INFLAMMATORY CYTOKINES AS NOVEL TARGETS FOR INHIBITING SEIZURES AND EPILEPTOGENESIS

About one third of epileptic sufferers is pharmacoresistant and the only efficacious intervention is surgical removal of the epileptic tissue. Thus, it is important to develop novel drugs to effectively antagonize also those forms of epilepsy refractory to current anticonvulsant treatments. We found that an endogenously produced protein, named -interleukin-1 receptor antagonist- (IL-1Ra), when administered in the brain of experimental rats or mice, decreases up to 90% epileptic fits. IL-1Ra is produced by white blood cells and its biological function is that of antagonizing the proinflammatory action of interleukin-1beta. We found that cytokines are also produced by brain cells called glial cells and their levels increase in rodent brain during experimentally provoked seizures. Simultaneously, IL-1Ra increases as well: the ratio between these two proteins with opposite action on seizures, appears to represent a crucial mechanism to control epileptic activity. IL-1Ra does not easily cross the blood brain barrier, that allows the communication between brain and periphery, thus it works only if intracerebrally injected. We plan therefore to develop pharmacological intervention to increase the level of IL-1Ra normally produced in the brain or to enhance its entry after systemic administration or decrease IL-1beta produced during epileptic activity. We will also study the functional role of TNF-alpha produced by the brain during seizures in the onset and recurrence of epileptic activity. The availability of experimental models of seizures will permit us to assess the anticonvulsant efficacy of our pharmacological approaches and to understand which are the mechanisms underlying the role of proinflammatory cytokines in seizures induction or in their control.