The anticonvulsant effects of allopregnanolone against amygdala-kindled seizures in female rats.
It has long been known that the steroid hormone progesterone has anticonvulsant actions. These have been documented both in animals and humans. In 2003, we reported that progesterone's first metabolite, 5alpha-dihydroprogesterone (5alpha-DHP), has strong anticonvulsant effects in amygdala-kindled female rats. These occur without sedation, and involve suppression of the kindled amygdala focus, as well as the secondarily generalized kindled seizure. The purpose of this study was to investigate the anticonvulsant actions of progesterone's secondary metabolite, allopregnanolone, in the amygdala kindling model. Adult female Wistar rats were implanted with chronic indwelling electrodes in the right amygdala, and kindled to 30 stage 5 seizures. Varying doses of allopregnanolone were then administered to each subject in randomized order, and the effects on the kindled amygdala focus and the secondarily generalized kindled seizure were observed. Immediately before each drug trial, ataxia was rated using the Löscher scale. Complete suppression of the generalized kindled convulsion was seen in all subjects, with an ED(50) of 1.1 mg/kg. Ataxia--scored as Löscher stage 2 or higher--was seen at higher doses, with a TD(50) of 8.6 mg/kg. The therapeutic index for suppression of the generalized convulsion was 7.8. Even at the highest doses tested, however, there was no suppression of the kindled amygdala focus. Allopregnanolone has anticonvulsant effects--and a good therapeutic index--against the secondarily generalized component of amygdala-kindled seizures.
Lonsdale
Deborah
D
The University of Toronto Epilepsy Research Program, Canada; The University of Toronto, Department of Pharmacology, Canada. deborah.lonsdale@utoronto.ca
Burnham
W M
WM
D000679:Amygdala / Q000187:drug effects* / Q000503:physiopathology / Q000528:radiation effects; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D001522:Behavior, Animal; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation / Q000009:adverse effects; D005260:Female; D007696:Kindling, Neurologic / Q000187:drug effects*; D011280:Pregnanolone / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D012720:Severity of Illness Index; D013997:Time Factors
D000927:Anticonvulsants; D011280:Pregnanolone