4. Anticonvulsant doses of 5-alpha-dihydroprogesterone and allopregnanolone: Behavioral toxicity results in male and female rats

Abstract

The effects of the hormones on seizures have been recognized for decades. One third of all women with epilepsy experience catamenial seizure exacerbation, an increased risk of seizures when plasma progesterone levels are low, or the ratio of estradiol to progesterone is high. A primary metabolite of progesterone, 5-alpha-dihydroprogesterone (5 α DHP), has recently been discovered by our laboratory to be the first compound to suppress the complex partial seizure focus in rats at non-toxic doses in over 25 years. Progesterone → 5 α Reductase 5 α DHP ↔ 3 α HSO Allopregnanolone Progesterone and allopregnanolone both confer seizure protection by activating GABA A channels, which accounts for their highly sedative side effects. A different and novel mechanism of anti-convulsant action, however, is implicated for 5 α DHP; it is the only compound that suppresses the seizure focus in the amygdala-kindling model, has a rapid (15 min) onset of action, and subjects exhibit no ataxia or sedation. The discovery of 5 α DHP’s ability to control complex seizures at non-sedating doses deserves further research. Behavioural studies of male and female rats have tested toxicity of anti-convulsant doses of 5 α DHP and allopregnanolone. Compounds were administered intraperitoneally (ip) at doses that had produced anticonvulsant effects in earlier studies. The presenter will present results of the following behavioural experiments: The Elevated Plus Maze, a model of anxiety; the Morris Water Maze, a model of learning and memory; the Forced Swim Test, a model of depression; the Open Field Test, a model of locomotor and anxiety behaviours. Possible mechanisms of 5 α DHP’s anti-convulsant action will be explored in relation to current publications. Unexpected results and potentially confounding factors will be discussed. Future electrophysiological and biomolecular experiments will produce data to elucidate the compound’s novel mechanism of action. It is hoped that a better understanding of neurosteroids in epilepsy will lead to a better understanding of the pathophysiology of seizures, and improve treatment outcome.