The anticonvulsant effects of progesterone, its metabolites, and 5alpha-dihydroprogesterone novel analogs in amygdala-kindled seizures in rats.

摘要

Introduction: Complex partial epilepsy is the most common type of drug-resistant epilepsy in adults. The present study was designed to test the anticonvulsant activity of 5alpha-dihydroprogesterone (5alpha-DHP) novel analogs in an animal model of human complex partial epilepsy -- the rat amygdala-kindling model.;Methods: Confirmatory replication studies were carried out on progesterone and its metabolites. Subsequently, nine 5alpha-DHP novel analogs were screened for anticonvulsant potential. Finally, emerging lead compounds, MC008 and MC009, were examined in dose-response studies, time-response studies, and Loscher's ataxia toxicity studies.;Results: Progesterone and its metabolites were generally anticonvulsant. Analogs MC008 and MC009 were effective against both the focal and the generalized kindled seizures. Toxic side-effects (ataxia), however, accompanied focal seizure suppression.;Conclusion: MC008 and MC009 do not seem to be ideal candidates for the treating human complex partial seizures due to potential toxicity. Other 5alpha-DHP analogs have been synthesized and will be tested in future experiments.