risperidone; Ritanserin; Seizures; Serotonin; Serotonin Antagonists; Synaptic Transmission; Tryptamines

The effects of excitatory amino acid antagonists on convulsions induced by intracerebroventricular (i.c.v.) or systemic (s.c.) administration of the gamma-aminobutyric acidA (GABAA) antagonist bicuculline (BIC) were tested in mice. 3-[+/-)-2-Carboxypiperazin-4-yl)-propyl-1-phosphonate (CPP), 2-amino-7-phosphonoheptanoate (AP7) and (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cycloheptan-5,10-imine maleate (MK-801) were used as representatives of N-methyl-D-aspartate (NMDA) antagonists. gamma-D-Glutamylaminomethylsulphonate (gamma-D-GAMS) typified a preferential kainate (KA) antagonist, 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX) represented a preferential quisqualate (QA) antagonist, and kynurenic acid (KYNA) was used as a mixed NMDA/KA antagonist. Bicuculline methiodide (BMI) induced clonic convulsions following i.c.v. administration with a CD50 of 0.183 nmol (range 0.164-0.204). The excitatory amino acid antagonists blocked clonic seizures induced by BMI in the dose of 0.224 nmol (approximately CD97) when coinjected into the lateral ventricle. CPP (ED50 0.0075 nmol) was the most potent anticonvulsant and was followed by AP7 (0.182 nmol), MK-801 (0.22 nmol), gamma-D-GAMS (0.4 nmol), KYNA (1.7 nmol) and CNQX (5.17 nmol). Muscimol (MSC), the GABAA agonist, blocked BMI-induced seizures with an ED50 of 0.25 nmol. Systemic (s.c.) administration of BIC induced in mice generalized seizures with a CD50 of 2.2 mg/kg (range 1.9-2.5) for clonus and CD50 of 2.4 mg/kg (range 2.2-2.7) for tonus.2+ the pathogenesis of seizures triggered by bicuculline in mice.

Topics: Animals; Bicuculline; Dibenzocycloheptenes; Dizocilpine Maleate; Dose-Response Relationship, Drug; Male; Mice; Muscimol; Pipecolic Acids; Piperazines; Piperidines; Receptors, Amino Acid; Receptors, Cell Surface; Seizures

The PCP-like compounds ketamine and dexoxadrol were evaluated in two behavioral test procedures known to be sensitive to competitive N-methyl-D-aspartate (NMDA) receptor antagonists. In the NMDA-induced convulsion test in mice, ketamine and dexoxadrol blocked convulsant activity only at doses that also induced nonspecific effects of PCP-like behaviors, thereby confounding the interpretation of results. These compounds also blocked NMDA-induced discriminative stimuli in rats; however, this effect was produced at doses lower than those which induced the nonspecific behavioral effects. These results provide evidence that in behavioral procedures, PCP-like compounds may block excitatory amino acid receptor stimulation by NMDA. The NMDA discrimination identifies these interactions without the influence of motor deficit or other behavioral motor effects.

Topics: Animals; Aspartic Acid; Behavior, Animal; Dioxolanes; Dioxoles; Ketamine; Male; Mice; Motor Activity; N-Methylaspartate; Piperidines; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Seizures

The N-Methyl-D-aspartate (NMDA)-type receptor blocking properties of CGS 19755, a novel, rigid analog of 2-amino-5-phosphonopentanoate, were demonstrated in vitro by the ability of the compound to block NMDA-evoked [3H]acetylcholine release (pA2 = 5.93). CGS 19755 (0.045 and 0.224 mmol/kg i.p.) was shown to be active in vivo as well by its ability to block harmaline-induced increases in cerebellar cGMP. Finally, CGS 19755 blocked sound-induced seizures in DBA/2 mice completely at doses of 1.0 nmol i.c.v. or 0.1 mmol/kg i.p. Taken together, these data indicate that CGS 19755 is a potent and competitive NMDA antagonist in vitro which is also active in vivo.

Topics: Acetylcholine; Animals; Aspartic Acid; Binding, Competitive; Blood-Brain Barrier; Cerebellum; Cyclic GMP; Harmaline; Male; Mice; Mice, Inbred DBA; N-Methylaspartate; Pipecolic Acids; Piperidines; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Seizures

CGS 19755 (cis-4-phosphonomethyl-2-piperidine carboxylic acid) was found to be a potent, stereospecific inhibitor of N-methyl-D-aspartate (NMDA)-evoked, but not KCl-evoked, [3H] acetylcholine release from slices of the rat striatum. The concentration-response curve to NMDA was shifted to the right by CGS 19755 (pA2 = 5.94), suggesting a competitive interaction with NMDA-type receptors. CGS 19755 inhibited the binding of [3H]-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid to NMDA-type receptors with an IC50 of 50 nM, making it the most potent NMDA-type receptor antagonist reported to date. CGS 19755 failed to interact with 23 other receptor types as assessed by receptor binding, including the quisqualate- and kainate-type excitatory amino acid receptors. In crude P2 fractions, no evidence was obtained to suggest that CGS 19755 is taken up by an active transport system. Furthermore, CGS 19755 failed to affect the uptake of L-[3H]glutamate, or to interact with aconitine-induced inhibition of L-[3H]glutamate uptake, the latter finding suggesting a lack of membrane-stabilizing or local anesthetic properties. CGS 19755 selectively antagonized the excitatory effect of iontophoretically applied NMDA in the red nucleus of the rat without affecting the excitatory effects of quisqualate. CGS 19755 blocked the harmaline-induced increase in cerebellar cyclic GMP levels at a dose of 4 mg/kg i.p. with a duration of action exceeding 2 hr. CGS 19755 inhibited convulsions elicited by maximal electroshock in rat (ED50 = 3.8 mg/kg i.p. 1 hr after administration) and in mouse (ED50 = 2.0 mg/kg i.p. 0.5 hr after administration). Likewise, convulsions elicited by picrotoxin were inhibited by CGS 19755, whereas the compound was relatively weak in protecting against convulsions elicited by pentylenetetrazole or strychnine. CGS 19755 produced retention performance deficits in a dark avoidance task. However, CGS 19755 did not show a unique propensity for learning and memory disruption compared to other anticonvulsants.

Topics: Acetylcholine; Aconitine; Animals; Anticonvulsants; Aspartic Acid; Avoidance Learning; Binding, Competitive; Darkness; Glutamates; Glutamic Acid; Male; N-Methylaspartate; Pentylenetetrazole; Picrotoxin; Pipecolic Acids; Piperidines; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Seizures; Structure-Activity Relationship; Tetrodotoxin

In the present report we have investigated the effects of apomorphine, (-)3-PPP, L-DOPA and haloperidol on the elicitation of convulsions induced in mice by exposure to oxygen at high pressure (HBO) (5 ata O2). It was found that the administration of apomorphine (0.025-0.1 mg X kg-1 s.c.), (-)3-PPP (4 mg X kg-1 i.p.) L-DOPA (200-400 mg X kg-1 i.p.) as well as haloperidol (0.25-2.0 mg X kg-1 i.p.) produced a significant protection against HBO-induced convulsions. Haloperidol was the only drug to produce a dose-dependent decrease in respiration, and this effect does probably explain the anticonvulsant effects observed. The low doses at which apomorphine was effective, and the effects produced by (-)3-PPP, indicate an effect mediated via DA autoreceptors. Alternatively, and more likely taking the effects of L-DOPA into account, the DA receptors involved are sensitive enough to disclose postsynaptic agonist properties of apomorphine and (-)3-PPP at the doses employed.

Topics: Animals; Antiparkinson Agents; Apomorphine; Body Temperature; Dose-Response Relationship, Drug; Haloperidol; Hyperbaric Oxygenation; Levodopa; Male; Mice; Mice, Inbred CBA; Piperidines; Reaction Time; Receptors, Dopamine; Respiration; Seizures

Topics: Acute Kidney Injury; Aminopyrine; Analgesics; Benzophenones; Child; Dipyrone; Drug Combinations; Humans; Hypertension; Male; Piperidines; Seizures

The 3-[(2-ethoxyphenoxy)methyl]piperidine derivatives 3-5 were synthesized and screened as potential antidepressant agents by the reserpine interaction test in mice and the evaluation of reuptake inhibition of biogenic amines in pig brain synaptosomal fractions. In addition, their anticonvulsant activity, tested by pentyleneetrazole antagonism, and approximate acute toxicity were evaluated. In vivo and in vitro tests showed that compounds 3 and 5 possess a biological activity comparable to that of the antidepressant drug viloxazine.

Topics: Animals; Antidepressive Agents; Blepharoptosis; Brain; Desipramine; Dopamine; Drug Evaluation, Preclinical; Ethyl Ethers; Hypothermia; Indicators and Reagents; Mice; Norepinephrine; Phenyl Ethers; Piperidines; Reserpine; Seizures; Serotonin; Structure-Activity Relationship; Synaptosomes; Viloxazine

Topics: Alkaloids; Animals; Azepines; Central Nervous System Stimulants; Diazepam; Drug Synergism; gamma-Aminobutyric Acid; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; Humans; Lactones; Male; Mice; Piperidines; Seizures

The effects of intravenous infusions of paroxetine, a novel inhibitor of 5-hydroxytryptamine (5HT) uptake, and of the tricyclic antidepressant, amitriptyline, on the cardiovascular system have been compared in the conscious rabbit and in the anaesthetised cat. As judged by the dose required to produce changes in ECG waveform (including PR and QTc intervals) and disorders of heart rhythm, paroxetine was less cardiotoxic than amitriptyline in both species. Thus, paroxetine has the advantage over amitriptyline of being less toxic to the cardiovascular system which could constitute a considerable advantage in clinical use particularly as other work has shown it to be more potent than amitriptyline in tests for antidepressant activity.

Topics: Amitriptyline; Animals; Antidepressive Agents; Cats; Drug Evaluation, Preclinical; Electrocardiography; Female; Heart Conduction System; Hypotension; Infusions, Parenteral; Male; Myocardial Contraction; Paroxetine; Piperidines; Rabbits; Seizures; Serotonin Antagonists; Tachycardia

SCH 29851 was studied for its ability to interact with selected drugs used in man. The non-sedating antihistamine terfenadine and the sedating antihistamine diphenhydramine were also studied for comparison. SCH 29851 at 80 mg/kg po in mice, a dose about 50 times its ED50 for blocking histamine-induced paw edema in the same species, potentiated the anticonvulsant effects of diazepam. At the high dose of 320 mg/kg po, about 80 times its ED50 for antihistamine effects, SCH 29851 potentiated the ability of high doses of ethanol and hexobarbital to induce loss of righting reflexes (LRR). However, no potentiation was seen when SCH 29851 was studied with lower doses of ethanol or phenobarbital that had anticonvulsant effects but did not cause LRR. At this high dose of 320 mg/kg po, SCH 29851 also did not interact with the antihypertensive drugs propranolol and alpha-methyldopa, the anti-ulcer drug cimetidine, the nasal decongestant pseudoephedrine, or the CNS stimulant d-amphetamine. A nearly identical profile of interactions was seen with terfenadine, including potentiation of diazepam at 50 times its antihistamine ED50, potentiation of ethanol- and barbiturate-induced LRR at 80 times its antihistamine ED50, and lack of interaction effects at 320 mg/kg po with each of the other tested drugs. The demonstration in this study of the significant interactions between diphenhydramine and many of the tested drugs is consistent with the clinical experience in man that this drug does have sedating properties and significant interactions with drugs like ethanol and diazepam.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Benzhydryl Compounds; Diphenhydramine; Dose-Response Relationship, Drug; Electroshock; Hexobarbital; Histamine Antagonists; Loratadine; Male; Mice; Motor Activity; Piperidines; Reflex; Seizures; Stereotyped Behavior; Terfenadine; Vocalization, Animal

Here I have reviewed evidence from electron microscopic studies showing that each of several sustained limbic seizure syndromes is associated with a type of acute brain damage which is ultrastructurally indistinguishable from the brain damage induced by Glu and other excitotoxins. In addition, I have presented evidence that persistent stimulation of specific axonal tracts that use Glu as transmitter results in Glu-like excitotoxic degeneration of postsynaptic neurons innervated by such tracts. Phencyclidine and ketamine, which powerfully block the neurotoxicity of the Glu analog NMA, protect against seizure-related brain damage. This may be explained by either an anticonvulsant or antiexcitotoxic mechanism, or both. Recent evidence suggests that an excitotoxic mechanism (excessive activation of Glu/Asp receptors) may underlie both seizure-mediated and anoxic brain damage. The acute fulminating type of neuronal degeneration induced by Glu is a Na+ and Cl- but not Ca2+ dependent phenomenon. According to a recent study, however, Glu may induce neuronal necrosis not only by an acute Ca2+ independent process but by a more slowly evolving Ca2+ dependent process. If, as these data suggest, an excitotoxic mechanism underlies brain damage associated with anoxia and epilepsy, a better understanding of excitotoxic mechanisms may lead eventually to prophylactic approaches for preventing such forms of brain damage.

Topics: Action Potentials; Animals; Brain; Cell Survival; Chick Embryo; Cholinergic Fibers; Disease Models, Animal; Edema; Epilepsies, Partial; Folic Acid; Hippocampus; Hypoxia; Kainic Acid; Ketamine; Microscopy, Electron; Parasympathomimetics; Phencyclidine; Piperidines; Seizures; Synaptic Transmission; Thalamus

It is well established that the putative excitatory neurotransmitters, glutamate (Glu) and aspartate (Asp), are neurotoxins that have the potential of destroying central neurons by an excitatory mechanism. Kainic acid (KA), a rigid structural analog of Glu, powerfully reproduces the excitatory neurotoxic (excitotoxic) action of Glu on central neurons and, in addition, causes sustained limbic seizures and a pattern of seizure-linked brain damage in rats that closely resembles that observed in human epilepsy. In the course of studying the seizure-related brain damage syndrome induced by KA, we observed that a similar type of brain damage occurs as a consequence of sustained seizure activity induced by any of a variety of methods. These included intraamygdaloid or supradural administration of known convulsants such as bicuculline, picrotoxin and folic acid, or systemic administration of lithium and cholinergic agonists or cholinesterase inhibitors that have not commonly been viewed as convulsants. We have further observed that this type of brain damage can be reproduced in the hippocampus by persistent electrical stimulation of the perforant path, a major excitatory input to the hippocampus that is thought to use Glu as transmitter. It is a common feature of all such neurotoxic processes that the acute cytopathology resembles the excitotoxic type of damage induced by Glu or Asp, which is acute swelling of dendrites and vacuolar degeneration of neuronal soma, without acute changes in axons or axon terminals. We have found that the seizure-brain damage syndrome induced by cholinergic agents can be prevented by pretreatment with atropine and that the syndrome induced by any of the above methods, cholinergic or noncholinergic, can be either prevented or aborted respectively by either pre-or posttreatment with diazepam. Our findings in experimental animals may be summarized in terms of their potential relevance to human epilepsy as follows. Sustained complex partial seizure activity consistently results in cellular damage if allowed to continue for longer than 1 hr. Hippocampal, or Ammon's horn, sclerosis is the primary pathological result. It may be a priority goal, therefore, in the management of human epilepsy to control such seizure activity within very narrow limits. This proposal is discussed in terms of three major transmitter systems that may be involved; cholinergic, GABAergic, and glutamergic/aspartergic. The cholinergic system may play a role in genera

Topics: Administration, Topical; Amygdala; Animals; Axons; Biomechanical Phenomena; Brain; Choline; Cholinesterase Inhibitors; Convulsants; Corpus Striatum; Epilepsy; Folic Acid; Injections; Kainic Acid; Lithium; Motor Cortex; Neural Pathways; Neurotoxins; Piperidines; Rats; Seizures; Somatosensory Cortex

Experiments were undertaken to determine the site of action of securinine and related convulsant indolizidines. All of these compounds induced tonic seizures in mice, with CD50 values ranging from 11 to 87 mg/kg. The CD50 for bicuculline was found to be 8 mg/kg. Equilibrium binding assays revealed that securinine and dihydrosecurinine inhibit [3H]GABA binding to rat brain membranes with an IC50 of approximately 50 microM, which is some 7 times less potent than bicuculline. Allosecurinine and virosecurinine have IC50 values greater than 1 mM. Both dihydrosecurinine and securinine inhibited GABA-stimulated benzodiazepine binding in rat brain membranes, though they were somewhat weaker than bicuculline in this respect. Other binding assays revealed that securinine and its analogs were inactive as inhibitors of bicuculline-insensitive GABA binding, benzodiazepine, cholinergic muscarinic, and beta-adrenergic receptor binding. In addition, while thiocyanate ion increased the apparent binding potency of bicuculline 10-fold, it had little effect on that of securinine. Extracellular electrophysiological studies on neurons in the cat spinal cord indicated that securinine and dihydrosecurinine blocked the inhibitory action of GABA while having no effect on that of glycine. Allo- and virosecurinine were much less active as GABA receptor antagonists in this test. These results suggest that, like bicuculline, securinine and dihydrosecurinine are selective antagonists of GABA recognition sites on mammalian central neurons.

Topics: Alkaloids; Animals; Azepines; Bicuculline; Cats; Central Nervous System; Convulsants; Female; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; Lactones; Mice; Mice, Inbred ICR; Piperidines; Receptors, GABA-A; Seizures; Stimulation, Chemical

Lysine and its metabolic intermediates were studied for their effect on pentylenetetrazol (PTZ)-induced seizures in mice. L-Lysine at dosages above 2 mmol/kg given i.p. significantly increased seizure protection and seizure latency (the time required to develop seizures after PTZ injection) with a peak effect dose at 10 mmol/kg. A pretreatment time of 15 min was required to significantly prolong seizure latency with a peak effect time of 45 min. D-Lysine at 10 mmol/kg i.p. afforded some seizure protection and significantly prolonged seizure latency but has a peak effect time of 15 min. When administered intracerebroventricularly, both L-lysine and piperidine at 0.1 mmol/kg prolonged seizure latency significantly, and increased seizure protection slightly. L-Pipecolic acid at the same dose given through the same route, however, shortened seizure latency significantly. L-alpha-Aminoadipic acid, on the other hand, had no significant effect. Lysine metabolites that prolonged seizure latency also increased seizure protection and decreased seizure death, and one that shortened seizure latency had the opposite effect. The anticonvulsant activity of lysine and its metabolites was explained on the basis of their connection with the GABAergic transmission.

Topics: 2-Aminoadipic Acid; Animals; Anticonvulsants; gamma-Aminobutyric Acid; Lysine; Male; Mice; Pentylenetetrazole; Pipecolic Acids; Piperidines; Seizures; Synaptic Transmission

Convulsions of E1 mice were completely suppressed by 60 mg/kg of piperine injected intraperitoneally. The ED50 was 21.1 mg/kg. The brain 5-HT, dopamine and norepinephrine levels were estimated 1 hour after the intraperitoneal injection of piperine. The 5-HT level was significantly higher in the cerebral cortex of piperine treated mice than in control mice. This increase may be related directly to the mechanism of inhibition of convulsions by piperine. On the other hand, lower levels of 5-HT were observed in the hippocampus, midbrain and cerebellum. The dopamine level in the piperine treated mice was markedly higher only in the hypothalamus, while the norepinephrine levels were lower in every part of the brain.

Topics: Alkaloids; Animals; Anticonvulsants; Benzodioxoles; Brain Chemistry; Catecholamines; Dopamine; Mice; Norepinephrine; Piperidines; Polyunsaturated Alkamides; Seizures; Serotonin

Thirteen derivatives of 3-phenyl-2-piperidinone were synthesized and evaluated for anticonvulsant activity. The most active compounds from this group included two simple lactams, 3-hydroxy-1-methyl-3-phenyl-2-piperidinone and 3-methoxy-3-phenyl-2-piperidinone, and two N-ethoxycarbonyl lactams, 1-(ethoxycarbonyl)-3-hydroxy-3-phenyl-2-piperidinone and 1-(ethoxycarbonyl)-3-methoxy-3-phenyl-2-piperidinone, whose anticonvulsant activity was comparable to or better than that for valproic acid. Four related acyclic amides were also prepared, but these were essentially inactive as anticonvulsants.

Topics: Amides; Animals; Anticonvulsants; Chemical Phenomena; Chemistry; Lactams; Mice; Piperidines; Seizures; Structure-Activity Relationship

Piperine and its derivatives are effective anticonvulsant drugs that antagonize convulsions induced by physical and chemical methods. Their major anticonvulsant activity as shown in animal tests lies in modification of the maximal electroshock seizure pattern. They also have sedative-hypnotic, tranquilizing, and muscle-relaxing actions and can intensify the depressive action of other depressants, when used in combination. Antiepilepsirine, one of the derivatives of piperine, is used as an antiepileptic drug in treating different types of epilepsy. It has been proved effective and is being widely used in China. The anticonvulsant action of 7446, 7448, and 7903 is more potent than that of antiepilepsirine. The chemical structure of piperine and its derivatives is different from that of prototype antiepileptic drugs, and, therefore, these may become a new group of antiepileptic drugs.

Topics: Anticonvulsants; Chemical Phenomena; Chemistry; Humans; Piperazines; Piperidines; Seizures

Topics: Diarrhea, Infantile; Humans; Infant; Loperamide; Male; Piperidines; Seizures

Topics: Adult; Electroencephalography; Female; Humans; Piperidines; Seizures

Topics: Amygdala; Animals; Biotransformation; Convulsants; Kainic Acid; Oxotremorine; Piperidines; Rats; Receptors, Cholinergic; Seizures; Structure-Activity Relationship

Topics: Animals; Behavior, Animal; Diazepam; Hippocampus; Kainic Acid; Male; Piperidines; Pyrrolidines; Rats; Seizures

Topics: Alkaloids; Animals; Anticonvulsants; Benzodioxoles; Dioxolanes; Mice; Piperidines; Polyunsaturated Alkamides; Rats; Seizures

Topics: Adult; Age Factors; Alcohol Withdrawal Delirium; Basal Ganglia Diseases; Biperiden; Diagnosis, Differential; Encephalitis; Female; Humans; Male; Piperidines; Psychoses, Alcoholic; Seizures

Topics: Acoustic Stimulation; Animals; Biperiden; Cats; Cerebral Cortex; Drug Interactions; Electroencephalography; Evoked Potentials; Physostigmine; Piperidines; Seizures; Succinylcholine

Effects of ifenprodil tartrate, a potent vasodilator, on the autonomic, peripheral and central nerve system were studied in experimental animals. In isolated vas deferens of guinea pigs, the contraction in response to noradrenaline and sympathetic nerve stimulation was competetively antagonized by ifenprodil 10(-7)--10(-5) M (pA2: 7.69 against noradrenaline). Ifenprodil (50 approximately 1,000 mug/kg i.v.) inhibited the contraction of cat nictitating membrane and dog urinary bladder induced by sympathetic nerve stimulation. Ifenprodil (250 approximately 1,000 mug/kg i.v.) lowered adrenaline-induced lethality (ED50: 360 mug/kg). The drug produced a hypermotility of guinea pig uterus, and showed a transient hypertonus of dog gut which was abolished by atropine. Ifenprodil (10 approximately 20 mg/kg i.v.) inhibited the propulsion of charcoal meal in mice. In Shay rats, more than 10 mg/kg i.m. of the drug inhibited the secretion of acid gastric juice and the ulceration. Ifenprodil showed a potent local anesthetic action in the guinea pig cornea and skin. The spontaneous EEG of rabbits showed a resting pattern (0.25 approximately 2 mg/kg i.v.) followed by an arousal pattern (5 approximately 10 mg/kg). Ifenprodil (20 approximately 100 mg/kg p.o.) potentiated a hypnosis induced by barbital, and potentiated pentylenetetrazol, strychnine and picrotoxin induced convulsion. The drug (20 and 100 mg/kg p.o.) lowered the body temperature of rats. From these results it is concluded that ifenprodil produces a blocking action of alpha-adrenoceptors in various smooth muscle preparations and a direct relaxation of the smooth muscle itself without affecting the motor and central nerve systems.

Topics: Animals; Autonomic Nervous System; Barbiturates; Behavior; Cats; Central Nervous System; Dogs; Dose-Response Relationship, Drug; Drug Synergism; Electroencephalography; Female; Gastric Juice; Gastric Mucosa; Gastrointestinal Motility; Guinea Pigs; In Vitro Techniques; Male; Mice; Muscle, Smooth; Nictitating Membrane; Peripheral Nerves; Piperidines; Rabbits; Rats; Reflex; Salivation; Seizures; Sleep; Vas Deferens

1-Phenethyl-4-hydroxy-salicylamido-4-methylpiperidine-hydrochloride (S 1592) markedly inhibits coughing induced in laboratory animals by chemical or mechanical irritation of respiratory tract or by electrical stimulation of the superior laryngeal nerve. The drug has low acute toxicity in mice and rats. The new compound possesses bronchodilating and antianaphylactic properties and does not affect gastrointestinal propulsion. Cardiovascular effects are absent.

Topics: Analgesia; Anaphylaxis; Animals; Antitussive Agents; Body Temperature; Bronchi; Cats; Cough; Dogs; Gastrointestinal Motility; Guinea Pigs; Hemodynamics; Lethal Dose 50; Male; Mice; Motor Activity; Motor Skills; Muscle Contraction; Muscle Tonus; Muscle, Smooth; Piperidines; Rats; Respiration; Salicylamides; Seizures; Sleep

For purposes of carrying out structure-activity studies on a series of pure R and S enantiomorphs of various para-substituted N-acetyl-alpha-amino-N-phenylglutarimides, we synthesized the p-acetyl, iodo, cyano, ethyl, and n-butyl analogues. These compounds complimented previous R and S isomers (unsubstituted and the p-chloro, methyl, nitro, and methoxyl analogues) synthesized in our laboratories from amino acids of known absolute configuration. The neurotoxic doses (TD50's), anticonvulsant potencies [maximal electroshock seizures (MES) and subcutaneous metrazole (sc Met) ED50's], protective indices (PI = TD50/ED50), and effects on minimal seizure threshold (iv Met) were compared with similar values concomitantly determined for clinically employed anticonvulsants. A parallel relationship was shown between neutotoxicity (TD50) and potency (ED50) for the R and S analogues. In most cases R isomers had a more rapid onset of action and possessed greater neurotoxicity and greater anticonvulsant potency.

Topics: Animals; Anticonvulsants; Ethosuximide; Male; Mice; Phenytoin; Piperidines; Piperidones; Seizures; Stereoisomerism; Structure-Activity Relationship; Trimethadione

A review is given of an experimental study on cats where the influence of acid-base changes on central nervous system toxicity of local anaesthetic agents was studied. The conclusion of this study was that a respiratory acidosis increased the central nervous system toxicity of local anaesthetics and that the underlying metabolic conditions modified this increase. Thus a respiratory acidosis increased this toxicity more if it was based on a metabolic acidosis than on a metabolic alkalosis (Englesson, 1974; Englesson and Grevsten, 1974). An extended analysis is presented where automatic frequency analysis was performed on the e.e.g. recordings performed during the i.v. infusion of lignocaine, bupivacaine, L 134, HS 37 and its optical isomers. The preliminary results show that the electrical changes appearing in the e.e.g. from the start of the i.v. infusion until seizure activity were the same if this time interval was as short as 1 min or as long as 8 min. It also revealed remarkable individual differences between agents, for instance lignocaine displaying marked electrical changes already in the first third of this time period where bupivacaine showed no changes until shortly before seizures.

Topics: Acid-Base Equilibrium; Acidosis, Respiratory; Allyl Compounds; Amines; Anesthetics, Local; Anilides; Animals; Brain; Bupivacaine; Carbamates; Carbon Dioxide; Cats; Cerebral Cortex; Computers; Electroencephalography; Hydrogen-Ion Concentration; Lidocaine; Mepivacaine; Partial Pressure; Piperidines; Prilocaine; Procaine; Seizures; Structure-Activity Relationship; Time Factors

Topics: Amides; Animals; Anticonvulsants; Brain; Drug Synergism; In Vitro Techniques; Ketoglutaric Acids; Lethal Dose 50; Male; NAD; Oxidation-Reduction; Pentobarbital; Pentylenetetrazole; Piperidines; Pyruvates; Rats; Seizures; Sleep; Succinates; Time Factors

Topics: Action Potentials; Animals; Anticonvulsants; Behavior, Animal; Cats; Cordotomy; Dose-Response Relationship, Drug; Electric Stimulation; Electroshock; Female; Mice; Mice, Inbred ICR; Motor Activity; Muscle Contraction; Muscle Relaxants, Central; Neuromuscular Junction; Pentylenetetrazole; Phenyl Ethers; Piperidines; Pyrrolidines; Reflex, Monosynaptic; Seizures; Spinal Nerve Roots; Tropanes

Topics: Animals; Brain; Cattle; Electric Stimulation; Electroencephalography; Eye Movements; Female; Male; Microinjections; Muscles; Piperidines; Seizures; Sleep; Stereotaxic Techniques

Topics: Adolescent; Adult; Anticonvulsants; Antipsychotic Agents; Bipolar Disorder; Brain Diseases; Cerebrovascular Disorders; Child; Epilepsy; Humans; Hypertension; Hypnotics and Sedatives; Intracranial Arteriosclerosis; Middle Aged; Phenothiazines; Piperidines; Schizophrenia; Seizures

Topics: Aggression; Animals; Antiemetics; Apomorphine; Behavior, Animal; Cats; Chlorpromazine; Conditioning, Operant; Copper; Dextroamphetamine; Dioxoles; Dogs; Drug Synergism; Electroencephalography; Escape Reaction; Ethanol; Haplorhini; Humans; Indoles; Male; Mice; Motor Activity; Piperidines; Postural Balance; Rats; Seizures; Species Specificity; Stereotyped Behavior; Vomiting

Topics: Aminobutyrates; Analgesics; Animals; Barbiturates; Cats; Cerebral Cortex; Drug Synergism; Hexobarbital; Hypoxia; Lethal Dose 50; Mice; Morphine; Piperidines; Rabbits; Rats; Seizures; Thiopental; Thiosemicarbazones; Visual Cortex

Topics: Androstanes; Anesthesia, Inhalation; Aortic Aneurysm; Atropine; Autopsy; Blood Pressure; Calcium; Carbon Dioxide; Cerebrospinal Fluid Proteins; Gluconates; Glucose; Hematocrit; Humans; Male; Middle Aged; Neuromuscular Nondepolarizing Agents; Nitrous Oxide; Oxygen; Oxygen Consumption; Phenytoin; Piperidines; Postoperative Complications; Potassium; Respiration, Artificial; Seizures; Sodium; Thiopental; Urea

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: Animals; Body Weight; Butyrophenones; Dogs; Feeding Behavior; Female; Male; Movement Disorders; Piperidines; Rats; Seizures; Tranquilizing Agents

Topics: Amphetamine; Analgesics; Animals; Avoidance Learning; Behavior, Animal; Blood Pressure; Body Temperature; Brain Chemistry; Caffeine; Cats; Central Nervous System; Chlordiazepoxide; Chlorpromazine; Drug Synergism; Ethanol; Haplorhini; Indoleacetic Acids; Male; Meprobamate; Methylphenidate; Mice; Morphine; Motor Activity; Pentobarbital; Piperidines; Rats; Reserpine; Respiration; Salivation; Seizures; Serotonin; Triazines

Topics: Amphetamine; Animals; Antidepressive Agents; Catecholamines; Central Nervous System; Ephedrine; Male; Mice; Pentylenetetrazole; Piperidines; Seizures; Sensory Receptor Cells; Sympathomimetics; Time Factors; Tremor

Topics: Adolescent; Anticonvulsants; Child; Child, Preschool; Consciousness; Epilepsy, Tonic-Clonic; Ethosuximide; Extrapyramidal Tracts; Female; Humans; Hyperkinesis; Infant; Male; Piperidines; Pyrrolidinones; Seizures

Topics: Animals; Antidotes; Atropine; Bradycardia; Carbachol; Central Nervous System; Cholinesterase Inhibitors; Female; Guinea Pigs; Hallucinogens; Heart Rate; Mandelic Acids; Methacholine Compounds; Mice; Parasympatholytics; Peripheral Nerves; Phosphates; Piperidines; Pupil; Quaternary Ammonium Compounds; Rabbits; Scopolamine; Seizures; Trihexyphenidyl

Topics: Animals; Azoles; Benzimidazoles; Chemistry, Pharmaceutical; Cyanosis; Indoles; Mice; Motor Activity; Piperazines; Piperidines; Pyrrolidines; Seizures; Triazoles

Topics: Animals; Atropine; Benzilates; Diencephalon; Evoked Potentials; Hallucinogens; Mesencephalon; Muscles; Parasympatholytics; Pentobarbital; Pentylenetetrazole; Physostigmine; Piperidines; Rabbits; Reticular Formation; Sciatic Nerve; Scopolamine; Seizures; Telencephalon

Topics: Amino Alcohols; Analgesics; Animals; Aspirin; Biphenyl Compounds; Bradykinin; Butyrates; Codeine; Dextropropoxyphene; Female; Meperidine; Mice; Morphine; Phenols; Phenylbutazone; Piperidines; Quinones; Rats; Seizures

Topics: Acetylcholine; Animals; Antidepressive Agents; Conditioning, Classical; Guinea Pigs; Maleates; Mice; Parasympatholytics; Piperidines; Rats; Seizures; Sweating

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

Topics: Animals; Central Nervous System Stimulants; Chemistry, Pharmaceutical; Mice; Pharmacology; Pharmacy; Piperidines; Rabbits; Research; Seizures; Spectrum Analysis

Topics: Bemegride; Glutethimide; Hypnotics and Sedatives; Mice; Pentylenetetrazole; Pharmacology; Phenobarbital; Piperidines; Research; Seizures; Toxicology

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

Topics: Central Nervous System; Chemistry, Pharmaceutical; Mice; Pharmacology; Pharmacy; Piperidines; Research; Seizures; Toxicology; Tremor

Topics: Anthelmintics; Ascariasis; Electroencephalography; Humans; Oxyuriasis; Piperazine; Piperazines; Piperidines; Seizures

Topics: Acrylates; Central Nervous System Stimulants; Convulsants; Piperidines; Reserpine; Seizures

Topics: Animals; Anticonvulsants; Bemegride; Central Nervous System Stimulants; Hypnotics and Sedatives; Mice; Pentobarbital; Pentylenetetrazole; Pharmacology; Piperidines; Research; Seizures

Topics: Antihypertensive Agents; Blood Pressure; Chemistry, Pharmaceutical; Dogs; Heterocyclic Compounds; Indazoles; Indoles; Mice; Pharmacology; Piperidines; Research; Seizures; Selective Serotonin Reuptake Inhibitors; Serotonin; Toxicology; Tryptamines

Topics: Central Nervous System; Neuropharmacology; Piperidines; Seizures

Topics: Chlorpromazine; Convulsive Therapy; Piperidines; Reserpine; Schizophrenia; Seizures

Topics: Cell Nucleus; Piperidines; Seizures; Strychnine