Role of NMDA receptor signaling in the regulation of inflammatory gene expression after focal brain ischemia.
Inflammatory mediators are involved in the pathogenesis of focal ischemic brain damage. In this study we used quantitative reverse transcriptase-polymerase chain reaction to analyze the spatiotemporal pattern of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and inducible nitric oxide synthase (iNOS) expression in focal ischemia of the rat brain. Focal ischemia of the rat parietal cortex was induced noninvasively by photothrombosis of cortical microvessels. In a proportion of the animals NMDA receptor signaling was blocked by the noncompetitive receptor antagonist MK-801. Within 4 h after ischemia we found induction of TNF-alpha and IL-1beta mRNA not only in the infarcts but also in all representative tissue samples removed from noninfarcted frontal, lateral, and occipital cortex of the ipsilateral, but not contralateral hemisphere. Contrastingly, the expression of iNOS mRNA remained restricted to the evolving infarcts. Pretreatment with MK-801 strongly inhibited remote cytokine expression (mean reduction by 80% relative to vehicle treated animals at 4 h; P<0.001) whereas in the lesions only partial reductions in the expression of IL-1beta and iNOS mRNA were found. Our data for the first time demonstrate remote cytokine induction following focal brain ischemia and suggest that NMDA receptor-mediated signaling can activate inflammatory gene expression independently from the occurrence of neuronal cell death.
Jander
S
S
Department of Neurology, Heinrich-Heine-University, Moorenstr. 5, D-40225, Düsseldorf, Germany.
Schroeter
M
M
Stoll
G
G
D000818:Animals; D002545:Brain Ischemia / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D002540:Cerebral Cortex / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology; D013181:Cortical Spreading Depression / Q000187:drug effects / Q000276:immunology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology; D020244:Infarction, Middle Cerebral Artery / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D007375:Interleukin-1 / Q000235:genetics*; D020767:Intracranial Thrombosis / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D010777:Photochemistry; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D018691:Excitatory Amino Acid Antagonists; D007375:Interleukin-1; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D014409:Tumor Necrosis Factor-alpha; D016291:Dizocilpine Maleate; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat