The overall goal of this project is to investigate strategies for the drug treatment of epilepsy through pharmacological studies in animal models and clinical investigation in human subjects. Research was continued evaluating the role of neuroactive steroids in epilepsy and their possible uses in epilepsy therapy. Neuroactive steroids are endogenous steroid hormones (and their synthetic analogs) that rapidly alter the excitability of neurons by direct actions on membrane ion channels, including GABA-A and NMDA receptors. In prior reporting periods, several structurally-related neuroactive steroids, including the endogenous progesterone metabolite allopregnanolone, were demonstrated to be potent anticonvulsants in the mouse pentylenetetrazol (PTZ) seizure test, an effect that was associated with their ability to potentiate GABA-A receptor-mediated chloride current responses. In addition, it was shown that GABA-A receptor- potentiating neuroactive steroids are highly protective in models of status epilepticus. Chronic treatment studies indicated that unlike other GABA potentiating drugs tolerance does not develop to the anticonvulsant activity of neuroactive steroids, supporting their potential utility in seizure therapy. In a further study, it was found that progesterone has powerful anticonvulsant activity and demonstrated that this is due to its conversion via 5alpha-hydroxylation to the neurosteroid allopregnanolone. In the present reporting period, we sought to explore the mechanism underlying perimenstrual catamenial epilepsy and to explore the potential use of neuroactive steroids as a treatment approach in this disorder. Catamenial epilepsy, the exacerbation of seizures at specific times during the menstrual cycle, affects from 10 to 72 percent of women with epilepsy. At present, there is no specific therapy for catamenial epilepsy. In the most common form of catamenial epilepsy, there is an increase in seizures during the perimenstrual period, when serum progresterone levels are low. Seizure exacerbations in this form of catamenial epilepsy could be due to progesterone withdrawal. Neurosteroid replacement is a potential approach to therapy, but natural neurosteroids have poor bioavailability and may undergo metabolic conversion to analogs with undesired progestational activity. The synthetic 3beta-methyl analog of allopregnanolone (ganaxolone) is an orally effective neurosteroid that is not converted to the hormonally active 3-keto form. We developed an animal model of catamenial epilepsy to evalate the potential of ganaxolone in treating perimenstrual catamenial seizure exacerbations.A state of persistently high serum progesterone (pseudopregnancy) was produced in female rats by treatment with gonadotropins. Neurosteroid withdrawal was induced with the 5alpha-reductase inhibitor finasteride that blocks the conversion of progresterone to allopregnanolone. Finasteride-induced neurosteroid withdrawal during pseudopregnancy is associated with enhanced susceptibility to PTZ seizures. Following withdrawal, there was an unexpected three-fold increase in the anticonvulsant potency of ganaxolone. In contrast, there was no significant change in the potency for induction of toxicity (motor impairment), so that the separation between therapeutic activity and toxicity was substantially larger in the period following neurosteroid withdrawal. In contrast to the enhanced potency of ganaxolone, neurosteroid withdrawal was associated with a marked decrease in the anticonvulsant potency of diazepam and valproate. These results support the potential use of neuroactive steroids such as ganaxolone in the treatment of catamenial seizure exacerbations in perimenstrual catamenial epilepsy, and may explain why women with catamenial epilepsy are often resistant to treatment with conventional anticonvulsant agents. - epilepsy, catamenial epilepsy, seizure, neuroactive steroid, gaba receptor, ganaxolone
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