Neurosteroids and epilepsy

Abstract

Neurosteroids are a family of compounds synthesized directly in the brain by transforming cholesterol into pregnenolone, which is then converted to compounds such as allopregnanolone and allotetrahydrodeoxycorticosterone. In view of their ability to modulate neurotransmission, neurosteroids may influence the clinical course of epileptic disorders. In this review, we highlight two emerging properties of neurosteroids, that is, their anticonvulsant and antiepileptogenic activities. It has been shown that fluctuations in neurosteroid synthesis, such as those seen in response to stress or during the ovarian cycle, determine an increase in seizure threshold. Moreover, increased neurosteroid synthesis, presumably occurring in glial cells during epileptogenesis, delays the appearance of recurrent spontaneous seizures in an animal model of temporal lobe epilepsy; such an effect may be due to augmented tonic gamma-aminobutyric acid type A receptor-mediated inhibition. Finally, clinical trials with ganaxolone, an allopregnanolone analogue, have demonstrated beneficial effects in pharmacoresistant epileptic patients, whereas finasteride--which interferes with neurosteroid synthesis - facilitates seizures in catamenial epilepsy. The overall evidence suggests that neurosteroids may represent a novel therapeutic strategy in epileptic disorders and a future perspective to control epileptogenicity.