Enhanced anticonvulsant activity of ganaxolone after neurosteroid withdrawal in a rat model of catamenial epilepsy.
Perimenstrual catamenial epilepsy, the exacerbation of seizures in association with menstruation, may in part be due to withdrawal of the progesterone metabolite allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one), an endogenous anticonvulsant neurosteroid that is a positive allosteric modulator of gamma-aminobutyric acid(A) receptors. Neurosteroid replacement is a potential approach to therapy, but natural neurosteroids have poor bioavailability and may be converted to metabolites with undesired progestational activity. The synthetic neuroactive steroid ganaxolone (3alpha-hydroxy-3beta-methyl-5alpha-pregnane-20-one) is an orally active analog of allopregnanolone that is not converted to the hormonally active 3-keto form. To assess the potential of ganaxolone in the treatment of catamenial seizure exacerbations, a state of persistently high serum progesterone (pseudopregnancy) was induced in 26-day-old female rats with gonadotropins, and neurosteroids were withdrawn on postnatal day 39 with finasteride, a 5alpha-reductase inhibitor that blocks the conversion of progesterone to allopregnanolone. Finasteride treatment during pseudopregnancy results in a reduction in the threshold for pentylenetetrazol seizures. During this state of enhanced seizure susceptibility, there was a 3-fold increase in the anticonvulsant potency of ganaxolone (control ED(50) = 3.5 mg/kg; withdrawn = 1.2 mg/kg) without a change in the potency for induction of motor toxicity in the rotarod test. The plasma concentrations of ganaxolone did not differ significantly in control and withdrawn animals; the estimated plasma concentrations of ganaxolone producing 50% seizure protection were approximately 500 and approximately 225 ng/ml in control and withdrawn rats, respectively. Unlike ganaxolone, neurosteroid withdrawal was associated with a decrease in the anticonvulsant potency of diazepam (control ED(50) = 1.9 mg/kg; withdrawn = 4.1 mg/kg) and valproate (control ED(50) = 279 mg/kg; withdrawn = 460 mg/kg). The enhanced anticonvulsant potency of ganaxolone after neurosteroid withdrawal supports the use of ganaxolone as a specific treatment for perimenstrual catamenial epilepsy.
Reddy
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DS
Neuronal Excitability Section, Epilepsy Research Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-1408, USA.
Rogawski
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MA
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000633:toxicity; D003292:Convulsants; D003975:Diazepam / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004827:Epilepsy / Q000188:drug therapy* / Q000503:physiopathology; D005260:Female; D018120:Finasteride / Q000494:pharmacology; D008598:Menstruation; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D010433:Pentylenetetrazole; D011280:Pregnanolone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D011555:Pseudopregnancy / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D013256:Steroids / Q000037:antagonists & inhibitors*; D014635:Valproic Acid / Q000494:pharmacology
D000927:Anticonvulsants; D003292:Convulsants; D004791:Enzyme Inhibitors; D013256:Steroids; D018120:Finasteride; D014635:Valproic Acid; C105051:ganaxolone; D011280:Pregnanolone; D010088:Oxidoreductases; C022447:3-oxo-5-alpha-steroid 4-dehydrogenase (NADP(+)); D003975:Diazepam; D010433:Pentylenetetrazole