Abstracts

Rationale: The development of epilepsy is linked to complex alterations in neuroplastic mechanisms. Dysregulation of neurosteroid synthesis may also play a role. Neurosteroids, such as allopregnanolone, are synthesized within the brain and regulates neuronal excitability and tonic inhibition by modulating GABA-A receptor function. However, the pathophysiological roles of neurosteroids remain unclear. Here, we hypothesize that the prototype endogenous neurosteroid allopregnanolone is involved in controlling limbic epileptogenesis. Methods: In this study, we investigated the novel role of neurosteroids in limbic epileptogenesis and tested the above hypothesis using three different approaches for manipulating neurosteroid levels in the brain: (a) finasteride-induced inhibition of neurosteroids; (b) gonadotropin-induced elevations in neurosteroids; and (c) exogenous administration of neurosteroids. Adult mice were subjected to hippocampus kindling via implanted electrode in the hippocampus and the rate of kindling, behavioral seizure intensity, and afterdischarge (AD) duration were evaluated as indices of epileptogenesis.Results: Treatment with finasteride, a neurosteroid synthesis inhibitor, resulted in a significant increase in epileptogenesis in the hippocampus kindling, which is a model of functional limbic epileptogenesis since seizures develop after repeated subthreshold stimulation of hippocampus without induction of evident brain lesions. Sequential gonadotropin protocol resulted in persistent elevations in neurosteroids that were stable for at least 10 days, as measured by plasma allopregnanolone levels. Physiological levels of allopregnanolone induced by gonadotropin treatment significantly decreased epileptogenesis, while inhibition of neurosteroid synthesis prevented such retardation of epileptogenesis. Exogenous allopregnanolone, at doses that produce levels similar to gonadotropins, substantially decreased epileptogenesis. Dose-response study of allopregnanolone effect on seizure expression in fully-kindled animals shows that a lower dose of allopregnanolone (0.5 mg/kg) did not affect behavioral seizure stage or AD duration, indicating the lack of a significant effect on acute seizure susceptibility at this dose. Conclusions: These results demonstrate a new role of endogenous neurosteroids in limbic epileptogenesis and confirm that allopregnanolone-like neurosteroids have antiepileptogenic or disease-modifying properties. Thus, augmentation of neurosteroid synthesis may represent a unique strategy for preventing or retarding epileptogenesis. ** Supported by NIH grant NS051398 **