Cortical cell death induced by IL-1 is mediated via actions in the hypothalamus of the rat

The cytokine IL-l mediates diverse forms of neurodegeneration, but its mechanism of action is unknown. We have demonstrated previously that exogenous and endogenous IL-l. acts specifically in the rat striatum to dramatically enhance ischemic: and excitotoxic brain damage and cause extensive cortical injury. Here we tested the hypothesis that this distant effect of IL-l is mediated through polysynaptic striatal outputs to the cortex via the hypothalamus. We show that IL-1 beta injected into the rat striatum with the excitotoxin of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (S-AMPA) caused increased expression of IL-1 beta (mRNA and protein) mainly in the cortex where maximum injury occurs. Marked increases in IL-1 beta mRNA and protein were also observed in the hypothalamus. S-AMPA, injected alone into the striatum, caused only localized damage, but administration of IL-1 beta into either the striatum or the lateral hypothalamus immediately after striatal S-AMPA resulted in widespread cell loss throughout the ipsilateral cortex. Finally we showed that the cortical cell death produced by striatal coinjection of S-AMPA and IL-1 beta was significantly reduced by administration of the IL-I receptor antagonist into the lateral hypothalamus. These data suggest that IL-1 beta can act in the hypothalamus to modify cell viability in the cortex. We conclude that IL-l-dependent pathways project from the striatum to the cortex via the hypothalamus and lead to cortical injury, and that these may contribute to a number of human neurological conditions including stroke and head trauma.