2. The anticonvulsant effects of intravenous 5a-dihydroprogesterone on amygdala-kindled seizures in rats

Abstract

Background 5a-dihydroprogesterone (DHP), the first metabolite of progesterone and the precursor of allopregnanolone, has anticonvulsant properties. Past studies have reported the suppression of amygdala-kindled seizures by DHP administered via the subcutaneous route. We now demonstrate strong anticonvulsant effects of DHP administered intravenously (IV) via the jugular vein. Methods Female Wistar rats were implanted with an electrode in the right basolateral amygdala. They were kindled to 15 stage 5 seizures, stability tested, and cannulated in the jugular vein. The dose-response and time-response effects of IV DHP were then tested against focal electrographic seizures and secondarily generalized convulsions. Results Dose-Response Study - At 5 min post-injection, a dose-dependent suppression of both generalized and focal seizures was seen, with ED50s of 1.69 mg/kg for the generalized convulsive seizures and of 3.48 mg/kg for the focal electrographic seizures. Ataxia, as rated by the Loscher ataxia scale, was also seen, with a TD50 of 3.57 mg/kg. Results Time-Response Study - The time-response study, done with the ED75 for focal seizure suppression, showed suppression of both generalized and focal seizures from immediately after injection to about 60 min post-injection. Significance DHP has demonstrated anticonvulsant effects in a drug-resistant model of human complex-partial seizures. Its analogs might be developed as new anticonvulsants.