Ganaxolone, a selective, high-affinity steroid modulator of the gamma-aminobutyric acid-A receptor, exacerbates seizures in animal models of absence.
Ganaxolone (3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one) is a novel neurosteroid which has anticonvulsant properties in a number of seizure models as well as the ability to enhance function of the gamma-aminobutyric acid-A (GABA(A)) receptor complex via a neurosteroid binding site. The object of these experiments was to ascertain the efficacy of ganaxolone against absence seizures. Ganaxolone was assessed in the low-dose pentylenetetrazol (PTZ) and the gamma-hydroxybutyric acid (GHB) model of absence seizures in rats. Ganaxolone pretreatment resulted in a significant prolongation of absence seizure in both the PTZ and GHB models. Further, ganaxolone in doses above 20 mg/kg alone produced bilaterally synchronous spike wave discharges (SWDs) associated with behavioral arrest. These data suggest that augmentation of GABA(A) receptor complex function by neurosteroids has the potential to result in or exacerbate absence seizures.
Department of Pediatrics, Faculty of Medicine, University of Toronto, Hospital for Sick Children, Ontario, Canada.
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D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D003292:Convulsants; D004832:Epilepsy, Absence / Q000139:chemically induced / Q000503:physiopathology*; D018756:GABA Antagonists; D006885:Hydroxybutyrates; D008297:Male; D010433:Pentylenetetrazole; D011280:Pregnanolone / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects*
D000927:Anticonvulsants; D003292:Convulsants; D018756:GABA Antagonists; D006885:Hydroxybutyrates; D011963:Receptors, GABA-A; C111420:4-hydroxybutyric acid; C105051:ganaxolone; D011280:Pregnanolone; D010433:Pentylenetetrazole