Neurovascular protection by adropin in acute neural injury from subarachnoid hemorrhage

摘要 蛛网膜下腔出血（SAH）相关脑梗死的急性神经损伤发生在30 - 40%的 在最初出血后存活的患者，导致死亡和残疾，与3- 月结果。长期认知缺陷的发生率也很高。目前了解的 SAH后脑梗死的病理生理学指向涉及一氧化氮（NO）减少的损伤级联反应 生物利用度和氧化应激。在正常情况下，NO信号通路调节脑血 通过介导脑血管舒张和抑制血小板粘附来调节血流。然而，对于SAH，红细胞 溶解并释放血红蛋白，这是一种痉挛。血红蛋白清除NO;刺激产生 一氧化氮合酶（NOS）抑制剂（ADMA）;并产生活性氧（ROS）和氮 种（RNS）。我们相信最近鉴定的肽激素Adropin是一个有前途的治疗靶点， SAH后脑梗死。我们的团队和其他人已经证明adropin在大脑中大量表达， 调节内皮型一氧化氮合酶（eNOS）途径，与氧化应激标志物相关， 并响应于模拟的局部缺血而降低脑内皮通透性。我们的假设是， 对SAH后脑梗死的急性神经损伤具有保护作用。我们在这方面的总体目标 我们的建议是证明Adropin在SAH中的保护作用，并研究其潜在的分子机制， 这种保护的细胞机制。我们的初步数据支持这一假设，表明SAH 降低脑Adropin的表达，而内源性Adropin过表达的转基因小鼠， 在SAH模型中，β-肌动蛋白驱动的Adropin转基因（AdrTg）或用合成Adropin治疗降低了 脑水肿，保留紧密连接蛋白表达，消除微血栓形成，增加eNOS 磷酸化，预防脑血管痉挛，抑制神经元凋亡。目标1是确定是否 当以临床可翻译的剂量给予时，阿霉素可保护SAH后的急性神经损伤。 SAH后的时间点。在目标2中，我们将研究在以下情况下调节Enho基因表达的介质： SAH。在目的3中，我们将研究肾上腺素神经血管保护是否通过eNOS活性介导。我们 预期本研究将为肾上腺素介导的急性神经损伤保护提供新的知识， SAH。本研究的意义在于它是直接可译的，并且是第一次对基本原则进行探讨 SAH后Adropin对脑内皮细胞的调节作用。本研究将提供临床前数据， 1/2 SAH患者的人体临床试验。

ABSTRACT Acute neural injury from subarachnoid hemorrhage (SAH)-associated cerebral infarction occurs in 30-40% of patients who survive the initial hemorrhage, leads to death and disability, and most strongly correlates with 3- month outcome. There is also a significant rate of long-term cognitive deficits. Current understanding of the pathophysiology of post-SAH cerebral infarction points to injury cascades involving decreased nitric oxide (NO) bioavailability and oxidative stress. Under normal conditions, NO signaling pathways regulate cerebral blood flow by mediating cerebral vasodilation and inhibiting platelet adhesion. However, with SAH, red blood cells lyse and release hemoglobin, which is a spasmogenic. Hemoglobin scavenges NO; stimulates production of a nitric oxide synthase (NOS) inhibitor (ADMA); and generates reactive oxygen species (ROS) and nitrogen species (RNS). We believe the recently-identified peptide hormone adropin is a promising therapeutic target for post-SAH cerebral infarction. Our group and others have shown adropin is abundantly expressed in the brain, regulates the endothelial nitric oxide synthase (eNOS) pathway, correlates with markers of oxidative stress, and reduces brain endothelial permeability in response to simulated ischemia. Our hypothesis is that adropin confers protection against acute neural injury from post-SAH cerebral infarction. Our overall goal in this proposal is to demonstrate the protective role of adropin in SAH and investigate the underlying molecular and cellular mechanisms of this protection. Our preliminary data support this hypothesis by showing that SAH decreases brain adropin expression, and that endogenous adropin overexpression by transgenic mice with a β-actin-driven adropin transgene (AdrTg) or treatment with synthetic adropin in the SAH model reduces cerebral edema, preserves tight junction protein expression, abolishes microthrombosis, increases eNOS phosphorylation, prevents cerebral vasospasm, and inhibits neuronal apoptosis. Aim 1 is to determine whether adropin confers protection against acute neural injury after SAH when given in a clinically translatable timepoint after SAH. In Aim 2, we will study mediators that regulate Enho gene expression in the setting of SAH. In Aim 3, we will study whether adropin neurovascular protection is mediated via eNOS activity. We expect this study will provide novel knowledge on adropin-mediated protection against acute neural injury after SAH. The significance of this study is that it is directly translatable and the first to investigate the fundamentals of adropin regulation in brain endothelial cells after SAH. This study will provide the preclinical data for a Phase 1/2 human clinical trial in SAH patients.