PAF IN PERINATAL CEREBRAL HYPOXIC/ISCHEMIC INJURY

描述：危重婴儿是中枢神经系统损伤的高危人群。 流行病学和实验证据表明，TAT是炎症介质， 如血小板活化因子，参与了糖尿病的病理生理过程。 缺氧缺血性脑损伤。这项研究的目标是确定 强大的磷脂信使激活血小板的机制 因子(1-O-alkyl-2-acetyl-sn-glycero-3-phosphoclholine，PAF)起中介作用 未成熟脑的缺氧缺血性损伤。PAF是一名调解人 炎症与缺血再灌注损伤。PAF在大脑中含量丰富； 除了作为突触信使的复杂动作外，它还扮演着关键的 在正常大脑发育中的调节作用。这样做的理由是 建议源于我们的初步数据；我们发现PAF浓度在 建立新生大鼠脑缺氧缺血模型，并评价其对脑缺血的影响。 两种不同策略阻断PAF功能的神经保护作用 同一模型中的活动。PAF受体拮抗剂及其重组 降解酶PA乙酰水解酶均具有神经保护作用。 假说：单侧脑损伤后PAF在脑内蓄积 幼年大鼠缺氧缺血模型。PAF介导的缺氧缺血性脑损伤 激活脑PAF受体并诱导其产生损伤 大脑中的炎性细胞因子。治疗策略导致 PAF受体活性降低改善长期神经学和 新生儿卒中后的神经病理转归。目标：1.确定 单侧大脑皮质PAF蓄积的时间和幅度 缺氧-缺血。2.评估PAF的具体机制 介导性新生儿缺氧缺血性脑损伤的脑调节机制 血流；细胞因子产生的调节；白细胞的调节 黏附分子的表达。3.评估急救措施的效果 缺氧缺血后特异性PAF受体拮抗剂的治疗 大鼠成熟时的功能测量和神经病理学。方法：我们 单侧颈动脉致局灶性前脑缺氧缺血性损伤 结扎后暴露在中度低氧下的时间，新生儿 (出生后第7天)大鼠。我们将测量缺氧缺血内和缺氧后 损毁脑组织中PAF含量的变化。我们将评估 PAF介导的缺氧缺血损伤机制的研究 PAF受体拮抗剂治疗对CNS[~3H]-PAF结合部位的影响 肿瘤坏死因子-α和E-选择素的产生，以及局部脑血流量。 形态测量和神经行为测试是将被 用来评价新生儿神经保护效果的稳定性 当大鼠达到成熟期时，给予缺氧缺血后PAFF拮抗剂治疗。

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.