Finasteride, a 5α-reductase inhibitor, blocks the anticonvulsant activity of progesterone in mice

Tushar G. Kokate, Melissa K. Banks, Tamika Magee, Shun Ichi Yamaguchi, Michael A Rogawski

Research output: Contribution to journalArticle

152 Scopus citations

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 acid(A) 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 x 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.

Original languageEnglish (US)
Pages (from-to)679-684
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Volume288
Issue number2
StatePublished - Feb 1999
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology

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