Ac-SDKP for Treatment of Acute Stroke

描述（由申请人提供）：中风是全球死亡和残疾的主要原因，大约72%的中风患者年龄超过65岁。组织型纤溶酶原激活剂（tPA）是美国食品药品监督管理局（FDA）批准的唯一用于治疗急性卒中（4.5小时内）的药物。tPA治疗卒中后最可怕的并发症是脑出血风险增加。我们的初步数据表明，N-乙酰基-丝氨酰-乙酰基-赖氨酰-脯氨酸（Ac-SDKP），一种通常存在于人血浆中的肽，与tPA联合使用可使梗死体积减少50%以上，并改善神经功能结局，但不会增加年轻成年大鼠出血性转化的发生率。在本申请中，我们建议开发Ac-SDKP和tPA联合治疗老年大鼠急性卒中，并研究联合治疗对神经血管单位的分子机制。在特定目标1中，我们将使用MRI和3D激光共聚焦显微镜研究Ac-SDKP单独和Ac-SDKP与tPA联合对栓塞性大脑中动脉闭塞（MCAO）老年大鼠闭塞MCA再通、脑微血管灌注和血管完整性、脑出血和缺血性神经元损伤的影响。在具体目标2，我们将研究是否Ac-SDKP抑制缺血和tPA激活的核转录因子？B（NF-？B）通路，其通过减少血栓形成而导致脑微血管通畅性和完整性的增强。在特定目标3中，我们将研究Ac-SDKP是否阻断脑血管和星形胶质细胞中缺血和tPA激活的转化生长因子（TGF）信号通路，从而通过下调纤溶酶原激活物1（派-1）减少血栓形成。这些研究可能提供一种新的治疗方法，以最大限度地减少tPA对缺血性神经血管损伤的不良影响，从而改善急性卒中后的神经功能结局。

DESCRIPTION (provided by applicant): Stroke is a leading cause of death and disability worldwide and approximately 72% of people who suffer a stroke are over the age of 65. Tissue plasminogen activator (tPA) is the only drug approved by the Food and Drug Administration (FDA) for treatment of acute stroke (within 4.5h). The most feared complication after tPA treatment of stroke is an increased risk of cerebral hemorrhage. Our preliminary data indicate that N-acetyl- seryl-aspartyl-lysyl-proline (Ac-SDKP), a peptide normally presented in human plasma, in combination with tPA reduced infarct volume by more than 50% and improved neurological outcome, but did not increase the incidence of hemorrhagic transformation in young adult rats. In this application, we propose to develop a combination therapy of Ac-SDKP and tPA for treatment of acute stroke in aged rats and to investigate molecular mechanisms underlying the combination therapy on the neurovascular unit. In Specific Aim 1, using MRI and 3D laser confocal microscopy, we will investigate the effect of Ac-SDKP alone and Ac-SDKP in combination with tPA on recanalization of the occluded MCA, cerebral microvascular perfusion and vascular integrity, brain hemorrhage, and ischemic neuronal damage in aged rats subjected to embolic middle cerebral artery occlusion (MCAO). In Specific Aim 2, we will examine whether Ac-SDKP suppresses the ischemia- and tPA-activated nuclear transcription factor-?B (NF-?B) pathway in cerebral vessels, which leads to enhancement of cerebral microvascular patency and integrity by reduction of thrombosis. In Specific Aim 3, we will examine whether Ac-SDKP blocks the ischemia- and tPA-activated transforming growth factor ¿ (TGF¿) signaling pathway in cerebral vessels and astrocytes, which leads to reduction of thrombosis by downregulation of plasminogen activator inhibitor1 (PAI-1). These studies could potentially provide a new therapy to minimize the adverse effect of tPA on ischemic neurovascular damage, leading to improved neurological outcomes after acute stroke.