TY - JOUR
T1 - Finasteride, a 5α-reductase inhibitor, blocks the anticonvulsant activity of progesterone in mice
AU - Kokate, Tushar G.
AU - Banks, Melissa K.
AU - Magee, Tamika
AU - Yamaguchi, Shun Ichi
AU - Rogawski, Michael A
PY - 1999/2
Y1 - 1999/2
N2 - 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.
AB - 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.
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M3 - Article
C2 - 9918575
AN - SCOPUS:0032590065
VL - 288
SP - 679
EP - 684
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
SN - 0022-3565
IS - 2
ER -