Abstract
Progesterone is an effective anticonvulsant against pentylenetetrazol (PTZ) seizures. This action is hypothesized to require the metabolic conversion of progesterone to the γ-aminobutyric acidA receptor potentiating neuroactive steroid allopregnanolone by 5α-reductase isoenzymes followed by 3α-hydroxy oxidoreduction. We evaluated this possibility using the competitive 5α-reductase inhibitor finasteride. Progesterone (50–200 mg/kg, i.p.) protected mice against PTZ-induced seizures in a dose-dependent manner (ED50, 94 mg/kg). Pretreatment with finasteride (50–300 mg/kg, i.p.) produced a dose-dependent (ED50, 146 mg/kg) reversal of the protective effects of progesterone (2 × ED50 dose = 188 mg/kg). In contrast, finasteride (up to 300 mg/kg) failed to affect the anticonvulsant activity of allopregnanolone (10–30 mg/kg, i.p.; ED50, 12 mg/kg). Finasteride (up to 300 mg/kg) did not block the protective effect of high doses of progesterone (250–350 mg/kg) on tonic hindlimb extension in the maximal electroshock seizure test (progesterone ED50, 235 mg/kg). The anticonvulsant activity of progesterone against PTZ-induced seizures can be blocked by 5α-reductase inhibition, providing strong evidence that the anticonvulsant effect of the steroid in this model is mediated by its active metabolite allopregnanolone.
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, Building 10, Room 5N-250, 10 Center Dr. MSC 1408, Bethesda, MD 20892-1408. E-mail: rogawski{at}nih.gov
- Abbreviations:
- PTZ
- pentylenetetrazol
- MES
- maximal electroshock
- DOC
- deoxycorticosterone
- Received May 27, 1998.
- Accepted September 11, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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