piperidines and Epilepsy

Multiple medications have recently been approved or are nearing US Food and Drug Administration approval for treatment of pediatric epilepsy, while a number of other compounds are in development. Many of these therapies are seeking indications in rare epilepsy syndromes and present novel mechanisms of action for the treatment of epilepsy.. Data related to drugs in development or under study were accessed following literature search via PubMed or author knowledge of publically available data.. Several new compounds are recently approved or under study for epilepsy in children.. The following is a brief overview of the new and emerging medications for the treatment of pediatric epilepsy.

Topics: Anticonvulsants; Cannabidiol; Child; Dioxolanes; Epilepsy; Fenfluramine; Humans; Piperidines; Pregnanolone; Pyridines

Migraines are a common form of primary headache, affecting women more than men (17.4% and 5.7% of US population, respectively, a total of 12%) that carry significant morbidity and disability, as well as a hefty healthcare price tag. They are most prevalent in women of reproductive ages and are estimated to be the 6th disease in order of causing global burden. They are estimated to cause 45.1 million years lived with disability, or 2.9% of global years lost to disability. Migraine treatment divides into acute, abortive treatment for relief of an ongoing migraine attack, and prophylactic therapy to reduce the occurrence of migraines, specifically for patients suffering from chronic and frequent episodic migraines. Traditional abortive treatment usually begins with NSAID and non-specific analgesics that are effective in curbing mild to moderate attacks. 5HT

Topics: Benzamides; Calcitonin Gene-Related Peptide Receptor Antagonists; Disability-Adjusted Life Years; Epilepsy; Humans; Migraine Disorders; Piperidines; Pyridines

Molecular hybridization is a recent strategy based on the covalent fusion of two or more pharmacophores to create a single molecule with multiple mechanisms of action, which represents an encouraging approach in the development of new drugs with potential therapeutic application in several pathologies. This review provides a comprehensive perspective of the most relevant advances in the development of hybrid molecules acting in the central nervous system. For instance, several opioid hybrids based on endogenous opioid peptides (e.g. enkephalins, deltorphins and endomorphins) have been developed, and γ-aminobutyric acid agonists have also been designed for neuropathic pain control. In addition, a number of hybrid compounds have also been synthesized and evaluated for their anticonvulsant activity and neurotoxicity, which may be further developed as potential antiepileptic drugs. Moreover, several hybrid compounds have also been designed for the treatment of neurodegenerative diseases focusing primarily on Alzheimer's disease by targeting the cholinergic neurotransmission, as acetylcholinesterase inhibitors, and the amyloid β-protein deposition. There are also studies addressing hybrid compounds including an antioxidant moiety, which can be potentially useful in Alzheimer's and Parkinson's diseases and other neurodegenerative disorders. Additionally, other research works have also shown promising hybrid molecules for depression, autism and cocaine addiction. Thus, the development of molecular hybrid compounds seems to be a promising strategy in the discovery of novel therapeutic drugs.

Topics: Analgesics; Central Nervous System Diseases; Choline; Donepezil; Epilepsy; gamma-Aminobutyric Acid; Humans; Indans; Opioid Peptides; Pain; Piperidines; Tacrine

In electroconvulsive therapy (ECT), remifentanil is often used concurrently with anesthetics. The objective of this study was to provide an up-to-date and comprehensive review on how the addition of remifentanil to anesthetics affects seizure duration and circulatory dynamics in mECT. We performed a meta-analysis of RCTs that investigated seizure duration and circulatory dynamics in patients treated with ECT using anesthetics alone (non-remifentanil group) and with anesthetics plus remifentanil (remifentanil group). A total of 13 RCTs (380 patients and 1024 ECT sessions) were included. The remifentanil group showed a significantly prolonged seizure duration during ECT compared to the non-remifentanil group [motor: 9 studies, SMD = 1.25, 95 % CI (0.21, 2.29), p = 0.02; electroencephalogram: 8 studies, SMD = 0.98, 95 % CI (0.14, 1.82), p = 0.02]. The maximum systolic blood pressure (SBP) was significantly reduced in the remifentanil group compared to the non-remifentanil group [7 studies, SMD = -0.36, 95 % CI (-0.65, 0.07), p = 0.02]. Substantial heterogeneity was observed for meta-analyses for seizure durations, but a pre-planned subgroup analysis revealed that seizure duration was prolonged only when the use of the anesthetic dose was reduced in the remifentanil group. The results of our study suggest that addition of remifentanil to anesthesia in ECT may lead to prolonged seizure duration when it allows the use of reduced anesthetic doses. Further, the addition of remifentanil was associated with reduced maximum SBP.

Topics: Electroconvulsive Therapy; Epilepsy; Humans; Hypnotics and Sedatives; Piperidines; Randomized Controlled Trials as Topic; Remifentanil

Prevention of epileptogenesis is an unmet need in medicine. During the last 3 years, however, several preclinical studies have demonstrated remarkable favorable effects of novel treatments on genetic and acquired epileptogenesis. These include the use of immunosuppressants and treatments that modify cellular adhesion, proliferation, and/or plasticity. In addition, the use of antiepileptic drugs in rats with genetic epilepsy or proconvulsants in acquired epilepsy models has provided somewhat unexpected favorable effects. This review summarizes these studies, and introduces some caveats when interpreting the data. In particular, the effect of genetic background, the severity of epileptogenic insult, the method and duration of seizure monitoring, and size of animal population are discussed. Furthermore, a novel scheme for defining epileptogenesis-related terms is presented.

Topics: Animals; Anticonvulsants; Epilepsy; Epilepsy, Post-Traumatic; Humans; Imidazoles; Immunosuppressive Agents; Piperidines; Pyrazoles; Rats; Rimonabant; Sirolimus; Status Epilepticus; Terminology as Topic

Topics: Acetylcholine; Amygdala; Animals; Brain; Cholinesterase Inhibitors; Convulsants; Electric Stimulation; Epilepsy; Kainic Acid; Lithium; Nerve Degeneration; Neural Pathways; Neurons; Neurotransmitter Agents; Piperidines; Rats; Somatosensory Cortex; Synaptic Transmission

Topics: Adolescent; Adult; Aged; Alcoholism; Antisocial Personality Disorder; Child; Dementia; Epilepsy; Female; Humans; Intellectual Disability; Male; Mental Disorders; Middle Aged; Neurotic Disorders; Nitriles; Paranoid Disorders; Personality Disorders; Phenothiazines; Piperidines; Psychotic Disorders; Schizophrenia; Tranquilizing Agents

Medical therapy, the cornerstone of managing epilepsy, still fails a substantial portion of patients. Little information is available regarding the potential impact of different bispectral index (BIS) levels on electrocorticographic spike identification for surgical epileptic foci resection.. Twenty-two intractable epilepsy subjects were randomly allocated to the propofol-remifentanil or sevoflurane-remifentanil groups, and were further randomized to four BIS85 (BIS 71-85), BIS70 (BIS 56-70), BIS55 (BIS 41-55), and BIS40 (BIS ≤40) sequence order.. Two-way ANOVA revealed no differences between groups in spike frequency (P = 0.720), spike amplitude (P = 0.647), or number of spiking leads (P = 0.653). In the propofol and sevoflurane groups, decreasing BIS levels increased mean ± SD spike/min frequency (P < 0.001 and P < 0.001) at BIS85 (10 ± 12 and 10 ± 8), BIS70 (19 ± 17 and 17 ± 15), BIS55 (22 ± 17 and 18 ± 8), and BIS40 (25 ± 15 and 23 ± 17). Furthermore, in the propofol and sevoflurane groups, decreasing BIS levels increased spike microvolt amplitude (P = 0.006 and P = 0.009) at BIS85 (1,100 ± 400 and 750 ± 400), BIS70 (1,200 ± 460 and 850 ± 490), BIS55 (1,300 ± 560 and 940 ± 700), and BIS40 (1,400 ± 570 and 1,300 ± 700). Whereas, in the propofol and sevoflurane groups, there was no difference in the location or number of spiking leads (P = 0.057 and P = 0.109) at the four BIS levels. Compared with BIS85, spike frequency in the propofol and sevoflurane groups increased 100 and 170% at BIS70, 116 and 180% at BIS55, and 132 and 230% at BIS40. Compared with BIS85, spike amplitude increased 108 and 113% at BIS70, 121 and 125% at BIS55, and 128 and 170% at BIS40.. Decreasing BIS levels in the propofol and sevoflurane groups enhanced epileptogenic spike frequency and amplitude with the same location and number of spiking leads.

Topics: Adolescent; Adult; Anesthetics; Electroencephalography; Epilepsy; Female; Humans; Male; Methyl Ethers; Piperidines; Propofol; Remifentanil; 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

Piperine, the active principle of piper species, is commonly used as a spice and adjuvant in various traditional systems of medicine. It has been known as a bioavailability-enhancer. The present study aimed at evaluating the effect of piperine on the steady-state pharmacokinetics of a single dose of carbamazepine in poorly controlled epilepsy patients on carbamazepine monotherapy. Patients (n = 10 each) receiving either 300 mg or 500 mg dose of carbamazepine twice daily were selected. After administration of carbamazepine, venous blood samples were collected at 0, 0.5, 1, 2, 4, 6, 9, 12 h. Subsequently, piperine (20 mg p.o.) was administered along with carbamazepine and samples were collected similarly. The pharmacokinetic parameters were compared by Students t-test. Piperine significantly increased the mean plasma concentrations of carbamazepine at most of the time points in both dose groups. There was a significant increase in AUC(0-12hr) (p < 0.001), average C(ss) (p < 0.001), t(1\\2el) (p < 0.05) and a decrease in K(el) (p < 0.05), in both the dose groups, whereas changes in K(a) and t(1\\2a) were not significant. Cmax (p < 0.01) and t(max) (p < 0.01) were increased significantly following piperine administration in the 500 mg dose group; however, these parameters were not significant in the lower dose group. Piperine could significantly enhance the oral bioavailability of carbamazepine, possibly by decreasing the elimination and/or by increasing its absorption.

Topics: Adult; Alkaloids; Area Under Curve; Benzodioxoles; Biological Availability; Carbamazepine; Dose-Response Relationship, Drug; Drug Interactions; Epilepsy; Female; Humans; Male; Middle Aged; Piper; Piperidines; Polyunsaturated Alkamides; Young Adult

To determine whether an acetylcholinesterase inhibitor, such as donepezil, would improve memory or other cognitive/psychological functions in epilepsy patients with subjective memory complaints.. Twenty-three epilepsy patients with subjective memory difficulty were randomized to either 3 months of donepezil (10 mg/day) or 3 months of placebo treatment, and then crossed over to the other treatment arm. Patients and physicians were blinded to treatment phase throughout data acquisition. Assessment of memory and other cognitive functions, subjective memory, mood, and self-rated quality of life (QOL) and social functioning was performed at baseline and following completion of both treatment phases. Seizure frequency and severity as well as treatment emergent adverse effects were also monitored.. Donepezil treatment was not associated with improvement in memory or other cognitive functions, mood, social functioning or QOL. Comparable increases in self-rated memory functioning relative to baseline were evident during donepezil and placebo phases. Donepezil treatment was not associated with increased seizure frequency or severity. Similar to group results, analysis of change within individual patients as a function of treatment phase also showed neither significant benefit nor detriment associated with donepezil.. This study found no benefit on memory or other cognitive/psychological functions in a heterogeneous group of epilepsy patients with subjective memory difficulty. Further investigation would be required to determine whether individual patients, or those with particular epilepsy syndromes, might benefit from donepezil or other acetylcholinesterase inhibitors, or if a higher dosage might be effective.

Topics: Cholinesterase Inhibitors; Cognition Disorders; Cross-Over Studies; Donepezil; Dose-Response Relationship, Drug; Double-Blind Method; Epilepsy; Health Status; Humans; Indans; Memory Disorders; Neuropsychological Tests; Piperidines; Placebos; Quality of Life; Severity of Illness Index; Social Adjustment; Treatment Outcome

The subunit composition of glutamate receptors affects their functional properties, and could contribute to abnormal electrophysiology in pediatric cortical dysplasia (CD). We examined electrophysiological responses and subunit assembly of N-methyl-D-aspartate (NMDA) receptors in acutely dissociated normal-appearing pyramidal and cytomegalic neurons from CD tissue and normal-appearing pyramidal neurons from non-CD tissue. In most cytomegalic and approximately 30% of normal-appearing pyramidal neurons from CD tissue, NMDA currents showed decreased Mg(2+) sensitivity compared with neurons from non-CD tissue. Ifenprodil had less effect in CD compared with non-CD neurons, indicating a functional loss of NR2B subunits. NMDA-evoked current density was decreased in cytomegalic compared with normal-appearing neurons. Single-cell reverse transcriptase polymerase chain reaction showed that all non-CD neurons expressed NR2B subunit mRNA. By comparison, 22% of pyramidal neurons in CD tissue lacked NR2B mRNA. Immunofluorescence showed a decrease in NR2B subunit expression in cytomegalic neurons and a subset of normal-appearing pyramidal neurons from CD tissue. Taken together, these results demonstrate the presence of NMDA receptors with altered subunit composition and Mg(2+) sensitivity that could contribute to functional abnormalities in CD.

Topics: Adolescent; Cells, Cultured; Cerebral Cortex; Child; Child, Preschool; Epilepsy; Humans; Infant; Magnesium; Membrane Potentials; N-Methylaspartate; Piperidines; Pyramidal Cells; Receptors, N-Methyl-D-Aspartate; Reference Values

Antieplepsirine (AES) is a new antiepileptic drug (AED) which was originally extracted from a Chinese folk remedy, and is now chemically characterized and synthesized. Its chemical structure is different from those of other available AEDs. Animal experiments involving AES demonstrated significant antiepileptic activity. Only a few clinical studies of AES with open trial have been resorted, none of which were on children. A 6.5 month, add-on, double-blind, placebo-controlled, randomized, cross-over study on AES (10 mg/kg per day) was conducted on epileptic children (aged 1-14 years) refractory to treatment with standard AEDs. The seizure frequency was recorded, and the blood levels of AES and other co-medicated AEDs (phenobarbital, phenytoin, carbamazepine and valproate) were determined. Although not planned, patients or parents were allowed to refuse to cross-over to the alternate therapy. The results were compared to the children who crossed-over as well as for the entire group during the first 3 months of randomized treatment. A total of 58 children entered, but only 34/58 children completed the cross-over study. The 24 children whose parents refused to let them be crossed-over continued the original study treatment (AES or placebo) for the entire 6 months. There was no statistically significant difference in seizure control when the entire group of 58 patients was compared to a parallel study group for the first 3 months of therapy (P = 0.178). There was a significant difference (P<0.01) in seizure control between AES and placebo treatment for the 34 patients who completed the entire cross-over study. No significant changes were seen in the blood level of other AEDs, and no serious acute side effects were observed. The results of the present study indicate the efficacy of AES for epileptic children with refractory seizures.

Topics: Adolescent; Anticonvulsants; Child; Child, Preschool; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Electroencephalography; Epilepsy; Female; Humans; Infant; Male; Piperidines; Treatment Outcome

Sabeluzole, a new benzothiazol derivative, has shown positive effects on memory function in animals and in normal volunteers. The present study reports the results of sabeluzole, in memory-impaired patients with localization-related (partial) epilepsy. A randomized, double-blind placebo-controlled parallel-group design was used. A total of 38 patients entered a prospective baseline. Five patients dropped out from the study, thus 33 patients were randomly assigned to either a 12-weeks treatment with sabeluzole (n = 14) or placebo (n = 19). The treatment phase was preceded by a titration phase of 4 weeks to obtain serum levels of sabeluzole between 50 and 130 ng/ml. In order to maintain blindness, a sham titration was carried out in the placebo group. The number of 'responders', i.e. patients with a > 1 SD improvement on at least three of the memory tests was 9 out of 14 (64.3%) in the sabeluzole group and 7 out of 19 (36.8%) in the placebo group. This suggests a clinically relevant effect of sabeluzole. The analysis of the memory tests showed a statistically significant improvement with sabeluzole on the verbal long-term memory test. This could represent a specific drug effect and is in line with previous results of normal volunteer studies that also found improvement mainly restricted to the area of verbal long-term memory.

Topics: Adult; Affect; Cognition; Double-Blind Method; Epilepsy; Female; Functional Laterality; Humans; Intelligence Tests; Male; Memory; Memory Disorders; Memory, Short-Term; Neuropsychological Tests; Piperidines; Psychomotor Performance; Reaction Time; Speech; Thiazoles

The results of evaluating the therapeutic efficacy of the new psychotropic drugs adepren, didepil, anq tempalgin made by the "Farmakhim" plant (the People's Republic of Bulgaria) are presented. Clinical trials revealed new facts that allowed to expand the scope of the indications for use formulated in the "Farmakhim" recommendations. It was found that Adepren could be used with success (in addition to the indications suggested by "Farmakhim") in the treatment of patients with depressive-paranoid paroxysms of periodic schizophrenia taking its course in the presence of general depression, as well as patients with somatogenic lingering astheno-depressive states. The therapeutic efficacy of didepil (an antiepileptic) was found to be in a direct relationship with the disease duration, character of the attacks, presence or absence of epileptic chandes of personality. The effect was the best in cases of a short duration of the disease and absence of gross epileptic personality changes, when the paroxysmal disorders were confined mostly to grand mals. A new scheme for arresting the epileptic status with didepil solution is offered. For the first time the efficacy of tempalgin in the treatment of patients suffering from alcoholic abstinence syndrome was substantiated. Optimal doses of the drugs have been determined with regard to the disease nosology and the leading syndrome. Contraindications to the use of the drugs have also been formulated.

Topics: Adolescent; Adult; Aminopyrine; Aminoquinolines; Child; Clinical Trials as Topic; Depression; Dipyrone; Drug Combinations; Epilepsy; Female; Humans; Male; Mental Disorders; Middle Aged; Phenobarbital; Piperidines; Piperidones; Procyclidine; Psychotropic Drugs; Pyrrolidines; Substance Withdrawal Syndrome; Syndrome

Topics: Adult; Aggression; Anticonvulsants; Anxiety; Carbamazepine; Clinical Trials as Topic; Diazepam; Dibenzazepines; Epilepsy; Frustration; Hallucinations; Humans; Intellectual Disability; Middle Aged; Nitriles; Object Attachment; Perceptual Disorders; Phenothiazines; Piperidines; Psychiatric Status Rating Scales; Psychopathology; Schizophrenia; Thiazines; Tranquilizing Agents

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

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

In recent days, reported researches demonstrated that encapsulation of natural hydrophobic drug molecules (Piperine) into the biodegradable polymer system with nanoformulations opens a novel prospect in bio-nanomedicine field. Generally, the nanostructured materials embedded with the drug molecules could render enhanced efficiency in therapies. Piperine is a chief alkaloid compound of natural black pepper exhibits excellent anti-convulsant efficiency in the anti-epileptic treatment. Nonetheless, the poor water solubility of the piperine molecules has some difficulties in drug delivery and clinical applications. Herein we report the synthesis of Copper oxide quantum dots coated Hyaluronic acid (HA)/ Poly(lactic-co-glycolic acid) (PLGA) with for the effective delivery of piperine in the targeted drug delivery for epilepsy treatment. The physicochemical characterization was performed using the as prepared material. The crystal structure, surface morphology and the elemental composition were investigated from XRD, SEM, TEM and EDX analyses respectively. The surface morphology clearly stated the loading of CuO QDs loaded HA/PLGA microspheres. The capping of the polymer matrix was also studied using FTIR analysis. A Photoluminescence spectrum is also recorded. This study was illustrating that Piperine loaded CuQDs@HA/PLGA nanostructures exhibit improved neuroprotection and encourage the activation of astrocytes in chemical kindling model of epilepsy. This proposed material could be a novel and effective therapeutic platform for the targeted drug delivery systems.

Topics: Alkaloids; Animals; Anticonvulsants; Benzodioxoles; Cell Line; Cell Survival; Copper; Drug Delivery Systems; Drug Design; Drug Liberation; Epilepsy; Humans; Luminescence; Male; Pentylenetetrazole; Piperidines; Polylactic Acid-Polyglycolic Acid Copolymer; Polyunsaturated Alkamides; Quantum Dots; Rats, Wistar

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

Temporal lobe epilepsy (TLE) is a form of adult epilepsy involving the entorhinal cortex (EC). Layer II neurons of the medial EC (mEC) are spared and become hyperexcitable in TLE. Studies have suggested a role for T-type calcium channels (T-type Ca

Topics: Action Potentials; Animals; Benzamides; Calcium Channel Blockers; Calcium Channels, T-Type; Entorhinal Cortex; Epilepsy; Male; Neurons; Organ Culture Techniques; Piperidines; Rats; Rats, Sprague-Dawley

Piperine, an alkaloid from black pepper, has demonstrated beneficial effects in central nervous system, especially in epilepsy control. However, its therapeutic application remains limited due to the low aqueous solubility of piperine. Thus, the present study aimed to formulate piperine into a more solubilized form to enhance its oral bioavailability and facilitate its development as a potential anti-epileptic treatment. The nanoprecipitation method was applied to prepare piperine nanoparticles, which were then examined under transmission electron microscopy. A spherical nanosized particle was obtained with small particle size (average particle size 130.20 ± 1.57 nm), narrow size distribution (polydispersity index 0.195 ± 0.002) and efficient entrapment (entrapment efficiency 92.2 ± 2.5%). Compared with the unformulated piperine, nanosized piperine had a much faster dissolution rate with 3 times higher accumulated drug release after 24 h. After oral administration at 3.5 mg/kg in rats, the nanosized piperine formulations could improve its oral bioavailability by 2.7-fold with 16 times higher concentrations in brain at 10 h postdosing. Moreover, the piperine nanoparticles exhibited effective protection against pentylenetetrazol-induced seizures in both zebrafish and mice. In summary, the present study provided a simple formulation strategy for oral administration of piperine to overcome its limitation in water solubility. The developed formulations could effectively enhance oral bioavailability of piperine with promising anti-epileptic effect, which could be applied as a potential therapy in epilepsy control.

Topics: Administration, Oral; Alkaloids; Animals; Anticonvulsants; Benzodioxoles; Biological Availability; Drug Liberation; Embryo, Nonmammalian; Epilepsy; Male; Mice; Nanoparticles; Piperidines; Polyunsaturated Alkamides; Rats, Sprague-Dawley; Tissue Distribution; Zebrafish

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

Carbamazepine (CBZ) with piperine, the active ingredient in black pepper, which is omnipresent in food and may be potentially used for epilepsy control owing to its anticonvulsant effects, can be coadministered to epileptic patients. Since piperine has previously demonstrated its inhibition of the CYP3A-mediated metabolism of CBZ to carbamazepine-10,11-epoxide (CBZE), the present study aimed to investigate the impact of piperine on CBZ pharmacokinetics (PKs) in rats and pharmacodynamics in zebrafish and mouse acute seizure models. Plasma and brain PKs were studied in rats after a single-dose or 2-week combined oral administration of piperine (3.5/35 mg/kg, q.d.) and CBZ (40 mg/kg, t.i.d.) by blood sampling and brain microdialysis. Although no PK change was noticed after a single coadministration, significantly decreased plasma and brain concentrations of CBZ and CBZE with inhibited rat liver Cyp3a2 were demonstrated after long-term combined administration. Our developed compartmental model for the PK characterization of CBZ and CBZE in the blood and brain further estimated that coadministration with high-dose piperine could lead to decreases of 26%, 35%, and 38% in bioavailability, metabolism, and brain uptake of CBZ, respectively. Regardless of the PK changes, a limited impact on the antiepileptic effect of CBZ was found after the coadministration of CBZ and piperine in the tested seizure models. In conclusion, single-dose cotreatment of CBZ and piperine did not result in any significant PK or pharmacodynamic interactions, whereas their long-term cotreatment could lead to inhibited liver metabolism and the markedly reduced systemic and brain exposure of CBZ and CBZE.

Topics: Alkaloids; Animals; Anticonvulsants; Benzodioxoles; Brain; Carbamazepine; Cytochrome P-450 Enzyme Inhibitors; Disease Models, Animal; Drug Interactions; Epilepsy; Liver; Male; Mice; Mice, Inbred C57BL; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Tissue Distribution; Zebrafish

Recent evidence suggests that encapsulation of hydrophobic drugs in biodegradable polymers opens a new horizon in nanomedicine filed. Piperine, a main alkaloid form of black pepper possesses potent anticonvulsant activity. However, the low water solubility of piperine has limited its clinical application. In this study, piperine was loaded on chitosan-sodium tripolyphosphate nanoparticles (CS-STPP NPs) and the effect of piperine NPs on seizures behavior and astrocytes activation was assessed in pentylentetrazol (PTZ)-induced kindling model. Animals have received the daily injection of free piperine or piperine NPs at doses of 5 or 10mg/kg, 10days before PTZ injections and their intraperitoneally (i.p) administration continued until the last PTZ injection. The neuroprotective effects of piperine NPs were evaluated using nissl staining and immunostaining against NeuN. Astrocytes activation was examined by GFAP immunostaining. Behavioral data showed that piperine NPs have inhibited the development of seizure parameters compared to the free piperine groups. In addition, the levels of cell loss and astrocytes activation were reduced in piperine NPs groups. In conclusion, these data suggest that piperine NPs enhance the neuroprotection and ameliorate the astrocytes activation in chemical kindling model of epilepsy. This may provide an effective therapeutic strategy for the treatment of epilepsy disorder.

Topics: Alkaloids; Animals; Astrocytes; Benzodioxoles; Chitosan; Disease Models, Animal; Epilepsy; Humans; Hydrophobic and Hydrophilic Interactions; Kindling, Neurologic; Mice; Nanoparticles; Neurons; Organophosphorus Compounds; Pentylenetetrazole; Piperidines; Polyunsaturated Alkamides; Stearic Acids

NMDA receptors (NMDARs) play a key role in synaptic plasticity and excitotoxicity. Subtype-specific role of NMDAR in neural disorders is an emerging area. Recent studies have revealed that mutations in NMDARs are a cause for epilepsy. Hippocampus is a known focal point for epilepsy. In hippocampus, expression of the NMDAR subtypes GluN1/GluN2A and GluN1/GluN2B is temporally regulated. However, the pharmacological significance of these subtypes is not well understood in epileptic context/models. To investigate this, epilepsy was induced in hippocampal slices by the application of artificial cerebrospinal fluid that contained high potassium but no magnesium. Epileptiform events (EFEs) were recorded from the CA1 and DG areas of hippocampus with or without subtype-specific antagonists. Irrespective of the age group, CA1 and DG showed epileptiform activity. The NMDAR antagonist AP5 was found to reduce the number of EFEs significantly. However, the application of subtype-specific antagonists (TCN 201 for GluN1/GluN2A and Ro 25-69811 for GluN1/GluN2B) revealed that EFEs had area-specific and temporal components. In slices from neonates, EFEs in CA1 were effectively reduced by Ro 25-69811, but were largely insensitive to TCN 201. In contrast, EFEs in DG were equally sensitive to both of the subtype-specific antagonists. However, the differential sensitivity for the antagonists observed in neonates was absent in later developmental stages. The study provides a functional insight into the NMDAR subtype-dependent contribution of EFEs in hippocampus of young rats, which may have implications in treating childhood epilepsy and avoiding unnecessary side effects of broad spectrum antagonists.

Topics: 2-Amino-5-phosphonovalerate; Age Factors; Animals; Animals, Newborn; CA1 Region, Hippocampal; Dentate Gyrus; Epilepsy; Excitatory Amino Acid Antagonists; Female; Male; Organ Specificity; Phenols; Piperidines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Sulfonamides

Epilepsy is a kind of disease with complicated pathogenesis. KCNQ (Kv7) is a voltage dependent potassium channel that is mostly associated with epilepsy and thus becomes an important target in the treatment of epilepsy. In this paper, a series of substituted piperidine derivatives targeting KCNQ were designed and synthesized by using scaffold hopping and active substructure hybridization. Compounds were evaluated by fluorescence-based thallium influx assay, Rb

Topics: Anticonvulsants; Dose-Response Relationship, Drug; Drug Design; Epilepsy; Humans; KCNQ Potassium Channels; Molecular Structure; Piperidines; Structure-Activity Relationship

Vesicular acetylcholine transporter (VAChT) is a rate-limiting factor for synaptic acetylcholine transport. Our study focused on whether [. Morris water maze test was used to evaluate learning and memory deficits in pilocarpine-induced chronic epilepsy rats 12 weeks after status epilepticus. Interictal [. Epileptic rats exhibited significant memory deficits in Morris water maze test. [. [

Topics: Acholeplasmataceae; Animals; Brain; Chronic Disease; Disease Models, Animal; Epilepsy; Fluorodeoxyglucose F18; Male; Maze Learning; Memory Disorders; Muscarinic Agonists; Naphthols; Pilocarpine; Piperidines; Positron-Emission Tomography; Rats; Rats, Sprague-Dawley; Vesicular Acetylcholine Transport Proteins

Inflammatory processes play critical roles in epileptogenesis, but the exact mechanisms that underlie these processes are still not completely understood. In this study, we investigated the role of forkhead transcription factor 3 (Foxp3), a transcription factor that is involved in T-cell differentiation, in epileptogenesis. In both human epileptic tissues and experimental seizure models, we found significant up-regulation of Foxp3 in neurons and glial cells. Of importance, Foxp3

Topics: Adrenergic alpha-Antagonists; Animals; Anticonvulsants; Cells, Cultured; Epilepsy; Forkhead Transcription Factors; Gene Expression Regulation; Humans; Kainic Acid; Mice; Mice, Inbred BALB C; Mice, Knockout; Neuroglia; Neurons; Piperidines; Signal Transduction; Toll-Like Receptor 4

Epilepsy may arise following acute brain insults, but no treatments exist that prevent epilepsy in patients at risk. Here we examined whether a combination of two glutamate receptor antagonists, NBQX and ifenprodil, acting at different receptor subtypes, exerts antiepileptogenic effects in the intrahippocampal kainate mouse model of epilepsy. These drugs were administered over 5 days following kainate. Spontaneous seizures were recorded by video/EEG at different intervals up to 3 months. Initial trials showed that drug treatment during the latent period led to higher mortality than treatment after onset of epilepsy, and further, that combined therapy with both drugs caused higher mortality at doses that appear safe when used singly. We therefore refined the combined-drug protocol, using lower doses. Two weeks after kainate, significantly less mice of the NBQX/ifenprodil group exhibited electroclinical seizures compared to vehicle controls, but this effect was lost at subsequent weeks. The disease modifying effect of the treatment was associated with a transient prevention of granule cell dispersion and less neuronal degeneration in the dentate hilus. These data substantiate the involvement of altered glutamatergic transmission in the early phase of epileptogenesis. Longer treatment with NBQX and ifenprodil may shed further light on the apparent temporal relationship between dentate gyrus reorganization and development of spontaneous seizures.

Topics: Animals; Anticonvulsants; Dentate Gyrus; Disease Models, Animal; Drug Administration Schedule; Drug Therapy, Combination; Electroencephalography; Epilepsy; Humans; Kainic Acid; Male; Mice; Neurons; Piperidines; Quinoxalines; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Time Factors; Treatment Outcome

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

It has become clear that histamine H3 receptors (H3Rs) are implicated in modulating epilepsy and memory in laboratory animals. The new non-imidazole H3R antagonist DL77 has excellent selectivity profile and shows high in-vivo potency as well as in-vitro antagonist affinity with ED50 values of 2.1 ± 0.2 mg/kg and 8.4 ± 1.3 [nM], respectively. In the present study, the anticonvulsant effects of DL77 on maximal electroshock (MES)-, pentylenetetrazole (PTZ)-, and strychnine (STR)-induced seizure models were investigated. Moreover, the procognitive properties of DL77 were tested on acquisition, consolidation and retrieval processes in a one-trial inhibitory avoidance task in male Wistar rats. The results indicate that DL77 (5, 10, and 15 mg/kg, i.p.) significantly and dose-dependently reduced MES-induced seizure duration, whereas no protection was observed in PTZ- or STR-induced seizures. Importantly, the protective action observed for DL77 in MES-induced seizure was comparable to that of the reference antiepileptic drug (AED) phenytoin (PHT), and was also reversed when rats were pretreated with the CNS penetrant pyrilamine (PYR) (10 mg/kg, i.p.), or with the selective H3R agonist R-(α)-methyl-histamine (RAMH) (10 mg/kg, i.p.). Furthermore, the procognitive studies indicate that acute pre-training systemic administration of DL77 (2.5 mg/kg, i.p.) facilitated acquisition, whereas pre-testing acute administration of DL77 (5 and 10 mg/kg, i.p.) improved retrieval. Interestingly, the procognitive effect of DL77 on retrieval was completely abrogated when rats were pretreated with the centrally-acting H2R antagonist zolantidine (ZOL) but not the centrally acting H1R antagonist PYR, indicating that histaminergic pathways through activation of H2Rs appear to be participating in neuronal circuits involved in retrieval processes. Taken together, our results show that DL77 demonstrates anticonvulsant properties in the MES-induced seizure model and improves cognitive performance through actions on different memory stages. Therefore, H3Rs may have implications for the treatment of degenerative disorders associated with impaired memory function and may represent a novel therapeutic pharmacological target to tackle cognitive problems associated with the chronic use of antiepileptic drugs. This article is part of the Special Issue entitled 'Histamine Receptors'.

Topics: Animals; Anticonvulsants; Avoidance Learning; Benzothiazoles; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Epilepsy; Histamine Agonists; Histamine H2 Antagonists; Histamine H3 Antagonists; Male; Memory; Methylhistamines; Nootropic Agents; Phenoxypropanolamines; Phenyl Ethers; Phenytoin; Piperidines; Random Allocation; Rats, Wistar; Receptors, Histamine H3

Asleep-awake-asleep (AAA) protocol for epilepsy surgery is a unique opportunity to accurately map epilepsy foci involved in motor and eloquent areas, allowing the operator to optimize the resection. Two different application modes of intravenous anesthesia for AAA craniotomies are widely used: infusion by means of target-controlled infusion (TCI) and traditional manually-controlled infusion (MCI). We conducted this study to examine whether intravenous anesthesia using the TCI system with propofol and remifentanil would be a more effective method than MCI in AAA epilepsy surgery.. This prospective and single center study compared patients undergoing either TCI or MCI techniques for functional AAA epilepsy surgery. 35 cases used TCI including TCI-E (resection of epileptogenic foci in an eloquent area, n = 18) and TCI-M (resection of epileptogenic foci in a motor area, n = 17). Thirty-six cases used MCI including MCI-E (epileptogenic foci in an eloquent area, n = 16) and MCI-M (epileptogenic foci in a motor area, n = 20). Bispectral index value and hemodynamic profiles at different time points during the awake phase were recorded along with time for awakening and the occurrences of adverse events.. The TCI technique significantly shortened intraoperative awakening times during the third phase, TCI-E vs MCI-E 12.82 min ± 6.93 vs 29.9 min ± 9.04 (P = .000) and TCI-M vs MCI-M 16.8 min ± 5.19 vs 30.91 min ± 15.32 (P = .010). During the awake phase, the highest bispectral index score values appeared in the TCI-E group at all-time points. Mean arterial pressure and heart rate were more stable in the TCI-E group compared with the MCI-E group during the awake phase. Tachycardia and hypertension were most common in the MCI-E group (52.9% and 29.4%, P = .001 and P = .064).. We found the superiority of TCI, which is faster intraoperative awakening and better hemodynamics along with secure airway management conditions. It is suggested that the TCI technique may be a feasible and effective technique and it might be a viable replacement of the MCI technique for AAA epilepsy surgery.

Topics: Adult; Anesthesia, Intravenous; Anesthetics, Intravenous; Brain; Craniotomy; Drug Administration Schedule; Epilepsy; Female; Humans; Infusions, Intravenous; Male; Piperidines; Propofol; Prospective Studies; Remifentanil; Sleep; Wakefulness; Young Adult

A 69-year-old woman undergoing treatment for hypertension and epilepsy was scheduled to undergo cataract surgery. All preoperative examination results were within normal limits. Despite being tense, she walked to the operating room. Approximately 2 minutes after an intravenous line was established by an anesthesia resident, severe hypoxia and bradycardia developed, and she lost consciousness. Cardiopulmonary resuscitation was initiated immediately, and after 1 minute, she regained consciousness, and her breathing and circulation recovered. After admission to the intensive care unit, emergency coronary angiography was performed. The blood flow in all the coronary arteries was normal. However, a decrease in the apical left ventricular wall motion and an increase in the basal wall motion were observed. Based on these findings, Takotsubo cardiomyopathy was diagnosed. The wall motion gradually improved and the patient was discharged from the hospital on postoperative day 15. The respiratory depression and bradycardia were thought to be due to an inadvertent bolus of remifentanil. We surmised that the patient had received a slight amount of retained medication when the anesthesia resident established the intravenous line, which caused severe respiratory depression. It is important to note that adverse effects such as severe respiratory depression and bradycardia can be caused by even small doses of remifentanil.

Topics: Aged; Analgesics, Opioid; Anesthesia, General; Bradycardia; Cardiopulmonary Resuscitation; Cataract Extraction; Coronary Angiography; Electrocardiography; Epilepsy; Epinephrine; Female; Humans; Hypertension; Piperidines; Remifentanil; Respiratory Insufficiency; Takotsubo Cardiomyopathy; Vasoconstrictor Agents

The endocannabinoid system serves as a retrograde negative feedback mechanism. It is thought to control neuronal activity in an epileptic neuronal network. The purpose of this study was to evaluate the impact of the endocannabinoid and endovanilloid systems on both epileptogenesis and ictogenesis. Therefore, we modulated the endocannabinoid and endovanilloid systems genetically and pharmacologically, and analyzed the subsequent impact on seizure progression in the kindling model of temporal lobe epilepsy in mice. In addition, the impact of seizures on associated cellular alterations was evaluated. Our principal results revealed that the endocannabinoid system affects seizure and afterdischarge duration dependent on the neuronal subpopulation being modulated. Genetic deletion of CB1-receptors (CB1Rs) from principal neurons of the forebrain and pharmacological antagonism with rimonabant (5 mg/kg) caused longer seizure duration. Deletion of CB1R from GABAergic forebrain neurons resulted in the opposite effect. Along with these findings, the CB1R density was elevated in animals with repetitively induced seizures. However, neither genetic nor pharmacological interventions had any impact on the development of generalized seizures. Other than CB1, genetic deletion or pharmacological blockade with SB366791 (1 mg/kg) of transient receptor potential vanilloid receptor 1 (TRPV1) had no effect on the duration of behavioral or electrographic seizure activity in the kindling model. In conclusion, we demonstrate that endocannabinoid, but not endovanilloid, signaling affects termination of seizure activity, without influencing seizure severity over time. These effects are dependent on the neuronal subpopulation. Thus, the data argue that the endocannabinoid system plays an active role in seizure termination but does not regulate epileptogenesis.

Topics: Anilides; Animals; Bromodeoxyuridine; Calcium-Calmodulin-Dependent Protein Kinase Type 1; Cannabinoid Receptor Antagonists; Cinnamates; Disease Models, Animal; Epilepsy; gamma-Aminobutyric Acid; Gene Expression Regulation; Kindling, Neurologic; Male; Mice; Mice, Knockout; Neurogenesis; Neurons; Piperidines; Prosencephalon; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; TRPV Cation Channels

The β1 subunit of voltage-gated sodium channels, Nav β1, plays multiple roles in neurons spanning electrophysiological modulation of sodium channel α subunits to cell adhesion and neurite outgrowth. This study used immunohistochemistry to investigate Nav β1 subneuronal and regional expression. Nav β1 was enriched at axon initial segments (AIS) and nodes of Ranvier. Nav β1 expression at the AIS was detected throughout the brain, predominantly in the hippocampus, cortex, and cerebellum. Despite expression of Nav β1 in both excitatory and inhibitory AIS, it displayed a marked and fine-grained heterogeneity of expression. Such heterogeneity could have important implications for the tuning of single neuronal and regional excitability, especially in view of the fact that Nav β1 coexpressed with Nav 1.1, Nav 1.2, and Nav 1.6 subunits. The disruption of Nav β1 AIS expression by a human epilepsy-causing C121W genetic mutation in Nav β1 was also investigated using a mouse model. AIS expression of Nav β1 was reduced by approximately 50% in mice heterozygous for the C121W mutation and was abolished in homozygotes, suggesting that loss of Nav α subunit modulation by Nav β1 contributes to the mechanism of epileptogenesis in these animals as well as in patients.

Topics: Alkenes; Animals; Axons; Blotting, Western; Brain; Disease Models, Animal; Epilepsy; Humans; Immunohistochemistry; Interneurons; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Microscopy, Confocal; Mutation; Piperidines; Voltage-Gated Sodium Channel beta-1 Subunit

Prevailing literature supports the idea that common general anesthetics (GAs) cause long-term cognitive changes and neurodegeneration in the developing mammalian brain, especially in the thalamus. However, the possible role of GAs in modifying ion channels that control neuronal excitability has not been taken into consideration. Here we show that rats exposed to GAs at postnatal day 7 display a lasting reduction in inhibitory synaptic transmission, an increase in excitatory synaptic transmission, and concomitant increase in the amplitude of T-type calcium currents (T-currents) in neurons of the nucleus reticularis thalami (nRT). Collectively, this plasticity of ionic currents leads to increased action potential firing in vitro and increased strength of pharmacologically induced spike and wave discharges in vivo. Selective blockade of T-currents reversed neuronal hyperexcitability in vitro and in vivo. We conclude that drugs that regulate thalamic excitability may improve the safety of GAs used during early brain development.

Topics: 4-Butyrolactone; Action Potentials; Anesthesia, General; Animals; Animals, Newborn; Benzamides; Calcium Channel Blockers; Cerebral Cortex; Dose-Response Relationship, Drug; Epilepsy; Evoked Potentials, Somatosensory; Excitatory Postsynaptic Potentials; Female; In Vitro Techniques; Inhibitory Postsynaptic Potentials; Male; Neural Pathways; Neurons; Piperidines; Rats; Rats, Sprague-Dawley; Thalamus

Endocannabinoids, including 2-arachidonoylglycerol (2-AG), activate presynaptic cannabinoid type 1 receptors (CB1R) on inhibitory and excitatory neurons, resulting in a decreased release of neurotransmitters. The event-specific activation of the endocannabinoid system by inhibition of the endocannabinoid degrading enzymes may offer a promising strategy to selectively activate CB1Rs at the site of excessive neuronal activation with the overall goal to prevent the development epilepsy. The aim of this study was to investigate the impact of monoacylglycerol lipase (MAGL) inhibition on the development and progression of epileptic seizures in the kindling model of temporal lobe epilepsy. Therefore, we selectively blocked MAGL by JZL184 (8mg/kg, i.p.) in mice to analyze the effects of increased 2-AG levels on kindling acquisition and to exclude an anticonvulsive potential. Our results showed that JZL184 treatment significantly delayed the development of generalized seizures (p=0.0066) and decreased seizure (p<0.0001) and afterdischarge duration (p<0.001) in the kindling model of temporal lobe epilepsy, but caused only modest effects in fully kindled mice. Moreover, we proved that JZL184 treatment had no effects in conditional CB1R knockout mice lacking expression of the receptor in principle neurons of the forebrain. In conclusion, the data demonstrate that indirect CB1R agonism delays the development of generalized epileptic seizures but has no relevant acute anticonvulsive effects. Furthermore, we confirmed that the effects of JZL184 on kindling progression are CB1R mediated. Thus, the data indicate that the endocannabinoid 2-AG might be a promising target for an anti-epileptogenic approach.

Topics: Amygdala; Analysis of Variance; Animals; Benzodioxoles; Disease Models, Animal; Enzyme Inhibitors; Epilepsy; Gene Expression Regulation; Green Fluorescent Proteins; Kindling, Neurologic; Male; Mice; Mice, Transgenic; Monoacylglycerol Lipases; Piperidines; Reaction Time; Receptor, Cannabinoid, CB1

The N-methyl-d-aspartate (NMDA) receptor plays an important role in the pathophysiology of several neurological diseases, including epilepsy. The present study investigated the effect of NMDA receptor NR2B subunits on pentylenetetrazole (PTZ)-kindling-induced pathological and biochemical events in mice. Our results showed that PTZ-kindling up-regulates the expression of NMDA receptor NR2B subunits in the hippocampus and that kindled mice were characterized by significant astrocytosis and neuron loss in the hippocampus. Oxidative stress, including excessive malondialdehyde (MDA) production and decreased enzymatic activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX), were detected in the hippocampus after the mice were fully kindled. Additionally, expression of brain-derived neurotrophic factor (BDNF) in the hippocampus was found to be up-regulated in PTZ-kindled mice. However, selectively blocking NMDA receptor NR2B subunits by ifenprodil significantly suppressed PTZ-kindling-induced hippocampal astrocytosis, oxidative stress and neuron loss. Furthermore, blocking NMDA receptor NR2B subunits also abolished PTZ-kindling-induced BDNF expression. These results indicate that NMDA receptor NR2B subunits contribute to epilepsy-associated pathological and biochemical events, including hippocampal astrocytosis, oxidative stress and neuron loss, and these events might be correlated with up-regulation of BDNF expression.

Topics: Animals; Astrocytes; Brain-Derived Neurotrophic Factor; Cell Death; Epilepsy; Excitatory Amino Acid Antagonists; Gliosis; Glutathione Peroxidase; Hippocampus; Kindling, Neurologic; Male; Malondialdehyde; Mice, Inbred C57BL; Neurons; Oxidative Stress; Pentylenetetrazole; Piperidines; Receptors, N-Methyl-D-Aspartate; Superoxide Dismutase

Facilitating activation, or delaying inactivation, of the native Kv7 channel reduces neuronal excitability, which may be beneficial in controlling spontaneous electrical activity during epileptic seizures. In an effort to identify a compound with such properties, the structure-activity relationship (SAR) and in vitro ADME for a series of heterocyclic Kv7.2-7.5 channel openers was explored. PF-05020182 (2) demonstrated suitable properties for further testing in vivo where it dose-dependently decreased the number of animals exhibiting full tonic extension convulsions in response to corneal stimulation in the maximal electroshock (MES) assay. In addition, PF-05020182 (2) significantly inhibited convulsions in the MES assay at doses tested, consistent with in vitro activity measure. The physiochemical properties, in vitro and in vivo activities of PF-05020182 (2) support further development as an adjunctive treatment of refractory epilepsy.

Topics: Animals; Cell Line; Dose-Response Relationship, Drug; Drug Discovery; Electroshock; Epilepsy; Humans; Ion Channel Gating; KCNQ2 Potassium Channel; Microsomes; Molecular Structure; Piperidines; Pyrimidines; Rats; Structure-Activity Relationship

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

The majority of experimental and clinical studies show that ghrelin and cannabinoids are potent inhibitors of epileptic activity in various models of epilepsy. A number of studies have attempted to understand the connection between ghrelin and cannabinoid signalling in the regulation of food intake. Since no data show a functional interaction between ghrelin and cannabinoids in epilepsy, we examined the relationship between these systems via penicillin-induced epileptiform activity in rats. Doses of the CB1 receptor agonist arachidonyl-2-chloroethylamide (ACEA) (2.5 and 7.5 µg), the CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3 carboxamide (AM-251) (0.25 and 0.5 µg) and ghrelin (0.5 and 1 µg) were administered intracerebroventricularly (i.c.v.) 30 minutes after the intracortical (i.c.) application of penicillin. In the interaction groups, the animals received either an effective dose of ACEA (7.5 µg, i.c.v.) or a non-effective dose of ACEA (2.5 µg, i.c.v.) or effective doses of AM-251 (0.25, 0.5 µg, i.c.v.) 10 minutes after ghrelin application. A 1 µg dose of ghrelin suppressed penicillin-induced epileptiform activity. The administration of a 0.25 µg dose of AM-251 increased the frequency of penicillin-induced epileptiform activity by producing status epilepticus-like activity. A 7.5 µg dose of ACEA decreased the frequency of epileptiform activity, whereas a non-effective dose of ACEA (2.5 µg) did not change it. Effective doses of AM-251 (0.25, 0.5 µg) reversed the ghrelin's anticonvulsant activity. The application of non-effective doses of ACEA (2.5 µg) together with ghrelin (0.5 µg) within 10 minutes caused anticonvulsant activity, which was reversed by the administration of AM-251 (0.25 µg). The electrophysiological evidence from this study suggests a possible interaction between ghrelin and cannabinoid CB1 receptors in the experimental model of epilepsy.

Topics: Animals; Anticonvulsants; Arachidonic Acids; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Cerebral Cortex; Disease Models, Animal; Electroencephalography; Epilepsy; Ghrelin; Infusions, Intraventricular; Male; Penicillins; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1

Prior studies have demonstrated the involvement of leptin and cannabinoids in food intake and metabolism. However, the interaction between leptin and cannabinoids in epilepsy has not been studied. This study elucidated the relationship between leptin and cannabinoids in penicillin-induced epileptiform activity in rats.. The CB1 receptor agonist, arachidonyl-2-chloroethylamide (ACEA), at doses of 2.5 and 7.5 μg, the CB1 receptor antagonist, [N-(piperidine-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3 carboxamide] (AM-251), at doses of 0.125 and 0.25 μg, and leptin, at the dose of 1 μg, were administered intracerebroventricularly (i.c.v.) 30 min after intracortical penicillin (i.c.) application.. Leptin caused proconvulsant activity in all groups. The administration of AM-251, at a dose of 0.25 μg, increased the frequency of penicillin-induced epileptiform activity by producing status epilepticus-like activity, whereas AM-251, at a dose of 0.125 μg, was not effective when applied alone. ACEA, at a dose of 7.5 μg, decreased the frequency of epileptiform activity. Leptin reversed the anticonvulsant activity of ACEA and enhanced the proconvulsant activity of AM-251.. This study provides electrophysiological evidence that the proconvulsant activity of leptin is mediated, at least in part, by inhibition of cannabinoids in the experimental model of epilepsy.

Topics: Animals; Convulsants; Epilepsy; Infusions, Intraventricular; Leptin; Male; Penicillins; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1

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

Impairment of synaptic plasticity such as long-term potentiation (LTP) is a common finding in various animal models of a number of neurodegenerative disorders. While cognitive deficits associated with these models are plausibly attributed to impaired plasticity, it is an intriguing question whether learning impairment correlates in general with compromised synaptic plasticity. In the present study, we have addressed this issue and discovered an enhancement of theta-burst stimulation-induced LTP at Schaffer collateral-CA1 synapses from chronically epileptic animals. The LTP enhancement was abolished by the NMDA receptor 2B (NR2B) blocker Ro 25-6981 (1μM) while it was preserved following application of the NR2A blocker NVP-AAM077 (50nM). Moreover, pharmacological characterization of intracellularly recorded excitatory postsynaptic potentials (EPSP) from CA1 pyramidal neurons indicated an increased NR2B/NR2A ratio in epileptic tissue, and NMDA receptor mediated excitatory postsynaptic currents showed significantly longer decay times. Quantitative reverse-transcriptase PCR confirmed the transcriptional up-regulation of NR2B-mRNA in chronically epileptic animals. To test the significance for epileptiform activity, recurrent epileptiform discharges (REDs) in the CA1 area induced by bath application of either high K(+) (8mM) plus gabazine (5μM) or 4-aminopyridine (50μM), were also characterized pharmacologically. While in control slices the presence of Ro 25-6981 had no effect on the RED frequency, NR2B inhibition significantly increased epileptic activity in tissue from epileptic animals. Our results demonstrate that CA1 synapses in chronically epileptic tissue can undergo an LTP enhancement due to an NR2B up-regulation in CA1 pyramidal neurons. On the network level, this up-regulation appears to be a compensatory process, since blockade of these receptors leaves the tissue more susceptible to hyperexcitability.

Topics: Animals; CA1 Region, Hippocampal; Disease Models, Animal; Epilepsy; Excitatory Postsynaptic Potentials; Long-Term Potentiation; Male; Organ Culture Techniques; Patch-Clamp Techniques; Phenols; Piperidines; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Receptors, N-Methyl-D-Aspartate; Reverse Transcriptase Polymerase Chain Reaction; Up-Regulation

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

To investigate whether epileptiform activity in the immature brain is modulated by dopamine, we examined the effects of dopaminergic agonists and antagonists in an intact in vitro preparation of the isolated corticohippocampal formation of immature (postnatal days 3 and 4) C57/Bl6 mice using field potential recordings from CA3. Epileptiform discharges were induced by a reduction of the extracellular Mg(2+) concentration to 0.2 mM. These experiments revealed that low concentrations of dopamine (<0.3 μM) attenuated epileptiform activity, whereas >3 μM dopamine enhanced epileptiform activity. The D1-agonist SKF38393 (10 μM) had a strong proconvulsive effect, and the D2-like agonist quinpirole (10 μM) mediated a weak anticonvulsive effect. The proconvulsive effect of 10 μM dopamine was completely abolished by the D1-like receptor antagonist SCH39166 (2 μM) or the D2-like antagonist sulpiride (10 μM), whereas the D2 antagonist L-741626 (50 nM) and the D3 antagonist SB-277011-A (0.1 μM) were without effect. The anticonvulsive effect of 0.1 μM dopamine could be suppressed by D1-like, D2, or D3 receptor antagonists. A proconvulsive effect of 10 μM dopamine was also observed when AMPA, NMDA, or GABA(A) receptors were blocked. In summary, these results suggest that 1) dopamine influences epileptiform activity already at early developmental stages; 2) dopamine can bidirectionally influence the excitability; 3) D1-like receptors mediate the proconvulsive effect of high dopamine concentrations, although the pharmacology of the anticonvulsive effect is less clear; and 4) dopamine-induced alterations in GABAergic and glutamatergic systems may contribute to this effect.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Animals, Newborn; Benzazepines; Data Interpretation, Statistical; Dopamine; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Epilepsy; Hippocampus; Indoles; Magnesium Deficiency; Mice; Mice, Inbred C57BL; Nitriles; Piperidines; Quinpirole; Receptors, Dopamine D2; Synapses; Tetrahydroisoquinolines

Although the activation of CB1-receptor by cannabinoids and block of NMDA receptors are known to decrease seizure severity in epilepsy models, the interaction between these systems remain elusive. Therefore, the present study was initiated to evaluate the possible interactions between cannabinoid compounds and NMDA receptor antagonist in the penicillin-induced epileptiform activity in rat. In the first set of experiments, 30 min after intracortical injection of penicillin, five different doses of memantine (3,5-dimethyl-1-adamantanamine hydrochloride, 1, 2.5, 5, 10 or 20mg/kg) were administered intraperitoneally (i.p.). In the second set of experiments, intracerebroventricular (i.c.v.) AM-251 [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide], (0.25 μg) a CB1-receptor antagonist and ACEA (arachidonyl-2-chloroethylamide), (7.5 μg) a CB1-receptor agonist, were administered 15 min after memantine (i.p.) application. Memantine, NMDA receptor antagonist, at doses of 2.5 and 5mg/kg (i.p.) decreased the mean frequency of penicillin-induced epileptiform activity with a maximal effect at 5mg/kg. Memantine, at the lowest dose (1mg/kg, i.p.) and highest doses (10 and 20mg/kg, i.p.) did not change the frequency of epileptiform activity. ACEA, at a dose of 7.5 μg, also decreased the frequency of epileptiform activity, whereas AM-251, at a dose of 0.25 μg increased the frequency by causing status epilepticus-like activity. The best and earlier anti-epileptiform effects appeared in both the presence of memantine (5mg/kg, i.p.) and ACEA (7.5 μg, i.c.v.), which was blocked by CB1-receptor antagonist, AM-251. The results of the present study provide electrophysiologic evidence for an interaction between cannabinoid system and NMDA receptors, probably via NMDA-mediated Ca(2+) influx in the penicillin-induced epilepsy.

Topics: Animals; Arachidonic Acids; Data Interpretation, Statistical; Dose-Response Relationship, Drug; Drug Interactions; Electroencephalography; Epilepsy; Excitatory Amino Acid Antagonists; Male; Memantine; Penicillins; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptors, N-Methyl-D-Aspartate

Twenty new 1-(substituted benzylidene)-3-(1-(morpholino/piperidino methyl)-2,3-dioxoindolin-5-yl) urea derivatives were designed and synthesized. Antiepileptic screening was performed using MES and scPTZ seizures tests. The neurotoxicity was determined by rotorod test. In the preliminary screening, compounds 5c, 5g, 5j and 5n were found active in MES model, while 5o showed significant antiepileptic activity in scPTZ model. Further all these five compounds were administered orally to rats, 5c, 5g and 5n showed better activity than Phenytoin in oral route. Among these compounds 5c revealed protection in MES at a dose of 30 mg/kg and 100 mg/kg 0.5 h and 4 h after i.p. administration respectively. This molecule provided also protection in the scPTZ at a dose of 300 mg/kg in both time intervals.

Topics: Animals; Anticonvulsants; Electroshock; Epilepsy; Humans; Isatin; Male; Mice; Morpholinos; Piperidines; Rats; Rats, Wistar; Structure-Activity Relationship; Urea

In patients with epilepsy, a common comorbidity diagnosed is depression. Temporal lobe epilepsy or post status epilepticus (SE) animal model establish and validate the co morbidity and common pathogenesis of depression and epilepsy. Elevation in serotonin concentration gives an inhibitory response to epileptic discharge and stabilizes the depressed mood disorder. Piperine is a potent monoaminooxidase inhibitor and stimulates the synthesis of serotonin. So the present work is undertaken to investigate the effect of piperine on depression associated with by status epilepticus induced by pilocarpine in rats.. Status epilepticus was induced in the rats by administration of pilocarpine 350 mg/kg i.p.. Behaviour tests like forced swimming test (FST), saccharin consumption test, actophotometer test and rotarod test were conducted. Antidepressant effect and neuroprotective effect of piperine (25 mg/kg, p.o. for 10 days) in post status epilepticus animal model was evaluated. Brain serotonin concentration was also estimated. Fluoxetine (20 mg/kg p.o.) was used as standard.. Only piperine but not fluoxetine significantly increased the decrease in number of rotations of wheel in FST, and decrease volume of saccharine consumption caused by pilocarpine. Both fluoxetine and piperine significantly increase the pilocarpine induced decrease in activity score in actophotometer, time taken to fall in rotarod and concentration of serotonin in brain.. The underlying mechanism behind depression in epilepsy may be alteration in monoaminergic pathways and GABAergic pathways. The antidepressant activity of piperine in post-SE rats may be attributed to its MAO inhibitor activity and neuroprotective activity.

Topics: Alkaloids; Anhedonia; Animals; Anticonvulsants; Behavior, Animal; Benzodioxoles; Biogenic Monoamines; Brain Chemistry; Chromatography, Thin Layer; Convulsants; Depression; Epilepsy; Female; Fluoxetine; Male; Motor Activity; Pilocarpine; Piperidines; Polyunsaturated Alkamides; Postural Balance; Rats; Serotonin; Spectrophotometry, Infrared; Status Epilepticus; Swimming

In surgeries for epilepsy, electrocorticography (ECoG) enables tailored resection of the epileptogenic brain and pharmacological stimulation should be employed in surgeries under general anesthesia. To identify the efficacy of continuous remifentanil in surgeries for epilepsy, ECoG findings with remifentanil and those with sevoflurane were compared.. Sixteen patients with intractable epilepsy were included with institutional ethics committee approval and informed consent. General anesthesia was induced and maintained with sevoflurane, remifentanil and rocuronium. After dural opening, ECoG recordings were obtained before stimulation, with sevoflurane-stimulation (ET-sevoflurane 2.5%) and with remifentanil-stimulation (0.7 microg x kg(-1) x min(-1) for 2 min followed by 0.35 microg x kg(-1) x min(-1)).. In 11 of the 16 cases, activation was confirmed with remifentanil and numbers of spikes with remifentanil- and sevoflurane-stimulation were larger than those before stimulation.. There have been some reports on bolus remifentanil on ECoG but not on its continuous infusion. This is the first report of the effect of remifentanil on ECoG as compared to sevoflurane. In this study, continuous infusion of remifentanil showed a stimulating effect on ECoG with the same potency as sevoflurane. Remifentanil may be used as an alternative to sevoflurane.

Topics: Administration, Inhalation; Anesthesia, General; Anesthetics, Inhalation; Anesthetics, Intravenous; Cerebral Cortex; Electroencephalography; Epilepsy; Female; Humans; Infusions, Intravenous; Intraoperative Period; Male; Methyl Ethers; Piperidines; Remifentanil; Sevoflurane; Stimulation, Chemical

We assessed the anticonvulsant potential of the phytocannabinoid Δ⁹-tetrahydrocannabivarin (Δ⁹-THCV) by investigating its effects in an in vitro piriform cortex (PC) brain slice model of epileptiform activity, on cannabinoid CB1 receptor radioligand-binding assays and in a generalized seizure model in rats.. Δ⁹-THCV was applied before (10 μm Δ⁹-THCV) or during (10-50 μm Δ⁹-THCV) epileptiform activity induced by Mg²(+) -free extracellular media in adult rat PC slices and measured using multielectrode array (MEA) extracellular electrophysiologic techniques. The actions of Δ⁹-THCV on CB1 receptors were examined using [³H]SR141716A competition binding and [³⁵S]GTPγS assays in rat cortical membranes. Effects of Δ⁹-HCV (0.025-2.5 mg/kg) on pentylenetetrazole (PTZ)-induced seizures in adult rats were also assessed.. After induction of stable spontaneous epileptiform activity, acute Δ⁹ -THCV application (≥ 20 μm) significantly reduced burst complex incidence and the amplitude and frequency of paroxysmal depolarizing shifts (PDSs). Furthermore, slices pretreated with 10 μm Δ⁹-THCV prior to induction of epileptiform activity exhibited significantly reduced burst complex incidence and PDS peak amplitude. In radioligand-binding experiments, Δ⁹-THCV acted as a CB1 receptor ligand, displacing 0.5 nm [³H]SR141716A with a Ki∼290 nm, but exerted no agonist stimulation of [³⁵S]GTPγS binding. In PTZ-induced seizures in vivo, 0.25 mg/kg Δ⁹-THCV significantly reduced seizure incidence.. These data demonstrate that Δ⁹-THCV exerts antiepileptiform and anticonvulsant properties, actions that are consistent with a CB1 receptor-mediated mechanism and suggest possible therapeutic application in the treatment of pathophysiologic hyperexcitability states.

Topics: Animals; Cerebral Cortex; Competitive Bidding; Disease Models, Animal; Dronabinol; Drug Interactions; Epilepsy; Evoked Potentials; Female; Guanosine 5'-O-(3-Thiotriphosphate); In Vitro Techniques; Male; Pentylenetetrazole; Phosphorus Isotopes; Piperidines; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Rimonabant

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

It was previously reported that piperine (PIP) significantly blocks convulsions induced by intracerebroventricular injection of threshold doses of kainate, but had no or only slight effects on convulsions induced by L-glutamate, N-methyl-D-aspartate and guanidinosuccinate. In traditional Chinese medicine, black pepper has been used for epileptic treatment; however, the exact mechanism is still unclear. We reported here in that appropriate concentration of PIP effectively inhibites the synchronized oscillation of intracellular calcium in rat hippocampal neuronal networks and represses spontaneous synaptic activities in terms of spontaneous synaptic currents (SSC) and spontaneous excitatory postsynaptic currents (sEPSC). Moreover, pretreatment with PIP expects protective effect on glutamate-induced decrease of cell viability and apoptosis of hippocampal neurons. These data suggest that the neuroprotective effects of PIP might be associated with suppression of synchronization of neuronal networks, presynaptic glutamic acid release, and Ca(2+) overloading.

Topics: Alkaloids; Animals; Anticonvulsants; Apoptosis; Benzodioxoles; Calcium; Calcium Signaling; Cell Survival; Drugs, Chinese Herbal; Epilepsy; Glutamic Acid; Hippocampus; Neurons; Neuroprotective Agents; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Rats; Signal Transduction; Synapses; Synaptic Transmission

Pentylenetetrazol (PTZ)-induced oxidative stress results in disturbance of the antioxidant enzyme status accompanied by neuronal injury and the development of epilepsy in rats. The present study evaluated the antioxidant effects of curcumin against PTZ-induced convulsions. Over a period of 30 days, i.p. injections of subconvulsive doses of PTZ on alternate days resulted in the development of a well-known kindling model of epilepsy. Spectrophotometric analysis revealed a markedly elevated activity of the antioxidant enzymes malondialdehyde (MDA), catalase and glutathione S-transferase (GST) in the cerebrum and cerebellum of epileptic rats due to PTZ-induced oxidative stress. Oral supplementation of curcumin at a dose of 2 g/kg for 30 days resulted in a transient decrease in MDA, catalase and GST levels in the rat cerebrum and cerebellum. Piperine (20 mg/kg orally) was administered along with curcumin to enhance the bioavailability of the latter up to 20-fold more. Combined treatment with curcumin and carbamazepine (3.6 mg/kg orally) also gave similar results, indicating that the potent antioxidant curcumin can be used as an adjuvant in antiepileptic therapy.

Topics: Alkaloids; Animals; Antioxidants; Benzodioxoles; Biological Availability; Carbamazepine; Catalase; Curcumin; Disease Models, Animal; Drug Therapy, Combination; Epilepsy; Glutathione Transferase; Injections, Intraperitoneal; Male; Malondialdehyde; Oxidative Stress; Pentylenetetrazole; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar

Exposure to the group I metabotropic glutamate receptor (mGluR) agonist dihydroxy phenylglycine (DHPG) induces epileptiform activity in the CA3 region of the hippocampus that persists following washout of DHPG. DHPG also can cause long-term depression of synaptic transmission, and at some synapses this may be mediated by endocannabinoids. We evaluated whether the selective cannabinoid type 1 (CB1) receptor antagonists SR 141716 or AM 251 could modify induction of epileptiform activity produced by DHPG exposure. The induction of epileptiform activity by DHPG exposure was significantly reduced by CB1 receptor antagonists, SR 141716 or AM 251. Minimal effects on epileptiform activity were noted once the activity had been induced. In control slices, exposure to DHPG for 30 min produced long-term depression (LTD) of synaptic transmission, on average about a 70% reduction in slope of the field excitatory postsynaptic potential (EPSP). When slices were exposed to both DHPG and SR 141716 (3 microm), LTD did not occur and the population EPSP remained at control values or greater. These results suggest that CB1 receptors mediate some of DHPG effects that result in persistent epileptiform activity, and antagonism of CB1 receptors has antiepileptogenic properties. Paradoxically DHPG also caused LTD of excitatory synaptic transmission in the CA3 region and CB1 receptor antagonism prevents the depression. We hypothesize that the ictal activity induced by DHPG requires depression of synaptic strength and CB1 receptor antagonism prevents this depression and the induction of ictal activity.

Topics: Animals; Dose-Response Relationship, Drug; Epilepsy; Excitatory Postsynaptic Potentials; Methoxyhydroxyphenylglycol; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptors, Metabotropic Glutamate; Rimonabant; Synaptic Transmission

Pretreatment with the endocannabinoid-receptor antagonist, SR141716, has been reported to suppress the long-lasting hyperexcitability and increased seizure susceptibility present after 30 min of hyperthermia-induced convulsions in immature rats, an animal model of complex febrile seizures in children, which may be a cause of temporal lobe epilepsy. The present experiments tested the hypothesis that SR141716 suppresses epileptogenesis in the adult kainate model, an animal model of temporal lobe epilepsy. Adult male rats (n = 35), implanted for electroencephalography (EEG) recordings, were treated with kainate. Immediately after the first acute electrographic seizure during kainate-induced status epilepticus, either vehicle or SR141716 (10 mg/kg) was injected intraperitoneally. Chronic video-EEG data were collected for the first 2-week period after kainate-induced status epilepticus. More than one-half of both the vehicle- and drug-treated animals showed spontaneous recurrent seizures. Similarly, mean seizure frequency did not differ significantly for the drug- and vehicle-treated animals during the first 2 weeks (n = 9 and 8, respectively). Therefore, no significant differences were found between SR141716-treated and control animals during the first 2 weeks of epileptogenesis. These results suggest that the endocannabinoid-receptor antagonist, SR141716, had no detectable effect on the early stages of epileptogenesis in the adult kainate model. We discuss several potential explanations for the differences in the effects of SR141716 in the adult-rat, kainate versus immature-rat, hyperthermia models.

Topics: Age Factors; Animals; Brain; Cannabinoid Receptor Antagonists; Convulsants; Disease Models, Animal; Electroencephalography; Epilepsy; Kainic Acid; Male; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Recurrence; Rimonabant; Status Epilepticus

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

Anesthetic goals for procedures involving resections close to the motor cortex include immobility, analgesia, and a level of consciousness that allows for the ability to follow motor commands. Remifentanil as a single agent is an attractive choice, particularly when ventilation is controlled. The successful use of large-dose remifentanil infusion during an awake craniotomy in a 16 year-old man and the subsequent severe acute opioid tolerance is presented.

Topics: Adolescent; Analgesics, Opioid; Anesthesia; Consciousness; Craniotomy; Drug Tolerance; Epilepsy; Fentanyl; Hematoma, Epidural, Cranial; Humans; Male; Morphine; Motor Cortex; Pain, Postoperative; Piperidines; Postoperative Complications; Remifentanil; Wakefulness

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

Dopamine and the endocannabinoids, anandamide and 2-arachidonoylglycerol, interact at several levels in the brain, with the involvement of both cannabinoid CB(1) receptors and transient receptor potential vanilloid type-1 (TRPV1) channels (which are alternative anandamide receptors). Using pharmacological, immunohistochemical and analytical approaches, we investigated the response of dopamine D(3) receptor null (D3R((-/-))) mice in models of epilepsy and anxiety, in relation to their brain endocannabinoid and endovanilloid tone. Compared to wild-type mice, D3R((-/-)) mice exhibited a delayed onset of clonic seizures, enhanced survival time, reduced mortality rate and more sensitivity to anticonvulsant effects of diazepam after intraperitoneal administration of picrotoxin (7 mg/kg), and a less anxious-like behaviour in the elevated plus maze test. D3R((-/-)) mice also exhibited different endocannabinoid and TRPV1, but not CB(1), levels in the hippocampus, nucleus accumbens, amygdala and striatum. Given the role played by CB(1) and TRPV1 in neuroprotection and anxiety, and based on data obtained here with pharmacological tools, we suggest that the alterations of endocannabinoid and endovanilloid tone found in D3R((-/-)) mice might account for part of their altered responses to excitotoxic and anxiogenic stimuli.

Topics: Analysis of Variance; Animals; Anti-Anxiety Agents; Anti-Inflammatory Agents, Non-Steroidal; Anxiety; Arachidonic Acids; Brain; Cannabinoid Receptor Modulators; Capsaicin; Diazepam; Disease Models, Animal; Dose-Response Relationship, Drug; Endocannabinoids; Epilepsy; GABA Antagonists; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Knockout; Picrotoxin; Piperidines; Pyrazoles; Reaction Time; Receptor, Cannabinoid, CB1; Receptors, Dopamine D3; Serotonin; TRPV Cation Channels

Topics: Adult; Cannabinoid Receptor Antagonists; Cannabinoid Receptor Modulators; Child, Preschool; Clinical Trials as Topic; Epilepsy; Humans; Models, Neurological; Piperidines; Pyrazoles; Rimonabant; Seizures, Febrile

Status epilepticus (SE) is a major medical emergency associated with a significant morbidity and mortality. Little is known about the mechanisms that terminate seizure activity and prevent the development of status epilepticus. Cannabinoids possess anticonvulsant properties and the endocannabinoid system has been implicated in regulating seizure duration and frequency. Endocannabinoids regulate synaptic transmission and dampen seizure activity via activation of the presynaptic cannabinoid receptor 1 (CB1). This study was initiated to evaluate the role of CB1 receptor-dependent endocannabinoid synaptic transmission towards preventing the development of status epilepticus-like activity in the well-characterized hippocampal neuronal culture model of acquired epilepsy using patch clamp electrophysiology. Application of the CB1 receptor antagonists SR141716A (1 microM) or AM251 (1 microM) to "epileptic" neurons caused the development of continuous epileptiform activity, resembling electrographic status epilepticus. The induction of status epilepticus-like activity by CB1 receptor antagonists was reversible and could be overcome by maximal concentrations of CB1 agonists. Similar treatment of control neurons with CB1 receptor antagonists did not produce status epilepticus or hyperexcitability. These findings suggest that CB1 receptor-dependent endocannabinoid endogenous tone plays an important role in modulating seizure frequency and duration and preventing the development of status epilepticus-like activity in populations of epileptic neurons. The regulation of seizure activity and prevention of status epilepticus by the endocannabinoid system offers an important insight into understanding the basic mechanisms that control the development of continuous epileptiform discharges.

Topics: Action Potentials; Animals; Animals, Newborn; Benzoxazines; Cells, Cultured; Disease Models, Animal; Drug Interactions; Epilepsy; Hippocampus; Morpholines; Naphthalenes; Neurons; Patch-Clamp Techniques; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Rimonabant; Synaptic Transmission

We present data on the antiepileptic potency of 2-methyl-4-oxo-3H-quinazoline-3-acetyl piperidine (Q5) in juvenile (P9-13) rat hippocampal slices and in particular Q5's action mechanism and target. Q5 (200-500 microM), but not alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/Kainate receptor antagonists blocked low-[Mg2+]-induced seizure-like events (SLE) in the CA3 region. Q5 (100 microM) decreased Glu-induced [35S]guanosine 5'-O-(3-thiotriphosphate) binding enhancement in brain homogenates, without interaction with ionotropic Glu receptor sites and Glu transport. In voltage-clamped CA3 pyramidal cells, Q5 (500 microM) depressed activities of spontaneous excitatory and inhibitory postsynaptic currents without affecting miniature inhibitory currents. Metabotropic Glu receptor (mGluR) subtype antagonists affected network excitability dissimilarly. Intracellular Ca2+ ion transients induced by the mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) were suppressed by Q5. Agreeing predictions obtained by modelling Q5 binding to different experimental conformations of mGlu1, Q5 was bound partially to an mGluR binding site in the presence of 1mM ACPD. Findings suggest the apparent involvement of a novel phenotype of action or a new mGluR subtype in the specific suppression of epileptiform activity by Q5 through the depression of network excitability.

Topics: Age Factors; Animals; Anticonvulsants; Binding Sites; Calcium Channels; Cell Membrane; Epilepsy; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Glutamic Acid; Guanosine Triphosphate; Hippocampus; Male; Nerve Net; Neural Inhibition; Organ Culture Techniques; Patch-Clamp Techniques; Piperidines; Protein Subunits; Pyramidal Cells; Quinazolines; Rats; Rats, Wistar; Receptors, Metabotropic Glutamate; Synaptic Transmission

Piperine, the active principle of Piper longum, Piper nigrum and Zingiber officinalis, has been reported to enhance the oral bioavailability of phenytoin in human volunteers. The objective of this study was to explore the effect of a single dose of piperine in patients with uncontrolled epilepsy on the steady-state pharmacokinetics of phenytoin. Two groups of 10 patients each receiving either a 150 mg or 200 mg twice daily dose of phenytoin were selected. Twelve hours after the night dose, venous blood samples were collected at 0, 0.5, 1, 2, 4, 6, 9, 12 h after administration of phenytoin. On the next study day, piperine 20 mg was administered along with phenytoin and samples were collected similarly. The mean plasma drug concentrations at different time points and the pharmacokinetic parameters before and after piperine administration were compared by Student's t-test. Piperine increased significantly the mean plasma concentration of phenytoin at most of the time points in both dose groups. There was a significant increase in AUC((0-12h)) (p < 0.01), C(max) (p < 0.001) and K(a) (p < 0.05) whereas the changes in K(el) and t(max) were not significant. The results showed that piperine enhanced the bioavailability of phenytoin significantly, possibly by increasing the absorption.

Topics: Adult; Alkaloids; Anticonvulsants; Area Under Curve; Benzodioxoles; Biological Availability; Dose-Response Relationship, Drug; Drug Interactions; Epilepsy; Female; Humans; Male; Middle Aged; Phenytoin; Piper; Piperidines; Polyunsaturated Alkamides

Cortical malformations are often associated with refractory epilepsy and cognitive deficit. Clinical and experimental studies have demonstrated an important role for glutamate-mediated synaptic transmission in these conditions. Using whole cell voltage-clamp techniques, we examined evoked glutamate-mediated excitatory postsynaptic currents (eEPSCs) and responses to exogenously applied glutamate on hippocampal heterotopic cells in an animal model of malformation i.e., rats exposed to methylazoxymethanol (MAM) in utero. Analysis revealed that the late N-methyl-D-aspartate (NMDA) receptor-mediated eEPSC component was significantly increased on heterotopic cells compared with age-matched normotopic pyramidal cells. At a holding potential of +40 mV, heterotopic cells also exhibited eEPSCs with a slower decay-time constant. No differences in the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) component of eEPSCs were detected. In 23% of heterotopic pyramidal cells, electrical stimulation evoked prolonged burst-like responses. Focal application of glutamate (10 mM) targeted to different sites near the heterotopia also evoked epileptiform-like bursts on heterotopic cells. Ifenprodil (10 microM), an NR2B subunit antagonist, only slightly reduced the NMDA receptor (NMDAR)-mediated component and amplitude of eEPSCs on heterotopic cells (MAM) but significantly decreased the late component and peak amplitude of eEPSCs in normotopic cells (control). Our data demonstrate a functional alteration in the NMDA-mediated component of excitatory synaptic transmission in heterotopic cells and suggest that this alteration may be attributable, at least in part, to changes in composition and function of the NMDAR subunit. Changes in NMDAR function may directly contribute to the hyperexcitability and cognitive deficits reported in animal models and patients with brain malformations.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Epilepsy; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Hippocampus; In Vitro Techniques; Methylazoxymethanol Acetate; N-Methylaspartate; Patch-Clamp Techniques; Piperidines; Rats

To investigate the mechanisms of histamine on chronic epilepsy induced by pentylenetetrazole (PTZ).. To induce chemical kindling, a subconvulsive dose (35mg/kg) of PTZ was ip injected every 48 h in rats. Behavior changes were observed for 30 min after every injection of PTZ.. Ip injection of histidine or icv injection of clobenpropit inhibited the development of kindling induced by PTZ, presenting prolonged latency for myoclonic jerks and clonic generalized seizures and depressed seizure stages in a dose-dependent manner. H(3)receptor agonist, immepip, and histidine decarboxylase, alpha-fluoromethylhistidine reversed the ameliorating effect of clobenpropit on seizure development in a dose-dependent manner.. Brain histamine plays an important role in protection against myoclonic jerks and clonic generalized clonic seizures and its action may be via H(3)receptor.

Topics: Animals; Brain; Chronic Disease; Dose-Response Relationship, Drug; Epilepsy; Histamine; Histidine; Imidazoles; Male; Pentylenetetrazole; Piperidines; Rats; Rats, Sprague-Dawley; Thiourea

Topics: Adult; Anesthetics, Intravenous; Electric Stimulation Therapy; Epilepsy; Female; Heart Arrest; Humans; Intraoperative Complications; Piperidines; Remifentanil; Vagus Nerve

Abnormally high spiking activity can damage neurons. Signaling systems to protect neurons from the consequences of abnormal discharge activity have been postulated. We generated conditional mutant mice that lack expression of the cannabinoid receptor type 1 in principal forebrain neurons but not in adjacent inhibitory interneurons. In mutant mice,the excitotoxin kainic acid (KA) induced excessive seizures in vivo. The threshold to KA-induced neuronal excitation in vitro was severely reduced in hippocampal pyramidal neurons of mutants. KA administration rapidly raised hippocampal levels of anandamide and induced protective mechanisms in wild-type principal hippocampal neurons. These protective mechanisms could not be triggered in mutant mice. The endogenous cannabinoid system thus provides on-demand protection against acute excitotoxicity in central nervous system neurons.

Topics: Animals; Arachidonic Acids; Brain; Brain-Derived Neurotrophic Factor; Cannabinoids; Endocannabinoids; Epilepsy; Excitatory Amino Acid Agonists; Excitatory Postsynaptic Potentials; Furans; gamma-Aminobutyric Acid; Gene Expression Regulation; Genes, Immediate-Early; Glutamic Acid; Glycerides; Hippocampus; In Vitro Techniques; Kainic Acid; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Mitogen-Activated Protein Kinases; Mutation; Neurons; Neuroprotective Agents; Piperidines; Polyunsaturated Alkamides; Prosencephalon; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Signal Transduction

Neuronal activity is thought to play an important role in refining patterns of synaptic connectivity during development and in the molecular maturation of synapses. In experiments reported here, a 2-week infusion of tetrodotoxin (TTX) into rat hippocampus beginning on postnatal day 12 produced abnormal synchronized network discharges in in vitro slices. Discharges recorded upon TTX washout were called 'minibursts', owing to their small amplitude. They were routinely recorded in area CA3 and abolished by CNQX, an AMPA receptor antagonist. Because recurrent excitatory axon collaterals remodel and glutamate receptor subunit composition changes after postnatal day 12, experiments examined possible TTX-induced alterations in recurrent excitation that could be responsible for network hyperexcitability. In biocytin-labelled pyramidal cells, recurrent axon arbors were neither longer nor more highly branched in the TTX infusion site compared with saline-infused controls. However, varicosity size and density were increased. Whereas most varicosities contained synaptophysin and synaptic vesicles, many were not adjacent to postsynaptic specializations, and thus failed to form anatomically identifiable synapses. An increased pattern of excitatory connectivity does not appear to explain network hyperexcitability. Quantitative immunoblots also indicated that presynaptic markers were unaltered in the TTX infusion site. However, the postsynaptic AMPA and NMDA receptor subunits, GluR1, NR1 and NR2B, were increased. In electrophysiological studies EPSPs recorded in slices from TTX-infused hippocampus had an enhanced sensitivity to the NR2B containing NMDA receptor antagonist, ifenprodil. Thus, increases in subunit protein result in alterations in the composition of synaptic NMDA receptors. Postsynaptic changes are likely to be the major contributors to the hippocampal network hyperexcitability and should enhance both excitatory synaptic efficacy and plasticity.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Anesthetics, Local; Animals; Animals, Newborn; Axons; Disease Models, Animal; Epilepsy; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Hippocampus; Immunoblotting; Immunohistochemistry; In Vitro Techniques; Lysine; Membrane Potentials; Microscopy, Confocal; Microscopy, Electron; Nerve Net; Patch-Clamp Techniques; Piperidines; Pyramidal Cells; Rats; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Synapses; Synaptophysin; Tetrodotoxin; Time Factors

The effect of histidine on pentylenetetrazole-induced seizures was investigated in rats.. Chemical kindling was elicited by repeated ip injection a subconvulsant dose of pentylenetetrazole (35 mg/kg) once every 48 h until the occurrence of seizure stages 4-5, and seizure activity of kindling was recorded for 30 min.. In the kindling development process, ip injection of histidine (200, 500 mg/kg), a precursor of histamine, prolonged latency for the onset of myoclonic jerks and the clonic generalized seizure, and inhibited seizure stage in a dose-dependent manner. In the kindling challenge process, histidine (500, 1000 mg/kg) and H3 antagonist thioperamide (10, 20 microg) al so showed a significant anticonvulsant effect. The inhibitory action of histidine was enhanced significantly by thioperamide (5 microg), however, was antagonized by both alpha fluoromethylhistidine (20 microg), a selective histidine decarboxylase inhibitor and H1 ant agonist pyrilamine (2, 5 mg/kg), dose-dependently and significantly. In addition, H2 antagonist zolantidine appeared no appreciable effect, even at a dose of 10 mg/kg.. These results indicated that brain endogenous histamine may play certain important role in protect against generalized clonic seizures, its action may via presynaptic H3-receptors and postsynaptic H1-receptors.

Topics: Animals; Drug Synergism; Epilepsy; Histamine; Histamine Antagonists; Histamine H1 Antagonists; Histidine; Kindling, Neurologic; Male; Pentylenetetrazole; Piperidines; Pyrilamine; Rats; Rats, Sprague-Dawley; Receptors, Histamine H1; Receptors, Histamine H3

Topics: Anesthetics, Combined; Anesthetics, Intravenous; Epilepsy; Humans; Neurosurgery; Piperidines; Propofol; Remifentanil

The interaction of selective histamine H3-receptor agonist R(alpha)-methyl-histamine (RAMH) and antagonist thioperamide (THP) with some antiepileptic drugs [AED; phenytoin (PHT), carbamazepine (CBZ), sodium valproate (SVP), and gabapentin (GBP)] was studied on seizures induced by maximal electroshock (MES) and pentylenetetrazole (PTZ) in mice. It was found that subeffective dose of THP in combination with the subeffective doses of PHT and GBP provided protection against MES and/or PTZ-induced seizures. Further, RAMH reversed the protection afforded by either PHT or GBP on MES and/or PTZ seizures. In another set of experiments, the histamine content was measured in the whole brain and in different brain regions including cerebral cortex, hypothalamus, brain stem and cerebellum following convulsant (MES and PTZ) and AED treatment. It was seen that while MES exhibited a tendency to enhance brain histamine levels, PTZ showed the opposite effect. AEDs either increased (PHT and GBP) or decreased (SVP) brain histamine content in different regions to varying degrees. The results indicate a role for histamine in seizures and in the action of AEDs and suggest that selective H3-receptor antagonists may prove to be of value as adjuncts to conventional AEDs.

Topics: Animals; Anticonvulsants; Brain; Convulsants; Drug Synergism; Epilepsy; Histamine; Histamine Agonists; Histamine Antagonists; Male; Methylhistamines; Mice; Pentylenetetrazole; Piperidines; Receptors, Histamine H3

We have previously shown that presynaptic N-methyl-D-aspartate receptors (NMDARs) can facilitate glutamate release onto principal neurons in the entorhinal cortex (EC). In the present study, we have investigated the subunit composition of these presynaptic NMDARs. We recorded miniature alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated excitatory postsynaptic currents (mEPSCs), from visually identified neurons in layers II and V of the EC in vitro. In both layers, bath application of the NR2A/B subunit-selective agonist, homoquinolinic acid (HQA), resulted in a marked facilitation of mEPSC frequency. Blockade of presynaptic Ca(2+) entry through either NMDARs or voltage-gated Ca(2+) channels with Co(2+) prevented the effects of HQA, confirming that Ca(2+) entry to the terminal was required for facilitation. When the NR2B-selective antagonist, ifenprodil, was applied prior to HQA, the increase in mEPSC frequency was greatly reduced. In addition, we found that an NMDAR antagonist blocked frequency-dependent facilitation of evoked release and reduced mEPSC frequency in layer V. Thus we have demonstrated that NMDA autoreceptors in layer V of the EC bear the NR2B subunit, and that NMDARs are also present at terminals onto superficial neurons.

Topics: 2-Amino-5-phosphonovalerate; Animals; Autoreceptors; Calcium; Entorhinal Cortex; Epilepsy; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Glutamic Acid; Male; Neurons; Piperidines; Presynaptic Terminals; Quinolinic Acids; Rats; Rats, Wistar; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Tetrodotoxin

High-dose i.v. opioids (e.g., alfentanil, 50 microg/kg bolus) are known to increase the intraoperative reading of epileptiform activity during epilepsy surgery (ES), thereby facilitating localization of the epileptogenic zone (i.e., the site of ictal onset and initial seizure propagation). However, this phenomenon has not been studied with remifentanil (i.e., a novel ultra-short acting opioid). The purpose of the present study was to evaluate the effect of remifentanil on electrocorticography (ECoG) during ES.. After Institutional Review Board approval, 25 adult patients undergoing elective ECoG-guided anterior temporal corticectomy were enrolled. At the time of ECoG, anesthesia consisted of inhaled isoflurane < or =0.1% (end-tidal) in 50% N2O, and i.v. fentanyl, 2 microg/kg/h and vecuronium. Patients were maintained at normocapnia and normoxia during ECoG. After acquisition of baseline ECoG, bolus remifentanil, 2.5 microg/kg i.v., was administered. The number of epileptiform spikes occurring 5 min before and after this bolus were compared by using a one-sided sign test; p values < or =0.05 were considered statistically significant.. When compared with baseline ECoG, bolus i.v. remifentanil significantly increased the frequency of single spikes or repetitive spike bursts in the epileptogenic zone while suppressing activity in surrounding normal brain.. During ES, remifentanil enhanced epileptiform activity during intraoperative ECoG. Such observations facilitate localization of the epileptogenic zone while minimizing resection of nonepileptogenic eloquent brain tissue. Although not specifically evaluated in this study, we speculate that remifentanil's short elimination half-life will facilitate neurologic function testing immediately after ES. Should this be the case, we envision remifentanil has the potential to supplant other opioids (e.g., alfentanil) during ECoG-guided ES.

Topics: Adult; Aged; Brain Mapping; Cerebral Cortex; Dose-Response Relationship, Drug; Electroencephalography; Epilepsy; Epilepsy, Temporal Lobe; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Monitoring, Intraoperative; Neurologic Examination; Piperidines; Psychosurgery; Remifentanil; Temporal Lobe

Recent studies have demonstrated an important role for the N-methyl-D-aspartate receptor (NMDAR) in epilepsy. NMDARs have also been shown to play a critical role in hyperexcitability associated with several animal models of human epilepsy. Using whole-cell voltage clamp recordings in brain slices, we studied evoked paroxysmal discharges in the freeze-lesion model of neocortical microgyria. The voltage dependence of epileptiform discharges indicated that these paroxysmal events were produced by a complex pattern of excitatory and inhibitory inputs. We examined the effect of the NMDAR antagonist D-2-amino-5-phosphopentanoic acid (APV) and the NMDA receptor subunit type 2B (NR2B)-selective antagonist ifenprodil on the threshold, peak amplitude, and area of evoked epileptiform discharges in brain slices from lesioned animals. Both compounds consistently raised the threshold for evoking the discharge but had modest effects on the discharge peak and amplitude. For comparison with nonlesioned cortex, we examined the effects of ifenprodil on the epileptiform discharge evoked in the presence of 2 microM bicuculline (partial disinhibition). In slices from nonlesioned cortex, 10 microM ifenprodil had little effect on the threshold whereas 71% of the recordings in bicuculline-treated lesioned cortex showed a >25% increase in threshold. These results suggest that NR2B-containing receptors are functionally enhanced in freeze-lesioned cortex and may contribute to the abnormal hyperexcitability observed in this model of neocortical microgyria.

Topics: 2-Amino-5-phosphonovalerate; Animals; Brain; Cerebral Cortex; Epilepsy; Evoked Potentials; Excitatory Amino Acid Antagonists; Female; Humans; In Vitro Techniques; Patch-Clamp Techniques; Piperidines; Pregnancy; Pyramidal Cells; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

Potassium homeostasis plays an important role in the control of neuronal excitability, and diminished buffering of extracellular K results in neuronal Hyperexcitability and abnormal synchronization. Astrocytes are the cellular elements primarily involved in this process. Potassium uptake into astrocytes occurs, at least in part, through voltage-dependent channels, but the exact mechanisms involved are not fully understood. Although most glial recordings reveal expression of inward rectifier currents (K(IR)), it is not clear how spatial buffering consisting of accumulation and release of potassium may be mediated by exclusively inward potassium fluxes. We hypothesized that a combination of inward and outward rectifiers cooperate in the process of spatial buffering. Given the pharmacological properties of potassium homeostasis (sensitivity to Cs(+)), members of the ether-a-go-go (ERG) channel family widely expressed in the nervous system could underlie part of the process. We used electrophysiological recordings and pharmacological manipulations to demonstrate the expression of ERG-type currents in cultured and in situ hippocampal astrocytes. Specific ERG blockers (dofetilide and E 4031) inhibited hyperpolarization- and depolarization-activated glial currents, and ERG blockade impaired clearance of extracellular potassium with little direct effect on hippocampal neuron excitability. Immunocytochemical analysis revealed ERG protein mostly confined to astrocytes; ERG immunoreactivity was absent in presynaptic and postsynaptic elements, but pronounced in glia surrounding the synaptic cleft. Oligodendroglia did not reveal ERG immunoreactivity. Intense immunoreactivity was also found in perivascular astrocytic end feet at the blood-brain barrier. cDNA amplification showed that cortical astrocytes selectively express HERG1, but not HERG2-3 genes. This study provides insight into a possible physiological role of hippocampal ERG channels and links activation of ERG to control of potassium homeostasis.

Topics: Animals; Anti-Arrhythmia Agents; Astrocytes; Cation Transport Proteins; Cell Communication; Cesium; Dose-Response Relationship, Drug; Electrophysiology; Epilepsy; Ether-A-Go-Go Potassium Channels; Gene Expression; Heart; Hippocampus; In Vitro Techniques; Long QT Syndrome; Male; Membrane Potentials; Microscopy, Electron; Neurons; Oligonucleotide Probes; Phenethylamines; Piperidines; Potassium Channel Blockers; Potassium Channels; Potassium Channels, Voltage-Gated; Pyridines; Rats; Rats, Wistar; RNA, Messenger; Spinal Cord; Sulfonamides

Identification of changes in neurotransmitter function in animal models of epilepsy provides a basis for rational drug development and an understanding of the mechanisms underlying epileptogenesis. We investigated changes in the efficacy of the benzodiazepine type I agonist zolpidem and the polyamine site N-methyl-D-aspartate receptor antagonist ifenprodil in a rat model of microgyria.. Neonatal freeze lesions were used to produce a microsulcus in the normally lissencephalic rat neocortex with anatomical similarities to human polymicrogyria. Whole-cell voltage-clamp recordings were made from visually identified layer 2/3 pyramidal cells in acutely prepared brain slices from nonlesioned and lesioned rats.. The effect of 20 nmol/L zolpidem on the decay time constant of inhibitory postsynaptic currents was significantly less in neurons from brain slices containing the freeze lesion. A higher concentration (100 nmol/L) of zolpidem was equally efficacious in lesioned and nonlesioned cortex. In lesioned cortex, the threshold for evoking epileptiform discharges was significantly increased in the presence of 10 micromol/L ifenprodil. This effect was significant in both intrinsic hyperexcitability and partial disinhibition with 2 micromol/L bicuculline in lesioned cortex. Ifenprodil had significantly less effect on the threshold of discharges evoked in control cortex in the partial disinhibition model.. The decreased sensitivity of gamma-aminobutyric acid A receptors to 20 nmol/L zolpidem in the freeze-lesion model is consistent with a delayed or arrested maturation in this animal model. These data support a delay in the developmental switch from alpha2 to alpha1 subunits in gamma-aminobutyric acid A receptors of neocortical pyramidal cells in lesioned cortex. The increased ifenprodil sensitivity of the threshold for evoking epileptiform discharges in both control and disinhibited slices containing the microsulcus is explained by a delay in the expression of the 2A (NR2A) N-methyl-D-aspartate receptor subunit. Delayed development may be a hallmark of this type of cortical dysplasia.

Topics: Animals; Disease Models, Animal; Epilepsy; Excitatory Postsynaptic Potentials; Freezing; Neocortex; Neural Inhibition; Patch-Clamp Techniques; Piperidines; Pyridines; Rats; Receptors, GABA; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate; Zolpidem

1. The arachidonic acid derivative arachidonylethanolamide (anandamide) is an endogeneous ligand of cannabinoid receptors that induces pharmacological actions similar to those of cannabinoids such as delta9-tetrahydrocannabinol (THC). We examined whether anandamide can influence excessive neuronal activity by investigating stimulation-induced population spikes and epileptiform activity in rat hippocampal slices. For this purpose, the effects of anandamide were compared with those of the synthetic cannabinoid agonist WIN 55,212-2 and its inactive S(-)-enantiomer WIN 55,212-3. 2. Both anandamide (1 and 10 microM) and WIN 55,212-2 (0.1 and 1 microM) decreased the amplitude of the postsynaptic population spike and the slope of the field excitatory postsynaptic potential (field e.p.s.p.) without affecting the presynaptic fibre spike of the afferents. At a concentration of 1 microM, WIN 55,212-2 completely suppressed the postsynaptic spike, whereas the S(-)-enantiomer WIN 55,212-3 produced only a slight depression. The CB1 receptor antagonist SR 141716 blocked the inhibition evoked by the cannabinoids. SR 141716 had a slight facilitatory effect on neuronal excitability by itself. 3. Anandamide shifted the input-output curve of the postsynaptic spike and the field e.p.s.p. to the right and increased the magnitude of paired-pulse facilitation indicating a presynaptic mechanism of action. 4. Anandamide and WIN 55,212-2, but not WIN 55,212-3, attenuated both stimulus-triggered epileptiform activity in CA1 elicited by omission of Mg2+ and spontaneously occurring epileptiform activity in CA3 elicited by omission of Mg2+ and elevation of K+ to 8 mM. The antiepileptiform effect of these cannabinoids was blocked by SR 141716. 5. In conclusion, cannabinoid receptors of the CB1 type as well as their endogeneous ligand, anandamide, are involved in the control of neuronal excitability, thus reducing excitatory neurotransmission at a presynaptic site, a mechanism which might be involved in the prevention of excessive excitability leading to epileptiform activity.

Topics: Animals; Arachidonic Acids; Benzoxazines; Calcium Channel Blockers; Dose-Response Relationship, Drug; Electric Stimulation; Endocannabinoids; Epilepsy; Hippocampus; In Vitro Techniques; Male; Membrane Potentials; Morpholines; Naphthalenes; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Wistar; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Stereoisomerism; Synaptic Transmission

Seizures are one of the most frequent complications after cerebral ischemia in patients. Up to now it is unknown which mechanisms are responsible for this. As shown previously photothrombotic infarction in rat neocortex leads to a sweeping suppression of GABAergic inhibition. In this study we investigated whether and to what extent epileptiform discharges can be observed in this ischemia model. In neocortical slices from lesioned animals we did not find spontaneous epileptic activity or paroxysmal depolarisation shifts. However, ipsi- and contralateral to a photothrombotic lesion the frequency of double and multiple discharges was markedly increased when compared to unlesioned controls. Surprisingly, neither the drug lubeluzole which was has been shown to prevent the GABAergic disinhibition observed after photothrombotic lesioning of rat neocortex, nor the prevention of spreading depressions by the NMDA-receptor antagonist MK-801 during lesion induction significantly affected the frequency of epileptiform discharges. This indicates that the epileptiform discharges are probably caused by functional alterations of glutamatergic receptors.

Topics: Animals; Cerebral Infarction; Dizocilpine Maleate; Electric Stimulation; Electrophysiology; Epilepsy; In Vitro Techniques; Intracranial Embolism and Thrombosis; Light; Male; Neocortex; Neuroprotective Agents; Piperidines; Rats; Rats, Wistar; Reaction Time; Thiazoles

Some non-competitive antagonists of N-methyl-D-aspartate (NMDA) were evaluated for potency to antagonize audiogenic seizures in genetically epilepsy-prone rats, following intraperitoneal administration. Phencyclidine (PCP), dizocilpine (MK-801), ketamine, ifenprodil and dextromethorphan, displayed anticonvulsant activity at doses similar to those which impaired performance in the rotarod equilibrium procedure. The noncompetitive NMDA receptor antagonists, at doses which slightly overlapped with the doses required for a full anticonvulsant protection against audiogenic seizures in genetically epilepsy-prone rats, induced profound untoward behavioural effects. This behavioural syndrome was characterized by marked ataxia, hyperactivity, stereotypes and wet dog shakes. In contrast, the effective anticonvulsant dose of 3-(2-carboxypiperazin-4-yl)propenyl-1-phosphonic acid (CPPene) was less than that required to impair rotarod performance and did not produce the PCP-like syndrome. A potential use in antiepileptic therapy, of CPPene or other new selective NMDA antagonists, with fewer neurotoxic effects but not for non-competitive antagonists such as MK-801, is suggested.

Topics: Acoustic Stimulation; Adrenergic alpha-Antagonists; Animals; Anticonvulsants; Dextromethorphan; Dizocilpine Maleate; Epilepsy; Injections, Intraperitoneal; Ketamine; Male; Movement; Phencyclidine; Piperazines; Piperidines; Postural Balance; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

Antiepilepsirine (AES) is a new antiepileptic drug developed in China. Anticonvulsant effects of AES were studied in both pentylenetetrazol (PTZ, n = 20) and amygdala kindled (n = 10) rats. AES was given once per day by oral gavage for 4 weeks. On days 7, 14, 21 and 28, all rats were tested 2 h after daily AES administration: PTZ and amygdala kindled rats were given a PTZ injection (30 mg/kg, i.p.) or amygdala stimulation (400 microA, 1 s), respectively. Behavior was observed, and seizures were graded. AES (300 or 500 mg/kg) produced sustained, dose dependent, protective effects against PTZ induced seizures in PTZ kindled rats, while AES (500 mg/kg) had no effects in amygdala kindled rats.

Topics: Amygdala; Animals; Anticonvulsants; Epilepsy; Kindling, Neurologic; Male; Pentylenetetrazole; Piperidines; Rats; Rats, Sprague-Dawley

In order to investigate the mechanism of action of anticonvulsant drugs, we examined the effects of carbamazepine (CBZ) and antiepilepsirine (AE) on convulsions and on brain biogenic amines in genetically epilepsy-prone rats (GEPR). AE was an effective anticonvulsant in moderate seizure GEPR (GEPR-3, ED50 = 65.5 mg/kg) and in severe seizure GEPR (GEPR-9, ED50 = 68.5 mg/kg). Because GEPR are known to have deficiencies in brain norepinephrine (NE) and serotonin (5-HT), which are of etiologic significance in their seizure predisposition, we evaluated the effects of anticonvulsant doses of CBZ and AE on dialyzable NE, 5-HT and their metabolites. Dialysis probes were stereotaxically inserted into hippocampi of awake and unrestrained GEPR-3 and GEPR-9. Either AE (100 mg/kg in GEPR-3; 100 mg/kg in GEPR-9) or CBZ (45 mg/kg in GEPR-3; 6 mg/kg in GEPR-9) was administered i.p. after establishing basal release. Significant increases in dialyzable 5-HT, but not NE, were seen at the approximate time to peak anticonvulsant effect for each drug in both strains. The changes in 5-HT release remained closely associated with the anticonvulsant actions after i.v. administration of either AE (40 mg/kg) or CBZ (25 mg/kg) in GEPR-3. Pretreatment of GEPR-9 with p-chlorophenylalanine depleted brain 5-HT and greatly diminished the anticonvulsant effectiveness of both drugs. We conclude that both CBZ and AE are effective anticonvulsants in GEPR and that enhancement of serotonergic transmission may contribute to the anticonvulsant effect of these drugs.

Topics: Animals; Anticonvulsants; Brain; Carbamazepine; Chromatography, High Pressure Liquid; Epilepsy; Female; Hydroxyindoleacetic Acid; Injections, Intraperitoneal; Male; Neurons; Piperidines; Rats; Rats, Inbred Strains; Serotonin

The actions of pumiliotoxin-B, extracted from the skin of the frog Dendrobates pumilio, were examined on hippocampal slices and on acutely dissociated hippocampal neurons from the adult guinea pig. Application of 0.5-1 microM pumiliotoxin-B to hippocampal slices caused spontaneous, repetitive field discharges in the CA3 subfield. In whole-cell patch-clamp recordings of isolated CA1 and CA3 neurons, 1-2 microM pumiliotoxin-B shifted the midpoint of Na+ current activation by -11.4 +/- 1.1 mV. This shift was not dependent upon prior activation of the sodium channel. Pumiliotoxin-B did not block macroscopic Na+ inactivation but did reduce the apparent voltage-dependence of inactivation such that currents decayed faster at membrane potentials more negative than -30 mV. Single-channel recordings of sodium currents from excised membrane patches indicated that pumiliotoxin-B had little or no effect on channel closings due to entry into inactivated state(s) but did increase the rate of channel closings due to reversal of channel opening. The increase in the channel closing rate was consistent with a +8.7 mV shift in voltage sensitivity. Negative shifts in activation and positive shifts in closing rates implied a negative shift in the voltage-dependence of channel opening, suggesting that pumiliotoxin-B increases the rate of Na+ channel opening and closing in cells at rest, which could result in spontaneous activity in the neurons.

Topics: Alkaloids; Amphibian Venoms; Animals; Epilepsy; Guinea Pigs; Hippocampus; In Vitro Techniques; Indolizines; Ion Channel Gating; Membrane Potentials; Neurons; Piperidines; Pyramidal Tracts; Sodium Channels

This study characterized the role of GABA in the central medial intralaminar nucleus on seizures induced by pentylenetetrazol given systemically. Injections of the direct selective GABAA agonist, piperidine-4-sulfonic acid or the indirect GABAA agonists, flurazepam and pentobarbital, in this region depressed arousal and facilitated myoclonic and clonic seizures induced by pentylenetetrazol but only caused slight inhibition of tonic seizures. In contrast the GABAB agonist (-)baclofen facilitated all three types of seizures. Recording after injection of piperidine-4-sulfonic acid and (-)baclofen revealed marked suppression and slowing of thalamic and cortical electrical activity. Thalamic injections of the GABAA antagonist, bicuculline methiodide, had opposite behavioral effects, causing hyperactivity and episodes of violent running, not accompanied by EEG discharges. When pentylenetetrazol was infused concommitantly there was marked facilitation of the tonic seizures, which occurred without preceding myoclonic of clonic seizures, or EEG spikes. These results demonstrate that GABA-mediated neurotransmission in the central medial intralaminar nucleus can control the threshold of seizures and that GABA agonists and antagonists have opposite effects. It is suggested that the central medial intralaminar nucleus is not a site of origination or spread of seizures, but controls seizures indirectly by regulating the excitability of other structures and that different synaptic mechanisms and anatomical connections mediate effects on different types of seizures.

Topics: Animals; Baclofen; Bicuculline; Electroencephalography; Epilepsy; Female; Flurazepam; gamma-Aminobutyric Acid; Pentobarbital; Pentylenetetrazole; Piperidines; Rats; Rats, Inbred Strains; Receptors, GABA-A; Thalamic Nuclei

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

The results of a one year treatment with Melperone are reported. 18 mentally retarded female patients with severe aggressive and autoaggressive behaviour had been included in this open study. Six patients suffered from various epileptic seizures. A significant reduction of aggressive and autoaggressive behaviour, measured by the AFGB, was found. The activity of alkaline phosphatase showed a significant tendency towards normalisation. EEG-controls of patients with epileptic seizures showed no increase of epileptic activity in the EEG. No severe side effects were noticed.

Topics: Adolescent; Adult; Aggression; Alkaline Phosphatase; Antipsychotic Agents; Butyrophenones; Electroencephalography; Epilepsy; Female; Humans; Intellectual Disability; Leukocytes; Piperidines

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: Adolescent; Anticonvulsants; Azepines; Child; Child, Preschool; Epilepsy; Female; Humans; Male; Nitriles; Phenothiazines; Piperidines; Tranquilizing Agents

Topics: Adolescent; Brazil; Child; Child, Preschool; Epilepsy; Evaluation Studies as Topic; Female; Humans; Male; Mental Disorders; Nitriles; Phenothiazines; Piperidines; Tranquilizing Agents

Topics: Cerebral Palsy; Child; Child, Preschool; Chlorpromazine; Epilepsy; Epilepsy, Absence; Glutamates; Humans; Infant; Infant, Newborn; Intellectual Disability; Muscles; Piperidines; Pyridoxine; Reserpine; RNA; Spasms, Infantile

Topics: Bemegride; Electroencephalography; Epilepsy; Humans; Piperidines

Topics: Antihypertensive Agents; Diet, Reducing; Epilepsy; Intellectual Disability; Methylphenidate; Muscle Spasticity; Piperidines; Reserpine; Secologanin Tryptamine Alkaloids; Spasm

Topics: Epilepsy; Humans; Piperidines

Topics: Anticonvulsants; Epilepsy; Humans; Piperidines

Topics: Epilepsy; Humans; Piperidines