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、里程碑式的转化研究计划，目标是验证一种新型的甘菊环硝酮抗氧化剂化合物- stilbazulenyl nitrone（STAZN）-作为三种相互关联的、普遍存在的急性神经系统疾病的神经保护治疗剂，其中活性氧有助于组织损伤：缺血性中风、创伤性脑损伤（TBI）和脑实质内出血（ICH）。目前没有临床上确定的神经保护治疗可用于这些疾病。STAZN具有高亲脂性和生理范围内的氧化电位的优点;它在初步研究中显示出很大的前景。该提案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，支持STAZN的神经保护功效，作为中风和创伤临床试验的前奏。将在短暂性和永久性大脑中动脉（MCA）缝合闭塞的大鼠模型中以及在可再通的光血栓性MCA闭塞（其产生再灌注损伤）中研究局灶性脑缺血。TBI研究将在标准中度至重度液压冲击模型中进行。纹状体脑内血肿是由双重注血造成的。我们将进行全面的剂量探索研究，阐明疗效的治疗时间窗，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血浆曲线和脑水平。NINDS计划的工作人员在制定这一建议时为我们提供了宝贵的意见。来自学术界和制药行业的两名世界知名的氧自由基生物化学和血管药理学权威将担任外部顾问，在整个项目中指导我们。

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.