PAF IN PERINATAL CEREBRAL HYPOXIC/ISCHEMIC INJURY

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

DESCRIPTION: Critically ill infants are at high risk for CNS injury. Epidemiologic and experimental evidence suggests tat inflammatory mediators, such as platelet-activating factor, contribute to the pathophysiology of hypoxic-ischemic brain injury. The goal of this study is to determine mechanisms by which the potent phospholipid messenger platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycero-3-phosphoclholine, PAF) mediates hypoxic-ischemic injury in the immature brain. PAF is a mediator of inflammation and ischemia-reperfusion injury. PAF is abundant in the brain; in addition to complex actions as a synaptic messenger, it plays a critical regulatory role in normal brain development. The rationale for this proposal stems from our Preliminary Data; we found PAF concentrations in a neonatal rat model of cerebral hypoxia-ischemia, and we evaluated the neuroprotective efficacy of two distinct strategies to block PAF functional activity in the same model. PAF receptor antagonists and the recombinant degradative enzyme PA acetylhydrolase were both neuroprotective. Hypotheses: PAF accumulates in the brain after unilateral cerebral hypoxia-ischemia in immature rats. PAF mediate hypoxic-ischemic brain injury by activating brain PAF receptors and inducing production of inflammatory cytokines in the brain. Treatment strategies that result in decreased PAF receptor activation improve long-term neurologic and neuropathologic outcome after neonatal stroke. Aims: 1. Determine the timing and magnitude of PAF accumulation induced by unilateral cerebral hypoxia-ischemia. 2. Evaluate specific mechanisms by which PAF could mediate neonatal hypoxic-ischemic brain injury: modulation of cerebral blood flow; modulation of cytokine production; modulation of leukocyte adhesion molecule expression. 3. Evaluate the effects of acute post-hypoxic-ischemic PAF receptor antagonist treatment of specific functional measures and neuropathology as rat reach maturity. METHODS: We will elicit focal forebrain hypoxic-ischemic injury by unilateral carotid ligation followed by time exposure to moderate hypoxia, in neonatal (postnatal day 7) rats. We will measure intra- and post-hypoxic-ischemic changes in PAF concentrations in lesioned brain. We will evaluate mechanisms of PAF-mediated hypoxic ischemic damage by determining the effects of PAF receptor antagonist treatment on CNS [3H]-PAF binding sites, production of TNF-alpha and E-selectin, and local cerebral blood flow. Morphometry and neurobehavioral testing are the primary indices that will be used to evaluate the stability of the neuroprotective efficacy of neonatal post-hypoxic-ischemic PAFF antagonist treatment, as rats reach maturity.