The effects of 5a-dihydroprogesterone and benzyl alcohol in amygdala-kindled seizures

Abstract

5a-dihydroprogesterone (DHP), the primary metabolite of progesterone, has anti-seizure properties. The present study investigated the time-course of the anti-seizure effects of 5a-dihydroprogesterone, injected via the IP route, in an animal model of human drug-resistant seizures – the amygdala-kindling model. Female, Wistar amygdala-kindled rats were injected intraperitoneally (I.P.) with 30 mg/kg of DHP, and the suppression of focal electrographic seizures and secondarily generalized convulsions was tested from 10 to 150 min post-injection. DHP was dissolved in the “benzyl vehicle” (benzyl alcohol: benzyl benzoate: cottonseed oil, 1.5:1.5:7, v:v:v), DHP in the benzyl vehicle demonstrated good anti-seizure effects at two time points: (1) immediately (10–20 min) after injection, and (2) at about 130 min after injection. Both generalized and focal seizures were suppressed at the early time point, but only generalized seizures were suppressed at 130 min. Ataxia was seen at the earlier time point, but not at the later time-point. When a vehicle control was done, we observed both focal and generalized seizure suppression at the early time point (10–20 min) in the absence of DHP. A subsequent examination revealed that benzyl alcohol was the only active ingredient in the benzyl vehicle, and that it has clear anti-seizure effects. No seizure suppression was seen with benzyl alcohol at later time points. In conclusion, the anti-seizure effects seen shortly after injection may relate to either DHP or benzyl alcohol, whereas the seizure suppression seen at later time points seems to relate to DHP, or perhaps a DHP metabolite. A future study might attempt to establish a time-course for DHP metabolism in the rat and to determine what compound relates to these late-developing effects. This study was supported by EpLink – The Epilepsy Research Program of the Ontario Brain Institute.