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 × 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.