Anticonvulsant effects of some calcium entry blockers in DBA/2 mice

1. The behavioural and anticonvulsant effects of several drugs acting by various mechanisms on calcium-channels or affecting intracellular Ca2+ concentrations were studied after both systemic and intracerebroventricular administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures. 2. The anticonvulsant effects were evaluated on seizures evoked by means of auditory stimulation (109 dB) in animals placed singly under a perspex dome. 3. Flunarizine and dihydropyridine derivatives, belonging to class I of calcium entry blockers, administered intraperitoneally, were the most potent compounds. 4. Diltiazem, a benzothiazepine derivative belonging to class III, and HA 1004, a calcium antagonist, acting by inhibiting Ca2+ mobilization from intracellular stores, injected intraperitoneally, were 3-7.6 fold and 5.8-10.7 fold less potent than flunarizine respectively. 5. Verapamil and methoxyverapamil, two phenylalkylamine derivatives, given intraperitoneally, were completely ineffective in preventing sound-induced seizures in DBA/2 mice. In addition, high doses of verapamil and its methoxyderivative occasionally produced spontaneous tonic-clonic seizures. 6. After intracerebroventricular administration of the hydrosoluble calcium entry blockers, belonging to different classes, the anticonvulsant effects were similar to those observed after systemic administration. 7. The systemic administration of Bay K 8644, a dihydropyridine analogue, having the ability to stimulate calcium entry into cells produced a dose-dependent increase in clonic and tonic convulsions and other neurological side effects. 8. The present results strongly support the idea that some Ca2+ antagonists may be useful in human epilepsy.