Neurosteroid withdrawal model of perimenstrual catamenial epilepsy

Purpose: Perimenstrual catamenial epilepsy, the increase in seizure frequen cy that some women with epilepsy experience near the time of menstruation. may in part be related to withdrawal of the progesterone metabolite allopre gnanolone, an endogenous anticonvulsant neurosteroid that is a potent posit ive allosteric gamma -aminobutyric acid, (GABA,) receptor modulator. The ob jective of this study was to develop an animal model of perimenstrual catam enial epilepsy for use in evaluating drug-treatment strategies. Methods: A state of prolonged high serum progesterone (pseudopregnancy) was induced in 26-day-old female rats by sequential injection of pregnant mare s' serum gonadotropin and human chorionic gonadotropin. Neurosteroid withdr awal was induced by treatment with finasteride (100 mg/kg, i.p.), a 5 alpha -reductase inhibitor that blocks the conversion of progesterone to allopre gnanolone. Plasma progesterone and allopregnanolone levels were measured by gas chromatography/electron capture negative chemical ionization mass spec trometry. Seizure susceptibility was evaluated with the convulsant pentylen etetrazol (PTZ). Results: Plasma allopregnanolene levels were markedly increased during pseu dopregnancy (peak level, 55.1 vs, control diestrous level, 9.3 ng/mL) and w ere reduced by 86% 24 h after finasteride treatment (6.4 ng/mL). Progestero ne levels were unaffected by finasteride. After finasteride-induced withdra wal, rats showed increased susceptibility to PTZ seizures. There was a sign ificant increase in the number of animals exhibiting clonic seizures when c hallenged with subcutaneous PTZ (60 mg/kg) compared with control pseudopreg nant animals not undergoing withdrawal and nonpseudopregnant diestrous fema les. The CD50 (50% convulsant dose) was 46 mg/kg, compared with 73 mg/kg in nonwithdrawn pseudopregnant animals and 60 mg/kg in diestrous controls. Th e threshold doses for induction of various seizure signs, measured by const ant intravenous infusion of PTZ, were reduced by 30-35% in neurosteroid-wit hdrawing animals compared with control diestrous females. No change in thre shold was observed in pseudopregnant rats treated from days 7 to 11 with fi nasteride, demonstrating that high levels of progesterone alone do not alte r seizure reactivity. Conclusions: Neurosteroid withdrawal in pseudopregnant rats results in enha nced seizure susceptibility, providing an animal model of perimenstrual cat amenial epilepsy that can be used for the evaluation of new therapeutic app roaches.