NEUROPROTECTIVE REPERFUSION THERAPY WITH PNA

该提案描述了一种新型药物的开发， 中风的治疗 该试剂，多硝基白蛋白（PNA），是一种 有效的抗氧化剂;治疗的基本原理是， 血管间隙中的自由基形成引发了毒性级联反应， 导致中风损伤的事件。 中期的初步结果 啮齿类动物的脑动脉闭塞（MCAO）研究表明， PNA保护脑缺血和再灌注损伤， 它减少了中风后的梗死体积， 通过血管扩张活性增强脑灌注。 PNA的保护作用 活性显著高于未修饰的人血清 白蛋白; PNA因此可以被认为是治疗胶体 具有抗氧化和血管扩张活性的溶液，或 “神经保护治疗再灌注剂”。 该项目将 包括PNA对脑血流动力学影响的研究， 脑卒中时代谢;弥散和灌注加权磁共振成像 PNA~s对缺血性脑血管病的影响 再灌注损伤和脑血流;研究证实， PNA减少MCAO后的梗死体积。 如果成功，这 该项目将使人们了解PNA的作用机制， 并导致其在中风治疗中的完整临床前开发， 第二阶段。 建议的商业应用 目前市场上没有有效的药物用于中风治疗， 溶栓治疗可能被证明是适当的， 中风患者 初步证据表明，PNA可减少中风 促进脑灌注，保护脑损伤 再灌注损伤 如果成功开发PNA， 减少中风的巨大人力和医疗成本。

This proposal describes the development of a novel agent for the treatment of stroke. The agent, polynitroxyl-albumin (PNA), is a potent antioxidant; the rationale for the therapy is that oxygen free radical formation in the vascular space initiates a cascade of toxic events leading to stroke injury. Preliminary results from middle cerebral artery occlusion (MCAO) studies in rodents have indicated that PNA protects against ischemic and reperfusion injury in the brain, that it reduces infarct volume following stroke, and that it may actually enhance cerebral perfusion via a vasodilator activity. PNA's protective activity is substantially greater than that of unmodified human serum albumin; PNA can therefore be thought of as a therapeutic colloid solution with antioxidant and vasodilator activities, or a 'neuroprotective therapeutic reperfusion agent'. The project will consist of studies on PNA's effects on cerebral hemodynamics and metabolism during stroke; diffusion- and perfusion-weighted magnetic resonance imaging studies of PNA~s effects on ischemic and reperfusion injury and cerebral blood flow; and studies to confirm that PNA reduces infarct volume following MCAO. If successful, this project will give an understanding of the mechanism of action of PNA, and lead to its complete preclinical development for stroke therapy in Phase II. PROPOSED COMMERCIAL APPLICATION There is no efficacious drug now on the market for stroke therapy, and thrombolytic therapy may turn out to be appropriate of relatively few stroke patients. Preliminary evidence suggests that PNA reduces stroke injury by promoting cerebral perfusion and protecting against reperfusion injury. If successfully developed PNA could significantly reduce the enormous human and health care costs of stroke.