INHIBITION OF CPB-MEDIATED NEUROLOGICAL DYSFUNCTION

描述(申请人提供)：脑损伤仍然是心脏手术最常见和最具破坏性的并发症之一，目前还没有已知的治疗方法。这些损伤，从中风到认知功能障碍，是相当大比例接受体外循环(CPB)的患者的长期问题，导致生活质量降低，就业可能性降低，并给患者和医疗保健系统带来巨大的成本负担。来自临床和实验研究的证据表明，载脂蛋白E(ApoE)通过调节神经胶质细胞的激活及其相关的谷氨酸、活性氧和炎性细胞因子的释放来减轻中枢神经系统(CNS)对损伤的反应，从而加剧了原发神经元的损伤。APOE还具有直接的神经保护作用。我们已经从apoE的受体结合区(COG-133)中创建并鉴定了一种小肽，并在体外和体内证明它保留了holo-apoE蛋白所表现出的神经保护特性。虽然CPB所致神经功能障碍的确切机制尚不清楚，但已证明CPB可诱导全身炎症反应。因此，COG-133的神经保护特性，特别是它下调炎性细胞因子分泌的能力，使 它是CPB引起的神经功能障碍领域的一种强有力的治疗干预手段。我们推测，载脂蛋白E模拟肽COG-133将在心脏手术引起的脑损伤领域显示出神经保护作用。我们将使用重复措施设计，在此设计中，我们将检查生理盐水和COG-133处理的CPB大鼠的以下终点：神经运动功能、旋转试验、Morris水迷宫任务，以及海马区荧光玉和胶质纤维酸性蛋白染色，以分别检测变性神经元和星形胶质细胞的增殖情况。目前，尚无明确的神经保护剂可用于预防或治疗心脏手术相关的脑损伤。我们相信，我们的载脂蛋白E模拟肽代表了一种预防和治疗神经功能障碍的新治疗策略，从而满足了目前尚未满足的医学需求。

DESCRIPTION (provided by applicant): Cerebral injury remains one of the most frequent and devastating complications of heart surgery, for which there is no known therapy. These injuries, ranging from stroke to cognitive dysfunction, are a long-term problem for a substantial percentage of patients undergoing cardiopulmonary bypass (CPB), resulting in lower quality of life, decreased likelihood of employment, and a substantial cost burden to patients, as well as the healthcare system. Evidence from clinical and experimental studies indicate that apolipoprotein E (apoE) attenuates central nervous system (CNS) response to injury by modulating glial activation and the associated release of glutamate, reactive oxygen species, and inflammatory cytokines which can exacerbate the primary neuronal injury. ApoE exerts direct neuroprotective effects as well. We have created and characterized a small peptide derived from the receptor-binding region of apoE (COG-133) and demonstrated, in vitro and in vivo, that it retains the neuroprotective properties exhibited by the holo-apoE protein. While, the exact mechanisms underlying CPB-induced neurological dysfunction are not clear, it has been demonstrated that CPB induces a systemic inflammatory response. Therefore, the neuroprotective properties of COG-133, its ability to down regulate the secretion of inflammatory cytokines in particular, make It a strong candidate for use as a therapeutic intervention in the arena of CPB-induced neurological dysfunction. We hypothesize that the apoE mimetic peptide, COG-133, will exhibit neuroprotective effects in the arena of cerebral injury stemming from cardiac surgery. We will use a repeated measures design in which we will examine the following endpoints for saline and COG-133 treated rats that have undergone CPB: neuromotor functioning, rotorod test, Morris Water Maze task, and fluoro-jade and glial fibrillary acidic protein staining of the hippocampus to examine degenerating neurons and astrocyte proliferation, respectively. Currently, there are no definitive neuroprotective agents available to prevent or treat cardiac surgery-related cerebral injuries. We believe that our apoE mimetic peptide represents a novel therapeutic strategy for the prevention and treatment of neurological dysfunction, thereby fulfilling a currently unmet medical need.