Nifedipine affects the anticonvulsant activity of topiramate in various animal models of epilepsy

Abstract

Topiramate (TPM), a new generation antiepileptic drug was investigated for its anticonvulsant effects in various models of genetically determined and chemically induced epilepsy in rodents. In addition, based on recent electrophysiological data suggesting that TPM may interact with L-type Ca 2+ channels, we evaluated the effects of a concomitant administration of L-type Ca 2+ channel modulators on TPM’s antiepileptic properties. TPM, dose-dependently, protected against audiogenic seizures in DBA/2 mice. Concomitant treatment with TPM and a low dose of L-type Ca 2+ channel antagonists nifedipine or verapamil or with the L-type Ca 2+ channel agonist, S(−)-1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-3-pyridinecarboxylic acid methyl ester (Bay k 8644) was able to increase the ED 50 for this drug. TPM also protected against seizures induced by α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), 4-aminopyridine (4-AP) and pentylenetetrazole (PTZ), but this activity was not significantly modified by nifedipine. TPM, dose-dependently, reduced the number and duration of epileptic spike-wave discharges (SWDs) both in WAG/Rij rats and lethargic ( lh/ lh) mice, two genetic models of absence epilepsy. Nifedipine decreased TPM’s activity in WAG/Rij rats but paradoxically enhanced it in lh/ lh mice, whereas Bay k 8644 displayed opposite effects in both absence models. These results confirm TPM’s broad spectrum of anticonvulsant activity and support the proposal that a modulation of neuronal L-type Ca 2+ channel activity plays an important role in its antiepileptic activity.