Powerful anticonvulsant action of IL-1 receptor antagonist on intracerebral injection and astrocytic overexpression in mice

IL-1 beta and its endogenous receptor antagonist (IL-1Ra) are rapidly induc ed by seizures in the rodent hippocampus. Exogenously applied IL-1 beta pro longs seizures in an IL-1R type I-mediated manner. This effect depends on N -methyl-D-aspartate receptor activation. We report here that intrahippocamp al application of recombinant IL-1Ra or its selective endogenous overexpres sion in astrocytes under the control of glial acidic fibrillary protein pro moter potently inhibits motor and electroencephalographic seizures induced by bicuculline methiodide in mice. Accordingly, transgenic mice show a redu ced seizure-related c-fos mRNA expression in various forebrain areas compar ed with their wild-type littermates. Recombinant IL-1Ra was ineffective in mice deficient in IL-1R type 1, having per se a delayed onset to generalize d convulsions, These results demonstrate that IL-1Ra mediates potent antico nvulsant effects acting on IL-1R type I and suggest that the balance betwee n brain IL-1 beta and IL-1Ra represents a crucial mechanism to control seiz ure generalization.