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ABSTRACT: Progesterone (P) plays an important role in seizure susceptibility in women with epilepsy. Preclinical and experimental studies suggest that P appears to interrupt epileptogenesis, which is a process whereby a normal brain becomes progressively susceptible to recurrent, unprovoked seizures due to precipitating risk factors. Progesterone has not been investigated widely for its potential disease-modifying activity in epileptogenic models. Recently, P has been shown to exert disease-modifying effects in the kindling model of epileptogenesis. However, the mechanisms underlying the protective effects of P against epileptogenesis remain unclear. In this study, we investigated the role of P-derived neurosteroids in the disease-modifying activity of P. It is hypothesized that 5α-reductase converts P to allopregnanolone and related neurosteroids that retard epileptogenesis in the brain. To test this hypothesis, we utilized the mouse hippocampus kindling model of epileptogenesis and investigated the effect of finasteride, a 5α-reductase and neurosteroid synthesis inhibitor. Progesterone markedly retarded the development of epileptogenesis and inhibited the rate of kindling acquisition to elicit stage 5 seizures. Pretreatment with finasteride led to complete inhibition of the P-induced retardation of the limbic epileptogenesis in mice. Finasteride did not significantly influence the acute seizure expression in fully kindled mice expressing stage 5 seizures. Thus, neurosteroids that potentiate phasic and tonic inhibition in the hippocampus, such as allopregnanolone, may mediate the disease-modifying effect of P, indicating a new role of neurosteroids in acquired limbic epileptogenesis and temporal lobe epilepsy.
Epilepsy & Behavior 07/2012; 25(1):92-7. · 2.06 Impact Factor