Aromatase inhibition by letrozole attenuates kainic acid-induced seizures but not neurotoxicity in mice

Evidence shows neurosteroids play a key role in regulating epileptogenesis. Neurosteroids such as testosterone modulate seizure susceptibility through its transformation to metabolites which show proconvulsant and anticonvulsant effects, respectively. Reduction of testosterone by aromatase generates proconvulsant 17-beta estradiol. Alternatively, testosterone is metabolized into 5 alpha-dihydrotestosterone (5 alpha-DHT) by 5 alpha-reductase, which is then reduced by 3 alpha-hydroxysteroid oxidoreductase enzyme (3 alpha-HSOR) to form anticonvulsant metabolite 3 alpha-androstanediol (3 alpha-Diol), a potent GABA(A) receptor modulating neurosteroid. The present study evaluated whether inhibition of aromatase inhibitor letrozole protects against seizures and neuronal degeneration induced by kainic acid (KA) (10 mg/kg, i.p.) in Swiss albino mice. Letrozole (1 mg/kg, i.p.) administered one hour prior to KA significantly increased the onset time of seizures and reduced the% incidence of seizures. Pretreatment with finasteride, a selective inhibitor of 5 alpha-reductase and indomethacin, a selective inhibitor of 3 alpha-hydroxysteroid oxidoreductase enzyme (3 alpha-HSOR), reversed the protective effects of letrozole in KA-induced seizures in mice. Microscopic examination using cresyl violet staining revealed that letrozole did not modify KA-induced neurotoxicity in the CA1, CA3 and DG region of the hippocampus. Letrozole treatment resulted in the reduced levels of 17-beta estradiol and elevated the levels of 5 alpha-dihydrotestosterone (DHT) and 3 alpha-Diol in the hippo.: campus. Finasteride and indomethacin attenuated letrozole-induced elevations of 5 alpha-DHT and 3 alpha-Diol. Our results indicate the potential anticonvulsant effects of letrozole against KA-induced seizures in mice that might be mediated by inhibiting aromatization of testosterone to 17 beta-estradiol, a proconvulsant hormone and by redirecting the synthesis to anticonvulsant metabolites, 5 alpha-DHT and 3 alpha-Diol. Acute aromatase inhibition, thus, might be used as an adjuvant in the treatment of status epilepticus and can be pursued further.