Prostanoids (prostaglandins and thromboxane), cyclooxygenase (COX)-derived products of arachidonic acid, are important mediators of cerebrovascular responses in neonatal animals. However, little is known about the in vivo regulation of COX isoforms in cerebral tissues and blood vessels. This proposal is based upon a number of exciting observations by our laboratory. First, cerebral vascular and parenchymal levels of COX-2 (supposed inducible form) but not COX-1 (supposed constitutive form) increase rapidly (2-8 hours) during the reperfusion period after 10 minutes of total ischemia (ischemia/reperfusion; I/R) in piglets. Second, oxygen radicals and prostanoids are produced by I/R prior to induction of COX-2. Third, indomethacin pretreatment suppresses increases in mRNA and protein levels of COX-2 after I/R. Fourth, inhibition of the nuclear transcription factor kappa B (NF-kappaB) or exogenous nitric oxide (NO) inhibits synthesis of COX-2 in cultured astroglia. And fifth, prostanoid- and NO-dependent dilator responses are suppressed following ischemia. Specific hypotheses to be tested: a) Oxygen radicals or prostanoids promote increased synthesis of COX-2; b) Oxygen radical effects on COX-2 synthesis are via activation of NF-kappaB; c) Increased COX-2 levels will alter responsiveness of the cerebral circulation; d) NO restrains increases in COX-2 levels after I/R; and f) Substrate availability for NOS and COX will affect COX-2 expression after I/R. To test these hypotheses, two specific aims will be addressed in anesthetized piglets: 1) CHARACTERIZATION OF EFFECTS OF ISCHEMIA/REPERFUSION ON COX LEVELS IN CEREBRAL BLOOD VESSELS AND TISSUES. AND 2) DETERMINATION OF THE MECHANISMS INVOLVED IN REGULATION OF COX LEVELS IN CEREBRAL BLOOD VESSELS AND TISSUES. These studies will expand our understanding of control mechanisms and will provide information to facilitate development of approaches to alleviate vascular and neuronal impairments associated with ischemic-like events in the brain.
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