Azulenyl nitrones: neuroprotectants in stroke and trauma

描述(由申请人提供)： 我们建议进行一项全面的、里程碑式的转译研究计划，旨在验证一种新型的唑基硝酮抗氧化剂--二苯乙烯基硝酮(STAZN)--作为三种相互关联的、普遍存在的急性神经疾病的神经保护治疗剂：缺血性中风、创伤性脑损伤(TBI)和脑实质出血(ICH)。目前还没有临床证实的神经保护性疗法可用于这些疾病。STAZN具有高亲脂性和生理范围内的氧化电位等优点，在初步研究中显示出巨大的前景。这项建议建立在迈阿密大学脑血管疾病研究中心和佛罗里达国际大学合成有机化学生产性实验室之间富有成效的合作基础上。该计划的目的是建立一个令人信服的临床前证据体系，支持STAZN的神经保护功效，作为中风和创伤临床试验的前奏。采用大鼠局灶性脑缺血模型，包括短暂性和永久性大脑中动脉(MCA)闭塞模型，以及可再通的光栓性MCA闭塞模型。脑损伤研究将在标准的中到重度液压冲击模型中进行。纹状体脑内血肿是通过双倍注血产生的。我们将进行全面的剂量发现研究，阐明疗效的治疗时间窗口，并使用定量组织病理学和神经行为策略评估急性和慢性终点。将考虑与性别和年龄有关的答复。药代动力学研究将记录STAZN的血浆曲线和脑水平。NINDS计划工作人员在制定这项建议时为我们提供了宝贵的意见。来自学术界和制药业的两位世界知名氧自由基生物化学和血管药理学权威将担任外部顾问，指导我们整个项目。

DESCRIPTION (provided by applicant): We propose to conduct a comprehensive, milestone-driven program of translational research targeted at the validation of a novel azulenyl nitrone antioxidant compound -- stilbazulenyl nitrone (STAZN) -- as a neuroprotective therapeutic agent for three interrelated, prevalent acute neurological disorders in which reactive oxygen species contribute to tissue injury: ischemic stroke, traumatic brain injury (TBI), and parenchymal intracerebral hemorrhage (ICH). No clinically established neuroprotective therapeutic is currently available for these disorders. STAZN has the advantages of high lipophilicity and an oxidation potential within the physiologic range; it has shown great promise in pilot studies. This proposal builds upon a fruitful collaboration between the Cerebral Vascular Disease Research Center at the University of Miami and a productive laboratory of synthetic organic chemistry at Florida International University. The intent of the program is to establish a compelling body of preclinical evidence supporting the neuroprotective efficacy of STAZN as a prelude to clinical trials in stroke and trauma. Focal cerebral ischemia will be studied in rat models of both transient and permanent middle cerebral artery (MCA) suture occlusion and in recanalizable photothrombotic MCA occlusion, which engenders reperfusion injury. TBI studies will be performed in the standard moderate-to-severe fluid percussion model. Striatal intracerebral hematoma is produced by double blood injection. We shall conduct comprehensive dose-finding studies, elucidate the therapeutic time-window of efficacy, and evaluate both acute and chronic endpoints using both quantitative histopathological as well as neurobehavioral strategies. Gender- and age-related responses will be considered. Pharmacokinetic studies will document STAZN plasma curves and brain levels. The NINDS program staff has provided valuable input to us in shaping this proposal. Two world-renowned authorities in oxygen-radical biochemistry and vascular pharmacology drawn from both academia and the pharmaceutical industry will serve as External Advisors to guide us throughout this project.