Ac-SDKP for Treatment of Acute Stroke

描述(申请人提供)：中风是世界范围内导致死亡和残疾的主要原因，大约72%的中风患者年龄在65岁以上。组织纤溶酶原激活剂(TPA)是美国食品和药物管理局(FDA)批准的唯一治疗急性中风(4.5小时内)的药物。卒中tPA治疗后最令人担心的并发症是脑出血风险增加。我们的初步数据表明，N-乙酰-丝氨酸-天冬氨酰-赖氨酰脯氨酸(Ac-SDKP)是一种通常存在于人血浆中的多肽，与tPA联合使用可使幼年大鼠的脑梗塞体积减少50%以上，并改善神经预后，但不会增加幼年大鼠出血性转化的发生率。在这一应用中，我们建议开发Ac-SDKP和tPA联合治疗老年大鼠急性卒中的方法，并探讨联合治疗神经血管单位的分子机制。本研究的主要目的：1利用MRI和3D激光共聚焦显微镜技术，观察Ac-SDKP和Ac-SDKP联合tPA对老年大鼠大脑中动脉闭塞(MCAO)后大脑中动脉再通、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中，我们将研究Ac-SDKP是否抑制缺血和tPA激活的脑血管核转录因子-β(NF-βB)途径，从而通过减少血栓形成来提高脑微血管的通畅性和完整性。在具体目标3中，我们将研究Ac-SDKP是否阻断缺血和tPA激活的脑血管和星形胶质细胞中的转化生长因子(TGF)信号通路，从而通过下调纤溶酶原激活物抑制物1(PAI-1)来减少血栓形成。这些研究可能提供一种新的治疗方法，将tPA对缺血性神经血管损伤的不良影响降至最低，从而改善急性中风后的神经预后。

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.