Abstract
Perimenstrual catamenial epilepsy, the exacerbation of seizures in association with menstruation, may in part be due to withdrawal of the progesterone metabolite allopregnanolone (3α-hydroxy-5α-pregnan-20-one), an endogenous anticonvulsant neurosteroid that is a positive allosteric modulator of γ-aminobutyric acidA 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 (3α-hydroxy-3β-methyl-5α-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serum progesterone (pseudopregnancy) was induced in 26-day-old female rats with gonadotropins, and neurosteroids were withdrawn on postnatal day 39 with finasteride, a 5α-reductase inhibitor that blocks the conversion of progesterone to allopregnanolone.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susceptibility, there was a 3-fold increase in the anticonvulsant potency of ganaxolone (control ED50 = 3.5 mg/kg; withdrawn = 1.2 mg/kg) without a change in the potency for induction of motor toxicity in the rotarod test. The plasma concentrations of ganaxolone did not differ significantly in control and withdrawn animals; the estimated plasma concentrations of ganaxolone producing 50% seizure protection were ∼500 and ∼225 ng/ml in control and withdrawn rats, respectively.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withdrawal was associated with a decrease in the anticonvulsant potency of diazepam (control ED50 = 1.9 mg/kg; withdrawn = 4.1 mg/kg) and valproate (control ED50 = 279 mg/kg; withdrawn = 460 mg/kg).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.
Footnotes
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Send reprint requests to: Michael A. Rogawski, M.D., Ph.D., National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Dr., Room 5N-250, MSC 1408, Bethesda, MD 20892-1408. E-mail: rogawski{at}nih.gov
- Abbreviations:
- GABA
- γ-aminobutyric acid
- PTZ
- pentylenetetrazol
- CL
- confidence limits
- Received December 21, 1999.
- Accepted May 8, 2000.
- U.S. Government
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