CYLOOXYGEANSE 2 AND ISCHEMIC NEURONAL INJURY

简介(摘自摘要)：环氧合酶(COX)，又名前列腺素 G/H合成酶，催化花生四烯酸转化为前列腺素。 目前已鉴定出COX的两种亚型。Coxi在构成中表达为 许多组织，包括血小板、内皮细胞、胃肠道 还有肾脏。COX2是一种可诱导的即刻早期基因，其在 巨噬细胞是由炎性刺激诱导的。在神经元中也发现了COX2， 它的表达由突触活动诱导，并被兴奋性阻断 氨基酸拮抗剂(1，2)。在初步研究中，我们已经表明 海马CA1区神经元COX2基因和蛋白表达增加 全脑缺血后注定死亡，CA3神经元注定死亡 在红藻氨酸诱导癫痫发作后，皮质神经元注定会在 大鼠短暂性局灶性脑缺血。在缺血症和癫痫中， 这些脆弱的神经元的死亡可以通过用一种 选择性COX2活性抑制剂SC58125。此外，还有初步的 COX2抑制剂在原代神经元培养中的保护作用 到一过性低血糖和缺氧。 有待检验的假设是，COX2活性有助于脑缺血 神经元损伤。具体目标是：1)确认COX2活性 促进体内缺血后的神经元损伤。2)确定效果 COX2抑制剂对细胞死亡和活性氧产生的影响 原代培养的神经元受到一过性低血糖/缺氧的影响。3) 确定COX2抑制剂和COX2基因中断对ROS的影响 缺血后脂质、蛋白质和DNA的形成和氧化损伤。4) 确定COX2抑制剂治疗和COX2基因破坏对血管紧张素转换酶活性的影响 血栓素合成、中性粒细胞聚集与血脑屏障 渗透性。 许多选择性抑制COX2的药物正在被开发为有效的 非类固醇抗炎药(NSAIDs)无肾脏、血液系统 以及常见非选择性非甾体抗炎药的胃肠道毒性。因此，我们的 结果表明，抑制COX2有望成为一种无毒的治疗方法。 缺血和其他神经系统疾病，其中兴奋性毒性和氧化 压力也与此有关。

DESCRIPTION (From Abstract): Cyclooxygenase (COX), also known as prostaglandin G/H synthase, catalyzes the conversion of arachidonic acid to prostaglandins. Two isoforms of COX have been identified. COXI is constitutively expressed in many tissues including platelets, endothelial cells, the gastrointestinal tract and kidney. COX2 is an inducible immediate early gene whose expression in macrophages is induced by inflammatory stimuli. COX2 is also found in neurons, where its expression is induced by synaptic activity and blocked by excitatory amino acid antagonists (1,2). In preliminary studies, we have shown that expression of COX2 mRNA and protein is increased in hippocampal CA1 neurons destined to die after global cerebral ischemia, CA3 neurons destined to die after kainate-induced seizures, and cortical neurons destined to die after temporary focal cerebral ischemia, in rats. In both ischemia and epilepsy, death of these vulnerable neurons may be prevented by treatment with a selective inhibitor of COX2 activity, SC58125. Moreover, there is preliminary data that COX2 inhibitors are protective in primary neuronal culture subjected to transient hypoglycemia and hypoxia. The hypothesis to be tested is that COX2 activity contributes to ischemic neuronal injury. Specific Aims are to 1) confirm whether COX2 activity contributes to neuronal injury after ischemia in vivo. 2) determine the effect of COX2 inhibitors on cell death and generation of reactive oxygen species in primary neuronal cultures subjected to transient hypoglycemia/hypoxia. 3) Determine the effect of COX2 inhibitors and COX2 gene disruption on ROS formation and oxidative damage to lipids, protein and DNA after ischemia. 4) Determine the effect of COX2 inhibitor treatment and COX2 gene disruption on thromboxane synthesis, neutrophil accumulation and blood brain barrier permeability. Many drugs that selectively inhibit COX2 are being developed as effective nonsteroidal anti-inflammatory drugs (NSAIDs) without the renal, hematological and gastrointestinal toxicity of common nonselective NSAIDs. Accordingly, our results suggest that COX2 inhibition has promise as a nontoxic treatment for ischemia and other neurologic diseases where excitotoxicity and oxidative stress have been implicated.