Enhanced anticonvulsant activity of neuroactive steroids in a rat model of catamenial epilepsy.
OBJECTIVE
Perimenstrual catamenial epilepsy may in part be due to withdrawal of the endogenous progesterone-derived neurosteroid allopregnanolone that potentiates gamma-aminobutyric acidA (GABA(A)) receptor-mediated inhibition. Here we sought to determine whether the anticonvulsant potencies of neuroactive steroids, benzodiazepines, phenobarbital (PB), and valproate (VPA) are altered during the heightened seizure susceptibility accompanying neurosteroid withdrawal in a rat model of perimenstrual catamenial epilepsy.


METHODS
Test drugs were evaluated for their ability to alter the convulsant activity of pentylenetetrazol (PTZ) in young adult female rats, in pseudopregnant rats with prolonged exposure to high levels of progesterone (and its neurosteroid metabolites), and in pseudopregnant rats 24 h after acute withdrawal of neurosteroids by treatment with the 5alpha-reductase inhibitor finasteride. Test drugs were administered at doses equivalent to twice their ED50 values for protection against PTZ-induced clonic seizures in naive young adult female rats.


RESULTS
The anticonvulsant activity of allopregnanolone (5 mg/kg, s.c.), pregnanolone (5 mg/kg, s.c.), allotetrahydrodeoxycorticosterone (15 mg/kg, s.c.), and tetrahydrodeoxycorticosterone (10 mg/kg, s.c.) were enhanced by 34-127% after neurosteroid withdrawal. The anticonvulsant activity of PB (65 mg/kg, i.p.) was also enhanced by 24% in neurosteroid-withdrawn animals. In contrast, the anticonvulsant activity of diazepam (4 mg/kg, i.p.), bretazenil (0.106 mg/kg, i.p.), and VPA (560 mg/kg, i.p.) were reduced or unchanged in neurosteroid-withdrawn animals.


CONCLUSIONS
The anticonvulsant activity of neuroactive steroids is potentiated after neurosteroid withdrawal, supporting the use of such agents in the treatment of perimenstrual catamenial epilepsy.
Reddy
D S
DS
Epilepsy Research Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-1408, USA.
Rogawski
M A
MA
D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D001570:Benzodiazepinones / Q000494:pharmacology / Q000627:therapeutic use; D003900:Desoxycorticosterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control*; D005260:Female; D008597:Menstrual Cycle / Q000502:physiology*; D010433:Pentylenetetrazole / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology / Q000627:therapeutic use; D011280:Pregnanolone / Q000097:blood* / Q000494:pharmacology* / Q000627:therapeutic use; D011555:Pseudopregnancy / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000187:drug effects / Q000502:physiology; D013256:Steroids / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D013375:Substance Withdrawal Syndrome / Q000097:blood / Q000517:prevention & control*; D014635:Valproic Acid / Q000494:pharmacology / Q000627:therapeutic use
D000927:Anticonvulsants; D001570:Benzodiazepinones; D018079:Receptors, GABA; D013256:Steroids; D003900:Desoxycorticosterone; C009413:tetrahydrodeoxycorticosterone; D014635:Valproic Acid; D011280:Pregnanolone; C054626:bretazenil; D003975:Diazepam; D010433:Pentylenetetrazole; D010634:Phenobarbital