CYLOOXYGEANSE 2 AND ISCHEMIC NEURONAL INJURY

描述（来自摘要）：环氧合酶（考克斯），也称为前列腺素 G/H合酶催化花生四烯酸转化为洋地黄素。 已经鉴定了考克斯的两种同种型。COXI组成型表达于 许多组织包括血小板、内皮细胞、胃肠道 和肾脏。COX 2是一种诱导型立即早期基因，其在人乳腺癌中的表达 巨噬细胞是由炎症刺激诱导的。COX 2也存在于神经元中， 其表达由突触活动诱导，并被兴奋性 氨基酸拮抗剂（1，2）。在初步研究中，我们已经表明， 海马CA 1区神经元COX 2 mRNA和蛋白表达增加 在全脑缺血后注定死亡，CA 3神经元注定死亡 在红藻氨酸诱导的癫痫发作后， 大鼠暂时性局灶性脑缺血。在缺血和癫痫中， 这些脆弱的神经元的死亡可以通过治疗来预防， COX 2活性选择性抑制剂SC 58125。此外，初步 数据表明，COX 2抑制剂在受到抑制的原代神经元培养物中具有保护作用， 短暂性低血糖和缺氧 待检验的假设是COX 2活性有助于缺血性心脏病。 神经元损伤具体目的是：1）确认COX 2活性是否 导致体内缺血后神经元损伤。2)确定影响 COX 2抑制剂对细胞死亡和活性氧产生的影响 对原代神经元培养物进行短暂性低血糖/缺氧。第三章 确定COX 2抑制剂和COX 2基因破坏对ROS的影响 脂质、蛋白质和DNA的氧化损伤。四、 确定COX 2抑制剂处理和COX 2基因破坏对C 0X 2表达的影响。 血栓素合成、中性粒细胞聚集和血脑屏障 磁导率 许多选择性抑制COX 2的药物正在开发， 非甾体类抗炎药（NSAID），不影响肾脏、血液 以及常见非选择性NSAID的胃肠道毒性。因此，我们的 结果表明，COX 2抑制有望作为一种无毒的治疗方法， 局部缺血和其他神经系统疾病，其中兴奋性毒性和氧化性 压力也有牵连。

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.