[Perspectives of neurosteroid derivative application in antiepileptic therapy].
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.
Borowicz
Kinga K
KK
Katedra i Zakład Patofizjologii, Akademii Medycznej w Lublinie, Lublin. kinga.borowicz@am.lublin.pl
Czuczwar
Stanisław J
SJ
D000927:Anticonvulsants / Q000145:classification* / Q000627:therapeutic use*; D003900:Desoxycorticosterone / Q000378:metabolism; D004827:Epilepsy / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D011374:Progesterone / Q000378:metabolism
D000927:Anticonvulsants; D003900:Desoxycorticosterone; D011374:Progesterone