Finasteride, a 5alpha-reductase inhibitor, blocks the anticonvulsant
activity of progesterone in mice
FULL TEXT:
jpet.aspetjournals.org/cgi/conte … /288/2/679
ABSTRACT:
Progesterone is an effective anticonvulsant against pentylenetetrazol (PTZ) seizures.
This action is hypothesized to require the metabolic conversion of progesterone to the -aminobutyric acidA receptor potentiating neuroactive steroid allopregnanolone by 5-reductase isoenzymes followed by 3-hydroxy oxidoreduction.
We evaluated this possibility using the competitive 5-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 5-reductase inhibition, providing strong evidence that the anticonvulsant effect of the steroid in this model is mediated by its active metabolite allopregnanolone.