dihydropyridines and Seizures

The synthesis and anticonvulsant properties of new N-diethylmalonyl derivatives of nifedipine and other isosteric analogues (7a-7n) were described. Anticonvulsant screening was performed by subcutaneous pentylenetetrazole (scPTZ) and maximal electroshock (MES) induced seizures tests. Majority of the compounds were effective in scPTZ and MES screens. Compound 7k showed good activity displaying maximum protection, which may be due to the presence of styryl moiety at position 4 of 1,4-dihydropyridine nucleus and the methyl groups of diester functionality. Compounds 7a-7d, 7g, 7i and 7k obeyed the Lipinski's "rule of five" and have drug-likeness. Based on computational prediction of molecular and pharmacokinetic properties, it was found that the compounds have good oral absorption.

Topics: Administration, Oral; Animals; Anticonvulsants; Dihydropyridines; Drug Design; Male; Mice; Molecular Structure; Rats; Rats, Wistar; Seizures; Structure-Activity Relationship; Toxicity Tests, Acute

Taurine, a sulfur-containing amino acid, has high hydrophilicity and is poorly absorbed. Tauropyrone, a taurine-containing 1,4-dihydropyridine derivative, is suggested to have greater activity than taurine owing to improved physicochemical properties that facilitate delivery of the compound to target cells. The aim of this study was to determine whether the 1,4-dihydropyridine moiety in tauropyrone improves the pharmacological efficacy of taurine in vitro and in vivo.. The effects of taurine and tauropyrone, as well as of the 1,4-dihydropyridine moiety were compared in in-vitro experiments to determine the binding to GABA receptors and influence on mitochondrial processes (isolated rat liver mitochondria), and in in-vivo tests to assess the influence on behavioural effects caused by the GABA-A receptor ligands, bicuculline, diazepam and ethanol.. Unlike taurine, tauropyrone did not display binding activity for the GABA-A receptor, and only taurine (but not tauropyrone) at low doses (0.1, 1.0 and 10 mg/kg) antagonised the bicuculline-induced convulsion effect. Taurine and tauropyrone had no effect on diazepam myorelaxing action, and they both exerted a comparable 'anti-ethanol' effect (shortening of the ethanol-sleeping time). Taurine and tauropyrone did not influence processes of mitochondrial bioenergetics.. The action of tauropyrone at the level of the GABA-A receptor differs qualitatively from that of taurine, probably because of its 1,4-dihydropyridine moiety, which may hinder access to the GABA-A receptor GABA site. Tauropyrone does not show improved pharmacological efficacy in in-vitro and in-vivo studies in comparison with taurine.

Topics: Animals; Behavior, Animal; Bicuculline; Diazepam; Dihydropyridines; Energy Metabolism; Ethanol; Hydrophobic and Hydrophilic Interactions; Male; Mice; Mice, Inbred ICR; Mitochondria; Motor Activity; Muscle Tonus; Protein Binding; Rats; Rats, Wistar; Receptors, GABA-A; Rotarod Performance Test; Seizures; Structure-Activity Relationship; Taurine

A group of alkyl, cycloalkyl and aryl ester analogs of nifedipine, in which the o-nitrophenyl group at position 4 is replaced by a 2-phenyl-4(5)-imidazolyl substituent, were synthesized and evaluated as calcium channel antagonist using the high K+ contraction of guinea-pig ileal longitudinal smooth muscle, and the activity of 5a-d, 8b and 8f against pentylenetetrazole (PTZ)-induced seizure was assessed. The results for symmetrical esters showed that lengthening of the methylene chain in C3 and C5 ester substituents increased activity. When increasing of the length is accompanied by increasing the hindrance, the activity decreased. In contrast to symmetrical derivatives, comparison of the activities of asymmetrical esters showed that increasing the length of the methylene chain was accompanied by a decrease in their activity. The results demonstrate that 8a was more active, and 5c and 8f were similar in effect to that of the reference drug nifedipine. The time-course of anticonvulsant effect on PTZ-induced seizure threshold of said compounds was assessed and showed that increasing the lipophilicity decreases the time needed for maximum effect. Mice treated with intraperitoneal injection of 25 mg/kg of these derivatives all exhibited increase seizure threshold as compared with control.

Topics: Animals; Calcium Channel Blockers; Calcium Channels; Dihydropyridines; Dose-Response Relationship, Drug; Guinea Pigs; Imidazoles; Lipids; Male; Mice; Pentylenetetrazole; Seizures

The purine nucleoside adenosine is released during seizure activity and exerts an anticonvulsant influence through inhibition of glutamate release and hyperpolarization of neurons via adenosine A(1) receptors. However, activation of adenosine A(2A) and A(3) receptors may counteract the inhibitory effects of A(1) receptors. We have therefore examined the extent to which endogenous adenosine released during seizure activity activates the different adenosine receptor subtypes and the implications for seizure activity in the rat hippocampus in vitro. Brief trains of high-frequency stimulation in nominally Mg(2+)-free artificial cerebrospinal fluid evoked epileptiform activity and resulted in a transient depression of the simultaneously recorded CA1 field excitatory postsynaptic potential. In the presence of 8-cyclopentyl-1,3-dimethylxanthine (CPT), an adenosine A(1) receptor antagonist, the occurrence of spontaneous seizure activity was greatly increased as was the duration and intensity of evoked seizures, whilst the postictal depression of basal synaptic transmission was greatly attenuated. Application of ZM 241385, an adenosine A(2A) receptor antagonist, shortened the duration of epileptiform activity, whereas administration of MRS 1191, an adenosine A(3) receptor antagonist, both decreased the duration and intensity of seizures. Combined application of the A(2A) and A(3) receptor antagonists also resulted in a reduction in seizure duration and intensity. However, no evidence was found for a role for protein kinase C in the regulation of seizure activity by endogenous adenosine. Our data confirm the dominant anticonvulsant role that endogenous and tonic adenosine play via the A(1) receptor, and suggest that the additional adenosine receptor subtypes may compromise this anticonvulsant property through promotion of seizure activity.

Topics: Adenosine; Animals; Animals, Newborn; Dihydropyridines; Dose-Response Relationship, Drug; Drug Interactions; Electric Stimulation; Enzyme Inhibitors; Excitatory Postsynaptic Potentials; Hippocampus; In Vitro Techniques; Indoles; Maleimides; Purinergic P1 Receptor Antagonists; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P1; Seizures; Theophylline; Time Factors; Triazines; Triazoles

The synthesis and pharmacological evaluation of novel 1-substituted-1,2-dihydro-pyridazine-3,6-diones (4a--l, 5a--j) as potential anticonvulsant agents are described. The compounds were tested in vivo for the anticonvulsant activity. The compound which have maximum protection against MES induced seizures is 1-[3-(2-aminophenylamino)-2-hydroxypropyl)-1,2-dihydro-pyridazine-3,6-dione 4h (ED(50)=44.7 mg x kg(-1) i.p.) 1-[2-hydroxy-3-piperazin1-yl-propyl)-1,2-dihydro-pyridazine-3,6-dione 4c (ED(50)=72 mg x kg(-1) i.p.) and 1-[2-hydroxy-3-imidazol-1-yl-propyl)-1,2-dihydro-pyridazine-3,6-dione 4d (ED(50)=79 mg x kg(-1) i.p.) were also found to have maximum protection against MES induced seizures. Whereas all these compounds failed to protect the animals from subcutaneous pentylenetetrazole (Metrozol) seizure threshold test (sc-Met).

Topics: Animals; Anticonvulsants; Dihydropyridines; Female; Male; Mice; Pyridazines; Seizures; Structure-Activity Relationship

Four dihydropyridine calcium channel antagonists were compared for their ability to protect against the hyperexcitability produced in mice by withdrawal from chronic ethanol treatment and to protect against seizures due to bicuculline or pentylenetetrazol. Comparison was also made of their effects on locomotor activity, body temperature and motor co-ordination, and with the corresponding effects of the benzodiazepine, diazepam. Nitrendipine, nimodipine, nicardipine (at 50 and 10 mg/kg) and isradipine (at 10 and 4 mg/kg) decreased the withdrawal hyperexcitability, but showed no anticonvulsant action against either bicuculline or pentylenetetrazol. Diazepam (1.5 and 4 mg/kg) both protected against the withdrawal signs and decreased seizure incidence after bicuculline and pentylenetetrazol, although the latter effects were of shorter duration than those on the withdrawal signs. The four dihydropyridines decreased spontaneous locomotor activity, an effect which lasted up to 6 h. Only isradipine and diazepam had any ataxic actions at the doses tested. All the dihydropyridines had hypothermic actions, considerably shorter in duration than effects on withdrawal hyperexcitability, with little evidence of dose dependence, except for nicardipine, which had a larger, dose-related, hypothermic action. Of the four compounds, isradipine was more potent in terms of dose, but not any more selective for effectiveness against the withdrawal signs, than the other three dihydropyridines, and nicardipine was slightly less effective in protecting against the withdrawal signs. The results indicate that the anticonvulsant effects of the dihydropyridines were selective for ethanol withdrawal hyperexcitability, whereas diazepam showed no such selectivity.

Topics: Animals; Anticonvulsants; Ataxia; Behavior, Animal; Bicuculline; Body Temperature; Calcium Channel Blockers; Central Nervous System Depressants; Convulsants; Dihydropyridines; Ethanol; GABA Antagonists; Hypnotics and Sedatives; Male; Mice; Motor Activity; Pentylenetetrazole; Seizures; Substance Withdrawal Syndrome

There is evidence that some calcium (Ca(2+)) channel inhibitors enhance the protective activity of antiepileptic drugs. Since clinical trials have not provided consistent data on this issue, the objective of this study was to evaluate the interaction of a dihydropyridine, niguldipine, with conventional antiepileptics in amygdala-kindled rats. Niguldipine (at 7.5 but not at 5 mg/kg) displayed a significant anticonvulsant effect, as regards seizure and afterdischarge durations in amygdala-kindled convulsions in rats, a model of complex partial seizures. No protective effect was observed when niguldipine (5 mg/kg) was combined with antiepileptics at subeffective doses, i.e. valproate (75 mg/kg), diphenylhydantoin (40 mg/kg), or clonazepam (0.003 mg/kg). Unexpectedly, the combined treatment of niguldipine (5 mg/kg) with carbamazepine (20 mg/kg) or phenobarbital (20 mg/kg) resulted in a proconvulsive action. BAY k-8644 (an L-type Ca(2+) channel activator) did not modify the protective activity of niguldipine (7.5 mg/kg) or the opposite action of this dihydropyridine (5 mg/kg) in combinations with carbamazepine or phenobarbital. A pharmacokinetic interaction is not probable since niguldipine did not affect the free plasma levels of the antiepileptics. These data indicate that the opposite actions of niguldipine alone or combined with carbamazepine (or phenobarbital) were not associated with Ca(2+) channel blockade. The present results may argue against the use of niguldipine as an adjuvant antiepileptic or for cardiovascular reasons in patients with complex partial seizures.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Amygdala; Animals; Anticonvulsants; Calcium Channel Agonists; Calcium Channel Blockers; Carbamazepine; Dihydropyridines; Drug Combinations; Injections, Intraperitoneal; Kindling, Neurologic; Male; Phenobarbital; Rats; Rats, Wistar; Seizures

Various studies have shown that stressful manipulations in rats and mice lower the convulsant potency of GABA-related, but also some GABA-unrelated convulsants. The mechanism of this anticonvulsive effect of stress is still unknown.. We tested the possible involvement of alpha2-adrenoceptors in the previously observed anticonvulsive effect of swim stress.. The mice were, prior to exposure to swim stress and the IV infusion of picrotoxin, pre-treated with clonidine (an alpha2-adrenoceptor agonist), yohimbine (a non-selective alpha2-adrenoceptor antagonist), idazoxan (a selective alpha2-adrenoceptor antagonist), or niguldipine (an alpha1-adrenoceptor antagonist), and the latency to the onset of two convulsant signs was registered.. In control unstressed animals clonidine (0.1 and 1 mg/kg IP), yohimbine (2 mg/kg IP) and idazoxan (1 mg/kg IP) failed to affect the doses of picrotoxin needed to produce convulsant signs, while niguldipine (5 mg/kg IP) prolonged the latency, i.e. it enhanced the doses of picrotoxin producing running/bouncing clonus and tonic hindlimb extension. In swim stressed mice clonidine enhanced, while idazoxan decreased doses of picrotoxin needed to produce two convulsive signs. Yohimbine decreased the dose of convulsant needed to produce tonic hindlimb extension, while niguldipine enhanced doses of picrotoxin needed to produce both symptoms.. The results demonstrate the alpha2-adrenoceptor agonist-induced potentiation and alpha2-adrenoceptor antagonist-induced diminution of the anticonvulsive effect of stress. Additionally, they show the anticonvulsive effect of niguldipine in unstressed and stressed animals. Hence, the results suggest that alpha2-adrenoceptors are involved in the anticonvulsive effect of swim stress in mice.

Topics: Adrenergic Agonists; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-2 Receptor Antagonists; Adrenergic Antagonists; Animals; Convulsants; Dihydropyridines; GABA-A Receptor Antagonists; Idazoxan; Infusions, Intravenous; Injections, Intraperitoneal; Male; Mice; Mice, Inbred CBA; Picrotoxin; Receptors, Adrenergic, alpha-2; Seizures; Stress, Physiological; Swimming

Pharmacological mechanisms involved in nicotine-induced seizures were investigated in mice by testing the ability of several nicotinic agonists in producing seizures after peripheral administration. In addition, nicotinic antagonists such as hexamethonium, mecamylamine, dihydro-beta-erythroidine, and methyllycaconitine citrate (MLA) were used in combination with nicotine. We also examined the involvement of calcium channels, N-methyl-D-aspartate receptors, and nitric oxide formation in nicotine-induced seizures. Our results showed that the peripheral administration of nicotine produced seizures in a stereospecific and mecamylamine-sensitive manner. Nicotine-induced seizures are centrally mediated and involve the activation of alpha7 along with other nicotinic receptor subunits. Indeed, MLA, an alpha7-antagonist, blocked the effects of nicotine after peripheral and central administration. The extent of alpha4beta2-receptor subtype involvement in nicotine-induced seizures was difficult to assess. On one hand, we observed that dihydro-beta-erythroidine (a competitive antagonist) failed to block the effects of nicotine. In addition, a poor correlation was found between binding affinity for (3)H-nicotine-labeled sites (predominantly alpha4beta2) and seizures potency for several nicotinic agonists. On the other hand, mecamylamine, a noncompetitive antagonist, blocked nicotine-induced seizures more potently than MLA. Furthermore, its potency in blocking seizures was in the same general dose range of other nicotinic effects that are not alpha7 mediated. These results suggest that this receptor subtype does not play a major role in nicotine-induced seizures. Our findings also suggest that nicotine enhances the release of glutamate either directly or indirectly (membrane depolarization that opens L-type calcium channels). Glutamate release in turn stimulates N-methyl-D-aspartate receptors, thus triggering the cascade of events leading to nitric oxide formation and possibly seizure production.

Topics: Animals; Anticonvulsants; Brain Chemistry; Calcium Signaling; Dihydropyridines; Glutamic Acid; Injections, Intraventricular; Injections, Subcutaneous; Male; Mice; Mice, Inbred ICR; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Nitric Oxide; Receptors, N-Methyl-D-Aspartate; Receptors, Nicotinic; Seizures

In animal models of epilepsy, calcium entry blockers have shown anticonvulsant properties. We studied the antiepileptic effects of nimodipine and two novel dihydropyridines, a calcium antagonist (PCA 50922) and a calcium agonist (PCA 50941), on pentylenetetrazole seizure and maximal electroshock seizure (MES) in mice. Anticonvulsant profile of nimodipine and PCA 50922 was similar to that of clonazepam, but markedly different from that of phenytoin. None of the doses of the PCA 50941 showed anticonvulsant effect.

Topics: Animals; Anticonvulsants; Calcium Channel Agonists; Calcium Channel Blockers; Clonazepam; Dihydropyridines; Electroshock; Female; Male; Mice; Mice, Inbred Strains; Nimodipine; Pentylenetetrazole; Phenytoin; Seizures; Thiazoles

We report the effects of two new dihydropyridine derivatives, isradipine (4-(4'-benzofurazanyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedic arboxylic acid methylisopropylester) and niguldipine (1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinecarboxylic acid 3-(4,4-diphenyl-1-piperidinyl)-propyl methyl ester hydrochloride), and of dantrolene (1-[(5-[p-nitrophenyl]furfurylidene)-amino]hydantoin sodium, an inhibitor of Ca2+ release from intracellular stores) on the protective efficacy of antiepileptic drugs against maximal electroshock-induced seizures. It was shown that dantrolene (5-20 mg/kg), isradipine (5-10 mg/kg) and niguldipine (up to 2.5 mg/kg) did not influence the electroconvulsive threshold in mice, although a higher dose of niguldipine (5 mg/kg) significantly elevated it. Dantrolene (10-20 mg/kg) and isradipine (1 mg/kg) did not affect the anticonvulsive activity of conventional antiepileptic drugs. In contrast, niguldipine (2.5-5 mg/kg) impaired the protective action of carbamazepine and phenobarbital. No effect of niguldipine (2.5-5 mg/kg) was observed upon the anticonvulsive efficacy of diphenylhydantoin and valproate. BAY k-8644 (methyl-1,4-dihydro-2,6-dimethyl-5-nitro-4- [(2-trifluoromethyl)-phenyl]-pyridine-5-carboxylate, an L-type Ca2+ channel agonist) did not reverse the action of niguldipine alone or the niguldipine-induced impairment of the anticonvulsive action of carbamazepine and phenobarbital. Niguldipine did not influence the free plasma levels of carbamazepine and phenobarbital, so a pharmacokinetic interaction is not probable. The results suggest that in contrast to the anticonvulsive activity of niguldipine against electroconvulsions, this Ca2+ channel inhibitor significantly weakened the protective action of both carbamazepine and phenobarbital. These effects do not seem to result from the blockade of voltage-dependent Ca2+ channels. Isradipine and dantrolene did not have a modulatory action on the threshold for electroconvulsions or on the anticonvulsive activity of antiepileptic drugs. It may be concluded that the use of niguldipine, isradipine, and dantrolene in epileptic patients seems questionable.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Animals; Anticonvulsants; Calcium Channel Agonists; Calcium Channel Blockers; Carbamazepine; Dantrolene; Dihydropyridines; Disease Models, Animal; Drug Interactions; Electroshock; Epilepsy; Female; Isradipine; Lethal Dose 50; Mice; Motor Activity; Phenobarbital; Phenytoin; Random Allocation; Seizures; Valproic Acid

S-312, S-312-d, but not S-312-l, L-type calcium channel antagonists, showed anticonvulsant effects on the audiogenic tonic convulsions in DBA/2 mice; and their ED50 values were 18.4 (12.8-27.1) mg/kg, p.o. and 15.0 (10.2-23.7) mg/kg, p.o., respectively, while that of flunarizine was 34.0 (26.0-44.8) mg/kg, p.o. Although moderate anticonvulsant effects of S-312-d in higher doses were observed against the clonic convulsions induced by pentylenetetrazole (85 mg/kg, s.c.) or bemegride (40 mg/kg, s.c.), no effects were observed in convulsions induced by N-methyl-D-aspartate, picrotoxin, or electroshock in Slc:ddY mice. S-312-d may be useful in the therapy of certain types of human epilepsy.

Topics: Administration, Oral; Animals; Anticonvulsants; Bemegride; Calcium Channel Blockers; Dihydropyridines; Disease Models, Animal; Electroshock; Female; Injections, Subcutaneous; Male; Mice; Mice, Inbred DBA; N-Methylaspartate; Pentylenetetrazole; Picrotoxin; Seizures

We have shown previously that the dihydropyridine calcium channel antagonist nitrendipine, given chronically, prevents the development of ethanol tolerance and physical dependence. The present study examines the effects on barbiturate tolerance and physical dependence. Nitrendipine, given acutely during withdrawal, provided little protection against barbiturate withdrawal, as measured by convulsive behaviour on handling. When nitrendipine was given chronically concurrently with the barbiturate, a prolonged protection against the withdrawal syndrome was seen. Acute nitrendipine significantly increased the latency of seizures in response to the partial benzodiazepine inverse agonist FG7142 during barbiturate withdrawal, but there was no effect on the seizure incidence in response to bicuculline. Chronic treatment with nitrendipine did not alter the development of tolerance to the ataxic or general anaesthetic actions of barbiturates, but evidence was found of a possible interaction between nitrendipine and pentobarbitone, which may have been pharmacokinetic. The results suggest that neuronal calcium channels may be involved to some degree in the development of the changes responsible for barbiturate withdrawal, but to a less extent than found previously for ethanol dependence.

Topics: Anesthesia, General; Animals; Ataxia; Barbiturates; Bicuculline; Calcium Channels; Carbolines; Dihydropyridines; Drug Tolerance; Male; Mice; Mice, Inbred Strains; Nitrendipine; Pentobarbital; Seizures; Substance Withdrawal Syndrome

The experiments on focal penicillin-induced epileptic activity in the brain cortex (Wistar rats) and bicuculline- and thiosemicarbazide-induced seizures (Icr:Icl mice) showed that the glutapyrone possessed a significant antiepileptic activity. As previously shown, that glutapyrone has an influence on 45Ca2+ uptake by rat cortical synaptosomes (evoked by K+ depolarization) as compared with nifedipine and nimodipine, and it was effective in pentylenetetrazol-induced seizures in rats and mice. The mechanism of action of convulsants is associated with the disturbance of different links of GABAergic inhibition. It is suggested that the antiepileptic effects of glutapyrone are realized at least in part by the participation of GABAergic system.

Topics: Animals; Anticonvulsants; Bicuculline; Convulsants; Dihydropyridines; Disease Models, Animal; Drug Evaluation, Preclinical; Epilepsies, Partial; Glutamates; Male; Mice; Mice, Inbred ICR; Penicillins; Rats; Rats, Wistar; Seizures; Semicarbazides

1. Chronic treatment with the dihydropyridine calcium channel antagonist, nitrendipine, given concurrently with ethanol, prevented the ethanol withdrawal syndrome in mice, even though the chronic nitrendipine treatment was stopped 24 h or 48 h before the withdrawal testing. 2. This effect was seen in two strains of mice with different methods of ethanol administration. Nitrendipine was effective when given for two weeks but not after only two days' treatment. 3. Two other dihydropyridine calcium antagonists, nimodipine and PN 200-110, given chronically with ethanol, also prevented the withdrawal syndrome. The tests were again made 24 h after the last administration of dihydropyridine. 4. The chronic nitrendipine treatment also prevented the rise in the number of central dihydropyridine binding sites that occurs on chronic ethanol administration. 5. Chronic administration of nitrendipine alone did not cause any withdrawal behaviour. 6. Chronic nitrendipine treatment did not affect the seizure threshold to bicuculline in mice that were not given ethanol. 7. Whole brain concentration measurements showed that the effects were not due to residual nitrendipine in the CNS at the time of withdrawal testing or to differences in central ethanol concentrations during the treatment. 8. It is suggested that the results provide evidence for a functional role for dihydropyridine-sensitive calcium channels in ethanol dependence.

Topics: Adaptation, Psychological; Administration, Inhalation; Animals; Behavior, Animal; Bicuculline; Brain; Calcium Channel Blockers; Dihydropyridines; Dose-Response Relationship, Drug; Ethanol; Isradipine; Male; Mice; Mice, Inbred C57BL; Nimodipine; Nitrendipine; Seizures; Substance Withdrawal Syndrome

The effects of low doses of dihydropyridine (DHP) calcium channel antagonists nimodipine, nifedipine, (-)-R-202-791, and amlodipine, the DHP calcium channel agonist BAY K 8644 were investigated on clonic convulsions to pentylenetetrazole (PTZ) in mice. Nimodipine (2-20 mg/kg) produced a dose-dependent increase in the onset time for convulsions, but did not decrease the number of mice convulsing. Nifedipine, amlodipine (10 mg/kg) and BAY K 8644 (2 mg/kg) also produced an increase in the onset time for convulsions. (-)-R-202-791 (10 mg/kg) was without effect on clonic convulsions to PTZ. BAY K 8644 increased the number of mice dying from tonic-extension convulsions to PTZ. Nimodipine did not affect convulsions elicited by strychnine. Thus, low doses of DHP calcium antagonists possess anticonvulsant properties which are structurally dependent, while DHP calcium channel activators may act to promote convulsions. These observations suggest and support previous evidence that DHP receptors are important modulatory sites for the convulsive state.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Amlodipine; Animals; Anticonvulsants; Calcium Channel Agonists; Calcium Channel Blockers; Dihydropyridines; Male; Mice; Nifedipine; Nimodipine; Seizures

Experiments utilising rodents in vivo and cultures of adrenal cells in vitro have suggested that genetic regulation of dihydropyridine-sensitive calcium channels may be involved in dependence on alcohol. Selection of mouse lines for either a very severe ethanol-withdrawal syndrome (withdrawal seizure prone) or a very mild syndrome (withdrawal seizure resistant), has produced lines which differ very markedly in these characteristics. In these experiments, mice bred selectively for these symptoms for 26 generations, were compared for the severity of withdrawal from alcohol after inhalation of ethanol (plus injections of pyrazole) for 3 days. A proportion of animals from each line was killed before withdrawal and membranes from whole brain were analysed by radioligand binding for binding sites for [3H] nitrendipine. Mice which were withdrawal seizure prone showed a markedly greater severity of the ethanol-withdrawal syndrome, and also showed a significantly greater up-regulation of binding sites for [3H]nitrendipine with no significant difference in binding affinity. The results suggest a relationship between genetic susceptibility to dependence on alcohol and genetic regulation of neuronal calcium channels in brain.

Topics: Alcoholism; Animals; Brain Chemistry; Calcium Channel Blockers; Calcium Channels; Dihydropyridines; Ethanol; Female; Gene Expression Regulation; Kinetics; Mice; Nitrendipine; Seizures; Substance Withdrawal Syndrome; Up-Regulation

Mice withdrawn from exposure for 14 days to ethanol inhalation showed the expected signs of ethanol withdrawal including convulsive behaviour. Injection of chlormethiazole (100 mg/kg) 5 h after the start of withdrawal, at the time that the convulsive behaviour was near maximal, resulted in the virtual disappearance of the withdrawal-induced behaviour within 30 min, with its reappearance by 60 min. A dose of chlormethiazole of 40 mg/kg was without effect. The time course of the effect of chlormethiazole (100 mg/kg) in the withdrawal test was similar to its effect in raising seizure threshold and decreasing locomotor activity. Chlormethiazole did not alter in vitro binding of [3H]-PN 200-110 to the dihydropyridine sensitive Ca2+ channel. Chlormethiazole, a drug used clinically to treat ethanol withdrawal, has therefore been shown to be effective in this animal model of withdrawal. Dihydropyridine calcium antagonists are also active in the model but chlormethiazole is likely to work by a different mechanism and it is suggested that this may be by increasing GABAergic function.

Topics: Animals; Calcium Channels; Chlormethiazole; Dihydropyridines; Ethanol; Isradipine; Male; Mice; Motor Activity; Oxadiazoles; Seizures; Substance Withdrawal Syndrome

By using a rat seizure model, a comparison of the antiseizure activity of 12 dihydropyridine calcium channel antagonists (administered i.c.v.) to their binding affinities for the neuronal site known to regulate L-type calcium channels was made. For these dihydropyridine calcium channel antagonists a correlation between physiologic activity and binding affinities would provide evidence that these agents exert their antiseizure actions via a mechanism involving a binding site that regulates L-type neuronal calcium channels. Despite i.c.v. administration, a parallel in antiseizure activity and binding affinities could not be demonstrated precisely, suggesting that the dihydropyridines may be exerting their antiseizure activity by more than just simple neuronal calcium channel blockade.

Topics: Animals; Calcium Channel Agonists; Dihydropyridines; Electroencephalography; Injections, Intraventricular; Male; Pentylenetetrazole; Rats; Rats, Inbred Strains; Seizures; Structure-Activity Relationship