Progesterone (P) and certain P metabolites have anticonvulsant effects in various animal models of epilepsy. The objectives of the present proposal are to characterize the novel steroid recognition site mediating the anticonvulsant actions of P metabolites along with the mechanism(s) involved and determine susceptibility to seizures produced by convulsant agents acting at the GABA/benzodiazepine receptor (GBR)-Cl- ionophore complex during different phases of the estrus cycle. These objectives will lead to a better understanding of the etiology of catamenial epilepsy associated with the menstrual cycle and the premenstrual stress syndrome. The hypothesis is: P and its metabolite(s) act as normal modulators of brain excitability via the GBR-Cl- ionophore complex. To investigate this hypothesis using a rodent model, the specific aims of this proposal are to 1) characterize in vitro the steroid site mediating the effects of P and P metabolites on brain excitability; 2) synthesize and identify anticonvulsant steroids; and 3) determine susceptibility to convulsant agents specific for the GBR-Cl- ionophore complex during different phases of the estrus cycle. The 1st aim will be fulfilled by applying the classic approach used in the characterization of neurotransmitter receptors. The 2nd specific aim will use novel steroids identified as being active in vitro in standard anticonvulsant screening tests in order to find clinically useful anticonvulsants. Finally, the 3rd specific aim will be achieved by determining the seizure threshold of convulsant agents and the brain levels of GBR-Cl- ionophore active steroids during specific phases of the estrus cycle. Collectively, these studies represent the first step in the systematic characterization of a novel membrane-bound steroid site and the identification of specific ligands for this site with anticonvulsant potential.
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