Novel Tissue Protector for Subarachnoid Hemorrhage

描述（由申请人提供）：在这个国家大约有30，000例新的蛛网膜下腔出血（SAH）病例，使其成为一个重要的医疗保健问题。尽管SAH患者的医疗和手术护理取得了进展，但这种疾病仍然具有高发病率和死亡率，30天死亡率接近50%。为了研究蛛网膜下腔出血后血管痉挛的病理生理学，并利用转基因技术，我们最近的特点是蛛网膜下腔出血的小鼠模型。该模型是我们实验室和世界各地其他实验室进行的标准单丝大脑中动脉闭塞（MCAO）模型的扩展（Parra等，2002）。使用这个模型，我们现在证明，表达载脂蛋白-E（apoE 4）亚型的动物在SAH后的行为测试中比apoES对应物明显受损。这种情况类似于阿尔茨海默病，其中表达apoE 4的患者比apoES对应者明显受损更严重，并且具有更早的发病年龄。Cognosci已经开发了apoE全蛋白的新型模拟肽，其似乎保留了apoE全蛋白的抗炎和神经保护特性。在初步研究中，我们表明，这些肽之一，COG 1410，可以显着提高生存时，给予SAH后，与动物接受SAH和生理盐水媒介物作为对照。基于这些初步研究，我们现在希望在小鼠模型中充分测试apoE肽模拟物抑制蛛网膜下腔出血实验应用后的行为和血管痉挛缺陷的能力。

DESCRIPTION (provided by applicant): There are approximately 30,000 new cases of aneurysmal subarachnoid hemorrhage (SAH) in this country, making it a significant health care problem. Despite advances in the medical and surgical care of patients with SAH, this condition still has a high morbidity and mortality, with a 30 day mortality of nearly 50%. In order to examine the pathophysiology of vasospasm following SAH and to take advantage of transgenic technology, we recently characterized a murine model of SAH. This model is an extension of the standard monofilament middle cerebral artery occlusion (MCAO) model performed in our lab and by others around the world (Parra et al. 2002). Using this model, we now demonstrate that animals expressing the epsilon 4 isoform of apolipoprotein-E (apoE4) are significantly more impaired on behavioral tests following SAH than their apoES counterparts. This situation is similar to Alzheimer's disease where patients expressing apoE4 are significantly more impaired and have an earlier age of onset than their apoES counterparts. Cognosci has developed novel mimetic peptides of apoE holo-protein which appear to retain the anti-inflammatory and neuroprotective properties of apoE holo-protein. In pilot studies, we show that 1 of these peptides, COG1410, can significantly improve survival when administered following SAH, compared to animals receiving SAH and saline vehicle as a control. Based on these pilot studies, we now wish to fully test the ability of apoE peptide mimetics to inhibit the behavioral and vasospastic deficits that follow experimental application of subarachnoid hemorrhage in a mouse model.