Cortical spreading depression induces proinflammatory cytokine gene expression in the rat brain

Cortical spreading depression(CSD) is characterized by reversible neuronal dysfunction in the absence of cell death. Preconditioning by CSD induces to lerance against subsequent lethal ischemia. In this study, we used quantita tive reverse transcriptase-polymerase chain reaction and immunocytochemistr y to analyze proinflammatory cytokine expression after CSD induced by topic al application of potassium chloride (KCl) to the cortical surface of rat b rains. Relative to control cortex, we found an increase of tamer necrosis f actor-alpha (mean 62-fold, P < 0.001) and interleukin (IL)-1<beta> (mean 24 -fold, P < 0.001) mRNA levels within 4 hours ipsilateral to the site of KCI application. At 16 hours cytokine expression was decreasing toward baselin e levels. Ipsilateral cytokine induction was abolished by pretreatment with the noncompetitive N-methyl-d-aspartate antagonist, MK-801. In contrast to focal cortical infarction, cytokine induction in CSD was not accompanied b y the expression of inducible nitric oxide synthase mRNA. In immunocytochem ical studies, expression of IL-I<beta> protein was localized to ramified mi croglia in cortical layers I to III of the ipsilateral hemisphere. Our find ing that NMDA receptor signaling without subsequent neuronal cell death is sufficient to induce inflammatory cytokine expression in the brain has basi c implications for central nervous system immunoregulation. We postulate th at cytokine expression in CSD forms part of a physiologic stress response t hat contributes to the development of ischemic tolerance in this and other preconditioning paradigms.