Neurosteroid withdrawal model of perimenstrual catamenial epilepsy.
OBJECTIVE
Perimenstrual catamenial epilepsy, the increase in seizure frequency that some women with epilepsy experience near the time of menstruation, may in part be related to withdrawal of the progesterone metabolite allopregnanolone, an endogenous anticonvulsant neurosteroid that is a potent positive allosteric gamma-aminobutyric acidA (GABA(A)) receptor modulator. The objective of this study was to develop an animal model of perimenstrual catamenial 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 mares' serum gonadotropin and human chorionic gonadotropin. Neurosteroid withdrawal was induced by treatment with finasteride (100 mg/kg, i.p.), a 5alpha-reductase inhibitor that blocks the conversion of progesterone to allopregnanolone. Plasma progesterone and allopregnanolone levels were measured by gas chromatography/electron capture negative chemical ionization mass spectrometry. Seizure susceptibility was evaluated with the convulsant pentylenetetrazol (PTZ).


RESULTS
Plasma allopregnanolone levels were markedly increased during pseudopregnancy (peak level, 55.1 vs. control diestrous level, 9.3 ng/mL) and were reduced by 86% 24 h after finasteride treatment (6.4 ng/mL). Progesterone levels were unaffected by finasteride. After finasteride-induced withdrawal, rats showed increased susceptibility to PTZ seizures. There was a significant increase in the number of animals exhibiting clonic seizures when challenged with subcutaneous PTZ (60 mg/kg) compared with control pseudopregnant animals not undergoing withdrawal and nonpseudopregnant diestrous females. 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. The threshold doses for induction of various seizure signs, measured by constant intravenous infusion of PTZ, were reduced by 30-35% in neurosteroid-withdrawing animals compared with control diestrous females. No change in threshold was observed in pseudopregnant rats treated from days 7 to 11 with finasteride, demonstrating that high levels of progesterone alone do not alter seizure reactivity.


CONCLUSIONS
Neurosteroid withdrawal in pseudopregnant rats results in enhanced seizure susceptibility, providing an animal model of perimenstrual catamenial epilepsy that can be used for the evaluation of new therapeutic approaches.
Reddy
D S
DS
Epilepsy Research Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Rockville, Maryland 20892-1408, USA.
Kim
H Y
HY
Rogawski
M A
MA
D004092:20-alpha-Dihydroprogesterone / Q000009:adverse effects / Q000494:pharmacology; D000328:Adult; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000097:blood / Q000453:epidemiology; D004827:Epilepsy / Q000097:blood / Q000175:diagnosis / Q000453:epidemiology*; D005260:Female; D018120:Finasteride / Q000494:pharmacology; D006064:Gonadotropins, Equine / Q000097:blood / Q000494:pharmacology; D006801:Humans; D008597:Menstrual Cycle / Q000502:physiology*; D010433:Pentylenetetrazole / Q000494:pharmacology; D011280:Pregnanolone / Q000097:blood / Q000494:pharmacology; D011374:Progesterone / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology; D011555:Pseudopregnancy / Q000097:blood / Q000139:chemically induced* / Q000453:epidemiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000097:blood / Q000187:drug effects; D013256:Steroids / Q000009:adverse effects* / Q000097:blood / Q000494:pharmacology; D013375:Substance Withdrawal Syndrome / Q000453:epidemiology* / Q000209:etiology
D006064:Gonadotropins, Equine; D018079:Receptors, GABA; D013256:Steroids; D004092:20-alpha-Dihydroprogesterone; D011374:Progesterone; D018120:Finasteride; D011280:Pregnanolone; D010433:Pentylenetetrazole