PAF IN PERINATAL CEREBRAL HYPOXIC/ISCHEMIC INJURY

描述：危重婴儿CNS损伤的风险很高。 流行病学和实验证据表明达特炎症介质， 例如血小板活化因子，有助于 缺氧缺血性脑损伤 本研究的目的是确定 磷脂信使激活血小板的机制 因子（1-O-烷基-2-乙酰基-SN-甘油-3-磷酸胆碱，PAF）介导 未成熟大脑的缺氧缺血性损伤。 PAF是一种介导剂， 炎症和缺血-再灌注损伤。 脑内PAF含量丰富; 除了作为突触信使的复杂作用外，它还起着关键的 在正常大脑发育中的调节作用。 这样做的理由 我们的建议源于我们的初步数据;我们发现PAF浓度在一个 新生大鼠脑缺氧缺血模型，并评估 两种不同策略阻断PAF功能的神经保护作用 在同一个模型中。 PAF受体拮抗剂和重组 降解酶PA乙酰水解酶均具有神经保护作用。 假设：PAF在单侧脑缺血后在脑内积聚 未成熟大鼠缺氧缺血。 PAF介导缺氧缺血性脑损伤 通过激活脑PAF受体并诱导产生 大脑中的炎症细胞因子。 治疗策略导致 PAF受体活化降低可改善长期神经功能， 新生儿卒中后的神经病理学结果。 目的：1. 确定 单侧脑缺血诱导PAF蓄积的时间和幅度 缺氧缺血 2. 评估PAF可通过哪些具体机制 新生儿中度缺氧缺血性脑损伤：脑组织的调节 血流量;细胞因子产生的调节;白细胞调节 粘附分子表达。 3. 评估急性 缺氧缺血后PAF受体拮抗剂治疗特异性 功能测量和神经病理学。 方法：我们 单侧颈动脉结扎引起局灶性前脑缺氧缺血性损伤 结扎后暴露于中度缺氧，在新生儿 （出生后第7天）大鼠。 我们将测量缺氧缺血性脑损伤 损伤脑内PAF浓度的变化。 我们将评估 PAF介导的缺氧缺血性损伤的机制 PAF受体拮抗剂处理对CNS [3 H]-PAF结合位点的影响， TNF-α和E-选择素的产生以及局部脑血流量。 形态测量学和神经行为测试是主要的指标， 用于评价新生儿神经保护效果的稳定性 缺氧缺血后PAFF拮抗剂治疗，大鼠达到成熟。

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.