Ganaxolone suppression of behavioral and electrographic seizures in the mouse amygdala kindling model.
Ganaxolone (3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one), a synthetic analog of the endogenous neurosteroid allopregnanolone and a positive allosteric modulator of GABAA receptors, may represent a new treatment approach for epilepsy. Here we demonstrate that pretreatment with ganaxolone (1.25-20 mg/kg, s.c.) causes a dose-dependent suppression of behavioral and electrographic seizures in fully amygdala-kindled female mice, with nearly complete seizure protection at the highest dose tested. The ED50 for suppression of behavioral seizures was 6.6 mg/kg. The seizure suppression produced by ganaxolone was comparable to that of clonazepam (ED50, 0.1 mg/kg, s.c.). To the extent that amygdala kindling represents a model of mesial temporal lobe epilepsy, this study supports the utility of ganaxolone in the treatment of patients with temporal lobe seizures.
Reddy
Doodipala S
DS
Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M System Health Science Center, College Station, TX 77843-1114, USA. reddy@medicine.tamhsc.edu
Rogawski
Michael A
MA
D000679:Amygdala / Q000187:drug effects / Q000503:physiopathology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D002998:Clonazepam / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004833:Epilepsy, Temporal Lobe / Q000503:physiopathology / Q000517:prevention & control*; D005260:Female; D007696:Kindling, Neurologic / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D011280:Pregnanolone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D012640:Seizures / Q000517:prevention & control*
D000927:Anticonvulsants; D002998:Clonazepam; C105051:ganaxolone; D011280:Pregnanolone