CYTOKINES IN NEURODEGENERATION AND REPAIR

Cytokines have diverse actions in the brain, some of which may facilit ate either neurodegeneration or neuroprotection. The expression of cyt okines, particularly interleukins-1 and -6 (IL-1, IL-6) and tumor necr osis factor alpha, is rapidly and markedly induced in response to expe rimentally induced or clinical neurodegeneration. We have demonstrated that central administration of the IL-1 receptor antagonist (IL-1ra) markedly inhibits neurodegeneration induced by focal cerebral ischaemi a, local infusion of glutamate receptor agonists or traumatic brain in jury in the rat. In contrast, IL-1ra offers no I protection against de generation of primary cortical neurones in culture caused by exposure to agonists of ionotrophic or metabotrophic receptors. In vivo, admini stration of IL-1 beta exacerbates ischaemic brain damage, whereas in c ell culture, exogenous IL-1 is neuroprotective at concentrations in th e nM range, an effect which appears to be mediated by release of endog enous nerve growth factor. Higher concentrations of IL-1 (mu M range) are neurotoxic to neurones in culture and may mimic the involvement of IL-1 in neurodegeneration in vivo. Thus, excessive production of cyto kines such as IL-1 appears to mediate experimentally induced neurodege neration in vivo, while neuroprotective effects of low concentrations of the cytokine suggest a dual role for IL-1 in neuronal survival.