thiourea and Seizures

Endoplasmic reticulum (ER) stress has been indicated to be involved in the pathogenesis of epilepsy. Sodium valproate (VPA), one of the most commonly used antiepileptic drugs, is reported to regulate ER stress in many neurological diseases. However, the effect of VPA on ER stress in epilepsy remains unclear. The current study was performed to investigate the role of ER stress in the neuroprotection of VPA against seizure induced by pentylenetetrzole (PTZ). Our results showed that VPA treatment could inhibit the increased expressions of ER stress proteins (GRP78 and CHOP), and significantly reduce neuronal apoptosis in the PTZ-induced experimental seizure model. In addition, Salubrinal, an ER stress inhibitor, was used as a positive control, and exhibited neuroprotective effects via inhibiting excessive ER stress in the seizure model, which further supported that the inhibition in ER stress by VPA treatment could exert neuroprotection in seizures. In summary, our work demonstrated for the first time that ER stress was involved in the neuroprotective potential of VPA for seizures.

Topics: Animals; Anticonvulsants; Apoptosis; Cinnamates; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Heat-Shock Proteins; Hippocampus; Male; Mice, Inbred C57BL; Neuroprotective Agents; Pentylenetetrazole; Seizures; Thiourea; Transcription Factor CHOP; Valproic Acid

In this paper, we report the synthesis of 2-[(6-substituted benzo[d]thiazol-2-ylcarbamoyl)methyl]-1-(4-substituted phenyl)isothiourea derivatives (4a-y) carrying active pharmacophores essential for anticonvulsant activity. The anticonvulsant activity was evaluated in vivo by maximal electroshock (MES) test and subcutaneous pentylenetetrazole (scPTZ) test in mice. Most of the compounds showed promising anticonvulsant activity. The most active compounds 4b and 4q were found active in both MES and scPTZ models, without signs of neurotoxicity. Compound 4b showed the moderate change in SGOT and alkaline phosphatase level as compared to control. Compounds 4b and 4w were also found to elevate GABA levels in the olfactory lobe, mid brain, medulla oblongata and cerebellum regions of rat brain. In molecular docking study, the title compounds exhibited good binding properties with epilepsy molecular targets such as GABA-A. Structure-activity relationships are also elaborated along with the analysis of lipophilicity. The results suggested that compound 4b is likely to have varied mechanisms of action including voltage-gated ion channel inhibition and modulating GABAergic action.

Topics: Animals; Anticonvulsants; Benzothiazoles; Disease Models, Animal; Drug Design; Electroshock; Female; Humans; Male; Mice; Molecular Docking Simulation; Rats, Wistar; Receptors, GABA-A; Seizures; Structure-Activity Relationship; Thiourea

In epilepsy, the GABA and glutamate balance may be disrupted and a transient decrease in extracellular calcium occurs before and during a seizure. Flow Cytometry based fluorescence activated particle sorting experiments quantified synaptosomes from human neocortical tissue, from both epileptic and non-epileptic patients (27.7% vs. 36.9% GABAergic synaptosomes, respectively). Transporter-mediated release of GABA in human and rat neocortical synaptosomes was measured using the superfusion technique for the measurement of endogenous GABA. GABA release was evoked by either a sodium channel activator or a sodium/potassium-ATPase inhibitor when exocytosis was possible or prevented, and when the sodium/calcium exchanger was active or inhibited. The transporter-mediated release of GABA is because of elevated intracellular sodium. A reduction in the extracellular calcium increased this release (in both non-epileptic and epileptic, except Rasmussen encephalitis, synaptosomes). The inverse was seen during calcium doubling. In humans, GABA release was not affected by exocytosis inhibition, that is, it was solely transporter-mediated. However, in rat synaptosomes, an increase in GABA release at zero calcium was only exhibited when the exocytosis was prevented. The absence of calcium amplified the sodium/calcium exchanger activity, leading to elevated intracellular sodium, which, together with the stimulation-evoked intracellular sodium increment, enhanced GABA transporter reversal. Sodium/calcium exchange inhibitors diminished GABA release. Thus, an important seizure-induced extracellular calcium reduction might trigger a transporter- and sodium/calcium exchanger-related anti-seizure mechanism by augmenting transporter-mediated GABA release, a mechanism absent in rats. Uniquely, the additional increase in GABA release because of calcium-withdrawal dwindled during the course of illness in Rasmussen encephalitis. Seizures cause high Na(+) influx through action potentials. A transient decrease in [Ca(2+)]e (seizure condition) increases GABA transporter (GAT)-mediated GABA release because of elevated [Na(+)]i. This amplifies the Sodium-Calcium-Exchanger (NCX) activity, further increasing [Na(+)]i and GABA release. The reduction in [Ca(2+)]e triggers a GAT-NCX related anti-seizure mechanism by augmenting GAT-mediated GABA release. This mechanism, obvious in humans, is absent in rats.

Topics: Adolescent; Adult; Aged; Aniline Compounds; Animals; Calcium; Child; Child, Preschool; Enzyme Inhibitors; Female; GABA Plasma Membrane Transport Proteins; Humans; Infant; Male; Middle Aged; Neocortex; Neurotoxins; Ouabain; Phenyl Ethers; Rats; Rats, Wistar; Seizures; Sodium; Synaptosomes; Tetanus Toxin; Thiourea; Tritium; Veratridine; Young Adult

A new series of quinazoline analogues was designed and synthesized to get the target compounds 18-21, 30-41, 46-53, and 57-76. The Obtained compounds were evaluated for their anticonvulsant activity using PTZ and picrotoxin convulsive models. Compounds 47, 63, 68 and 73 proved to be the most active compounds in this study with a remarkable 100% protection against PTZ induced convulsions. Compounds 47, 63, 68 and 73 proved to be 10, 4, 4, and 5 fold more active, respectively than the used positive control sodium valproate. Structure activity correlation concluded valuable pharmacophoric information which confirmed by molecular modeling studies. Molecular docking study of 68 suggested its agonistic behavior toward GABAA receptor. The studied quinazoline analogues could be considered as useful templates for future development and further derivatization.

Topics: Animals; Anticonvulsants; Dose-Response Relationship, Drug; Hydrazines; Mice; Models, Molecular; Molecular Structure; Pentylenetetrazole; Picrotoxin; Quinazolinones; Seizures; Structure-Activity Relationship; Sulfonamides; Thiourea

Kainic acid (KA)-induced neuronal death is closely linked to endoplasmic reticulum (ER) and mitochondrial dysfunction. Parkin is an ubiquitin E3 ligase that mediates the ubiquitination of the Bcl-2 family of proteins and its mutations are associated with neuronal apoptosis in neurodegenerative diseases. We investigated the effect of salubrinal, an ER stress inhibitor, on the regulation of ER stress and mitochondrial apoptosis induced by KA, in particular, by controlling parkin expression. We showed that salubrinal significantly reduced seizure activity and increased survival rates of mice with KA-induced seizures. We found that salubrinal protected neurons against apoptotic death by reducing expression of mitochondrial apoptotic factors and elF2α-ATF4-CHOP signaling proteins. Interestingly, we showed that salubrinal decreased the KA-induced parkin expression and inhibited parkin translocation to mitochondria, which suggests that parkin may regulate a cross-talk between ER and mitochondria. Collectively, inhibition of ER stress attenuates mitochondrial apoptotic and ER stress pathways and controls parkin-mediated neuronal death following KA-induced seizures.

Topics: Animals; Anticonvulsants; Apoptosis; Cinnamates; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Hippocampus; Kainic Acid; Male; Mice, Inbred ICR; Mitochondria; Neurons; Neuroprotective Agents; Nitric Oxide Synthase Type II; Random Allocation; Seizures; Survival Analysis; Thiourea; Ubiquitin-Protein Ligases

The Na⁺/Ca²⁺ exchanger (NCX) is thought to play an important role in the pathogenesis of pentylenetetrazole (PTZ)-induced tonic flexion in mice. Here, I investigated the expression of PTZ-induced generalized clonic and tonic-clonic seizures in rats, using two potent NCX reverse mode inhibitors, KB-R7943 and SN-6 for NCX subtypes 3 (NCX3) and 1 (NCX1), respectively. Pretreatment with KB-R7943 (3, 10, and 30 mg/kg; p.o.) significantly reduced the expression of PTZ-induced generalized seizures with clonic and tonic-clonic components in 12-62% and 25-62% of the treated animals, respectively. In the remaining animals that exhibited seizures, KB-R7943 (3 mg/kg; p.o.) pretreatment significantly delayed the onset of the first seizure episode and reduced the seizure severity. Following pretreatment with SN-6 (0.3, 1, 3, 10, and 30 mg/kg; p.o.), clonic and tonic-clonic PTZ-induced generalized seizures were reduced in 25-50% and 38-63% of treated animals, respectively. SN-6 (0.3, 1, and 3 mg/kg; p.o.) also significantly reduced PTZ-induced seizure severity scores, but did not alter seizure latencies. KB-R7943 (3 and 30 mg/kg; p.o.) or SN-6 (3 and 30 mg/kg; p.o.) administration potentiated the sub-anticonvulsant dose of diazepam (2.5 mg/kg; i.p.) that suppresses clonic and tonic-clonic PTZ-induced seizures. These findings suggested that Ca²⁺ influx via the NCX in reverse mode contributes to a neuronal hyperexcitability that leads to clonic and tonic-clonic generalized seizures and that the NCX1 and NCX3 isoforms may serve as novel molecular targets for seizure suppression.

Topics: Animals; Anticonvulsants; Benzyl Compounds; Chi-Square Distribution; Convulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Male; Pentylenetetrazole; Rats; Rats, Sprague-Dawley; Reaction Time; Seizures; Sodium-Calcium Exchanger; Thiazolidines; Thiourea

Clobenpropit, an H( 3) receptor antagonist, has been reported to modulate both the release of neurotransmitters and also the activity of histidine decarboxylase (HDC). Therefore, a decarboxylase-positive modulator, namely pyridoxine, was taken for interaction studies with clobenpropit in the electroshock (ES) model of seizures in mice and subsequent changes in brain histamine levels were estimated. A significant inhibition of ES-induced seizures was seen after the simultaneous use of clobenpropit and pyridoxine. No significant effects were evident on the brain histamine levels following this combination. The combination of clobenpropit with pyridoxine appears to exhibit beneficial pharmacodynamic interaction for the prevention of ES-induced seizures, which might not be mediated by the histaminergic mechanisms.

Topics: Animals; Anticonvulsants; Brain; Drug Interactions; Electroshock; Female; Histamine; Histamine H3 Antagonists; Histidine Decarboxylase; Imidazoles; Male; Mice; Pyridoxine; Seizures; Thiourea

Recent evidence suggests that the sodium calcium exchanger (NCX) may contribute to the etiology of pentylenetetrazol-induced seizures. Here we further investigated the role of NCX in the etiology of seizures by quantifying the effects of KB-R7943 and SN-6, potent inhibitors of the reverse mode of NCX subtypes 3 (NCX3) and 1 (NCX1), respectively, on the occurrence of acute seizures and status epilepticus induced by intraperitoneal administration of pilocarpine, a muscarinic acetylcholine receptor agonist. Pretreatment with KB-R7943 significantly reduced the incidence of pilocarpine-induced seizures and status epilepticus in 22-56% of treated animals. In the remaining animals that exhibited seizures, KB-R7943 pretreatment delayed the onset of seizures and status epilepticus, and reduced seizure severity. Delayed onset of seizures and reduced seizure severity also were seen following pretreatment with SN-6. These findings suggest that altered NCX activity may contribute to the pathophysiology of pilocarpine-induced seizures and status epilepticus.

Topics: Acute Disease; Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Male; Muscarinic Agonists; Pilocarpine; Rats; Rats, Sprague-Dawley; Seizures; Sodium-Calcium Exchanger; Thiourea

Several thiourea and urea derivatives were prepared by the reaction of 4-aminopyrazoles with substituted isothiocyanates or isocyanates. The novel compounds were tested anticonvulsant activity using by pentylenetetrazole-induced seizure (PTZ) and maximal electroshock seizure (MES) tests. Among the tested compounds, thiourea derivatives of 4b were afforded 90 and 100% protection in PTZ and MES tests at 50mg/kg, respectively. Urea derivatives of 5a and 5b were afforded 82 and 100% protection both at 25 and 50mg/kg. Also synthesized compounds were screened for antituberculosis activity against Mycobacterium tuberculosis H37Rv at 6.25 microg/mL concentration but they were not found active at these concentration. In addition, some selected compounds were evaluated for in vitro anti-HIV activity and they were all negative.

Topics: Animals; Anticonvulsants; Electroshock; Female; Male; Mice; Pentylenetetrazole; Seizures; Structure-Activity Relationship; Thiourea

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

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

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

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

The purpose of this study was to investigate whether or not clobenpropit, a selective and potent histamine H(3) receptor antagonist, can protect from pentylenetetrazole (35 mg/kg)-kindled seizures in rats. I.c.v. injection with clobenpropit (10 and 20 microg) significantly delayed the seizure stage and prolonged the latency to the onset of myoclonic jerks and the latency to the clonic generalized seizure in a dose-dependent manner. The protection by clobenpropit (20 microg) was completely antagonized by both immepip (5 and 10 microg, i.c.v.), a selective potent histamine H(3) receptor agonist, and alpha-fluoromethylhistidine (alpha-FMH, 50 microg, i.c.v.), a selective histidine decarboxylase inhibitor. In addition, clobenpropit markedly potentiated the histidine (100 and 200 mg/kg)-induced inhibition of pentylenetetrazole-kindled seizures. Pyrilamine (2 and 5 microg, i.c.v.) reversed the inhibition of pentylenetetrazole-kindled seizures induced by clobenpropit, whereas cimetidine had no effect even at a high dose of 5 microg. These results indicate that clobenpropit protects against pentylenetetrazole-kindled seizures in rats, and that its action is mainly due to the activation of endogenous histamine by blocking autoinhibitory presynaptic histamine H(3) receptors.

Topics: Animals; Dose-Response Relationship, Drug; Imidazoles; Male; Pentylenetetrazole; Rats; Rats, Sprague-Dawley; Receptors, Histamine H3; Seizures; Thiourea

The effects of GABAmimetic drugs on inhibition of amygdaloid kindled seizures induced by clobenpropit were investigated to clarify the relationship between histaminergic and GABAergic systems in seizures. I.p. injection of clobenpropit caused dose-dependent inhibition of amygdaloid kindled seizures. GABAmimetic drugs such as diazepam, sodium valproate and muscimol also inhibited amygdaloid kindled seizures in a dose-dependent manner. Diazepam at doses of 0.2 and 0.5 mg/kg, which showed no significant effect on amygdaloid kindled seizures when used separately, significantly potentiated the effect of clobenpropit. Similar findings were observed with sodium valproate and muscimol at doses of 100 mg/kg and 5 ng, respectively, although neither showed any significant effects when administered separately. Bicuculline caused significant antagonism of the inhibition of amygdaloid kindled seizures induced by clobenpropit, while the effect of diazepam was not antagonized by diphenhydramine. These results suggested that inhibition of amygdaloid kindled seizures induced by histamine is closely associated with the actions of GABA.

Topics: Amygdala; Animals; Bicuculline; Diazepam; gamma-Aminobutyric Acid; Histamine; Imidazoles; Kindling, Neurologic; Male; Muscimol; Rats; Rats, Wistar; Seizures; Thiourea; Valproic Acid

A series of thioureido derivatives of acetophenone semicarbazone were synthesized and evaluated for anticonvulsant activity. Some compounds provided significant protection against maximal electroshock (MES) and subcutaneous pentylenetetrazol (scPTZ) induced seizures. The compound (2e) was the most active compound in the series with a dose of 30 mg kg-1 and ED50 23.5 mg kg-1 and equipotent to phenytoin ED50 23.2 mg kg-1. The toxicity of the compounds was assessed by determination of their approximate TD50 and LD50 values in order to have a better assessment of their pharmacological profile and protective index.

Topics: Acetophenones; Animals; Anticonvulsants; Lethal Dose 50; Mice; Seizures; Semicarbazones; Thiourea

The lipophilic 1-cycloalkylamino-1-(pyrid-3-yl-sulfonamido)-2-nitr oethylenes were synthesized as bioisosteres of BM-34, an anticonvulsant sulfonylthiourea. Compound 17 (ip) emerged from the maximal electroshock seizure (MES) test with a 50% effective dose (ED50) of 8.25 mg/kg. Its anticonvulsant profile was similar to that of phenytoin (ED50 = 9.51 mg/kg) and of BM-34 (ED50 = 1.19 mg/kg): active in the MES test and inactive in seizures induced by subcutaneous injection of pentetrazole, strychnine, bicuculline, picrotoxin, or N-methyl-D,L-aspartate. The neurotoxicity of 17 (TD50 = 113.8 mg/kg) was lower than that of phenytoin (TD50 = 65.5 mg/kg) but higher than that of BM-34 (TD50 = 147.2 mg/kg). Crystallographic study revealed that BM-401 (17) was a zwitterionic structure. Its sulfonamido nitroethylene side chain adopted a conformation which placed the two cycloalkyl rings face to face to form a single hydrophobic area.

Topics: Animals; Anticonvulsants; Convulsants; Crystallography, X-Ray; Drug Design; Electroshock; Male; Mice; Mice, Inbred Strains; Models, Molecular; Molecular Conformation; Molecular Structure; Neurotoxins; Phenytoin; Seizures; Stereoisomerism; Structure-Activity Relationship; Thiourea

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

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

The anticonvulsant activity of clobenpropit, an isothiourea derivative of histamine and potent H3-receptor antagonist, was investigated in two representative seizure models in mice. In the maximal electroshock seizure threshold test, clobenpropit dose-dependently raised the electroconvulsive threshold for tonic (hindlimb extension) seizures, but a significant increase of about 15% was determined only at the high dose of 40 mg/kg i.p. The protective action of this drug was reduced by immepip and (R)-alpha-methylhistamine, selective H3-receptor agonists. In co-medication with two standard antiepileptics, clobenpropit (20 and 40 mg/kg) significantly increased the anticonvulsant effectiveness of carbamazepine and tended to increase the effectiveness of valproate. Additional studies indicated that the high dose of clobenpropit also significantly enhanced the plasma carbamazepine concentration. One the other hand, in the s.c. PTZ seizure threshold test clobenpropit revealed no protective effects. In the rotarod ataxia test, impaired motor function was observed at 80 mg/kg clobenpropit. In conclusion, the present findings indicated no pronounced anticonvulsant effects of clobenpropit against generalized tonic as well as clonic seizures.

Topics: Animals; Anticonvulsants; Behavior, Animal; Carbamazepine; Differential Threshold; Electroshock; Histamine Antagonists; Imidazoles; Male; Mice; Motor Activity; Pentylenetetrazole; Seizures; Thiourea; Valproic Acid

The N-[(4-cycloheptylaminopyrid-3-yl)sulfonyl]-N'-cycloheptyl urea, a neuroprotective agent, and 10 chemically related sulfonyl(thio)ureas were evaluated in the maximal electroshock seizure test in mice. This sulfonylurea, BM 27, and two structurally related sulfonylthioureas, BM 11 and BM 34, emerged with a 50% effective dose (ED50) of 2.87, 1.72, and 1.19 mg/kg, respectively. Their anticonvulsant profiles were found to be similar to that of phenytoin: active in the maximal electroshock seizure (MES) test and inactive in chemically induced seizures (pentetrazole, strychnine, bicuculline, picrotoxine, N-methyl-D,L-aspartic acid). These compounds exhibited a higher protective index and potency than those of phenytoin. Additional work remains necessary, however, to determine whether BM 27 is of clinical interest.

Topics: Animals; Anticonvulsants; Diuretics; Epilepsy; Male; Mice; Neuroprotective Agents; Seizures; Sulfonamides; Sulfonylurea Compounds; Thiourea; Torsemide

The effects of new and potent NOS inhibitors, S-methyl-L-thiocitrulline (S-Me-TC), 3-bromo 7-nitro indazole (3-Br-7-NI), and 1-(2-trifluoromethylphenyl) imidazole (TRIM), were examined on the pilocarpine-induced seizures in mice. 3-Br-7-NI and TRIM decreased the frequency of status epilepticus and mortality, while TRIM. In addition, significantly reduced the incidence of seizures. The latencies to onsets of seizures, status epilepticus, and mortality were significantly prolonged by all three NOS inhibitors, while duration of seizures was reduced by 3-Br-7-NI and TRIM. These data suggest an excitatory effect of NO in the neuronal structure involved in the pilocarpine-induced seizures.

Topics: Animals; Anticonvulsants; Citrulline; Disease Models, Animal; Enzyme Inhibitors; Imidazoles; Male; Mice; Nitric Oxide Synthase; Seizures; Thiourea

The effect of clobenpropit (VUF-9153), a new histamine H3 receptor antagonist, on electrically induced convulsions was studied in mice. Clobenpropit significantly and dose dependently decreased the duration of each convulsive phase. Its anticonvulsant effects were prevented by pretreatment with (R)-alpha-methylhistamine and imetit (VUF-8325), histamine H3 receptor agonists. These findings suggest that the effect of clobenpropit on electrically induced convulsions is due to an increase in endogenous histamine release in the brain, which is consistent with biochemical results that clobenpropit increased brain histidine decarboxylase activity dose dependently. The anticonvulsive effect of clobenpropit was antagonized by mepyramine, a histamine H1 receptor antagonist, but not by zolantidine, a histamine H2 receptor antagonist, indicating that histamine released by the anticonvulsant effect of clobenpropit interacts with histamine H1 receptors of postsynaptic neurons. The present findings of the effect of clobenpropit on electrically induced convulsions are fully consistent with those of thioperamide as described previously (Yokoyama et al., 1993, Eur. J. Pharmacol. 234, 129), supporting the hypothesis that the central histaminergic neuron system is involved in the inhibition of seizures.

Topics: Animals; Anticonvulsants; Brain; Brain Chemistry; Electroshock; Histamine Agonists; Histamine Antagonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Histidine Decarboxylase; Imidazoles; Male; Mice; Mice, Inbred Strains; Seizures; Thiourea

Topics: Animals; Brain Chemistry; Catecholamines; Cocaine; Drug Interactions; Exploratory Behavior; Infusions, Parenteral; Male; Methyltyrosines; Pimozide; Rats; Seizures; Thiourea; Time Factors

Topics: Alcohols; Amines; Aminobutyrates; Animals; Chlorpromazine; Esters; Male; Mice; Pentylenetetrazole; Recurrence; Seizures; Thiourea

Topics: Amphetamine; Animals; Benzimidazoles; Female; Male; Mice; Pentobarbital; Rats; Seizures; Sleep; Thiourea

Topics: Animals; Anticonvulsants; Benzimidazoles; Electroshock; Mice; Pentylenetetrazole; Rats; Seizures; Structure-Activity Relationship; Thiourea

Topics: Alanine; Animals; Anti-Bacterial Agents; Antimetabolites; Azaserine; Behavior, Animal; Central Nervous System; Chlorambucil; Cyclophosphamide; Cysteine; Drug Antagonism; Glycine; Male; Mannitol; Mechlorethamine; Melphalan; Nitrogen Mustard Compounds; Phenobarbital; Phenytoin; Rats; Seizures; Spasm; Thiourea; Triethylenemelamine; Tryptophan

Topics: Aldehydes; Animals; Anticonvulsants; Electroconvulsive Therapy; Mice; Pentylenetetrazole; Pyridines; Seizures; Semicarbazides; Thiourea; Urea

Topics: Amino Acids; Animals; Brain; gamma-Aminobutyric Acid; Hydrazines; Neurochemistry; Rats; Seizures; Semicarbazides; Thiourea