Both
steroid hormones and
neurosteroids affect seizure expression and propagation in the central nervous system (CNS).
Progesterone and allodeoxycorticosterone exhibit
anticonvulsant, while
estradiol and
cortisol present proconvulsant action. Effect of
testosterone on seizure phenomena depends on the metabolic route that this
androgen is involved in. Natural (
allopregnanolone) or synthetic (alphaxolone,
ganaxolone, Co 21068)
neuroactive steroids show protective effect against variety of experimental
seizures, including electrically-triggered convulsions, like maximal electroshock, electrical kindling, and chemically-evoked, like
pilocarpine-,
pentetrazole-,
picrotoxin-,
cocaine-,
bicuculline-,
kainate-, or
NMDA-induced ones. Influence of
neurosteroids on seizure processes results from their ability to modulate two basic
neurotransmitter systems, glutamatergic (mainly through
NMDA receptors) and
GABA-ergic (realized by GABAA receptors).
Neuroactive steroids devoid of hormonal activity, but they preserve the action on neuronal excitability. The
anticonvulsant efficacy of
allopregnanolone, one of the natural
neurosteroids, is greater than that of its hormonal precursor. However, a therapeutic application of natural
neuroactive steroids is significantly limited by their rapid biotransformation. Synthetic derivatives are orally-active and their half-life time is essentially longer. Therefore,
neurosteroids are good
drug candidates for both monotherapy and add-on treatment of
epilepsy. The best examined
neurosteroid, ganaksolone, is currently under phase II clinical investigation.