The role of pro- and antiinflammatory cytokines in neurodegeneration.

Experimental and clinical damage to the brain leads to rapid upregulation of an array of cytokines predominantly by glia. These cytokines may exert neurotoxic or neuroprotective actions. This paper will focus on the pro-inflammatory cytokine interleukin-1 (IL-1), which participates in diverse forms of brain damage including ischemia, brain trauma, and excitotoxic injury. Administration of low doses of IL-1 markedly exacerbates these forms of brain damage, whereas blocking IL-1 release or actions reduces neuronal death. IL-1 receptor antagonist (IL-1ra) is also upregulated by brain damage (mainly by neurons) and acts as an endogenous inhibitor of neurodegeneration, presumably by blocking IL-1 actions on its receptor. We have studied the actions of both IL-1 and IL-1ra in experimental models of ischemic and neurotoxic injury in rats, and have found site-specific effects within the striatum. On the basis of this and further work, we propose that IL-1 can exacerbate cell death in these conditions by modifying polysynaptic anterograde pathways leading from the striatum to the cortex. The precise nature of these pathways remains undetermined, as do the underlying mechanisms by which IL-1 can exert its effects, but appear to involve induction of IL-1 in specific brain regions and activation of cortical glutamatergic pathways.