Azulenyl nitrones: neuroprotectants in stroke and trauma

甘菊硝酮：中风和创伤中的神经保护剂

• 批准号: 7064212
• 负责人: MYRON DAVID GINSBERG
• 金额: $ 58.86万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-02 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7064212
• 关键词: antioxidants; brain injury; cerebral hemorrhage; cerebral ischemia /hypoxia; cooperative study; disease /disorder model; drug screening /evaluation; high performance liquid chromatography; histochemistry /cytochemistry; laboratory rat; magnetic resonance imaging; mass spectrometry; neuroprotectants; nitrone; pharmacokinetics; stroke; trauma

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.

描述（由申请人提供）： 我们建议开展一项全面的、具有里程碑意义的转化研究计划，旨在验证一种新型薁基硝酮抗氧化剂化合物——芪薁基硝酮（STAZN）——作为一种神经保护治疗剂，用于治疗三种相互关联的、普遍的急性神经系统疾病，其中反应性氧气会导致组织损伤：缺血性中风、创伤性脑损伤 (TBI) 和实质脑出血 (ICH)。目前尚无临床确定的神经保护疗法可用于这些疾病。 STAZN具有高亲脂性和生理范围内氧化电位的优点；它在试点研究中显示出了巨大的前景。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实验室之间富有成效的合作基础上。该计划的目的是建立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。将在暂时性和永久性大脑中动脉 (MCA) 缝线闭塞的大鼠模型以及可再通的光血栓 MCA 闭塞（导致再灌注损伤）中研究局灶性脑缺血。 TBI 研究将在标准中度至重度流体冲击模型中进行。纹状体脑内血肿是由双注血产生的。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相关的反应。药代动力学研究将记录 STAZN 血浆曲线和脑水平。 NINDS 项目工作人员为我们制定此提案提供了宝贵的意见。来自学术界和制药行业的两位世界知名的氧自由基生物化学和血管药理学权威将作为外部顾问，在整个项目中指导我们。