Repurposing Metformin to Offset Stroke Risk and Injury in Comorbid Populations of Smokers

重新利用二甲双胍来抵消吸烟者共病人群的中风风险和伤害

• 批准号: 10033325
• 负责人: Thomas J Abbruscato
• 金额: $ 59.53万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10033325
• 关键词: Address; Animals; Antidiabetic Drugs; Attenuated; Behavioral; Blood - brain barrier anatomy; Brain; Brain Injuries; Cardiovascular system; Caring; Carotid Arteries; Cells; Cerebral Ischemia; Chronic; Clinical; Clinical Research; Data; Disease; Dose; Edema; Effectiveness; Electronic cigarette; Endothelium; Evaluation; Female; Gender; Goals; Grant; Health; Hemorrhage; Histologic; Hour; Impairment; In Vitro; Infarction; Inflammation; Inflammatory; Inflammatory Response; Injury; Investigation; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Laboratories; Link; Lipids; Measurement; Mediating; Meta-Analysis; Metabolic; Metformin; Mitochondria; Molecular; Molecular Target; Mus; NF-kappa B; Neurologic; Neurons; Nicotine; Outcome; Oxidative Stress; Pathologic; Pathway interactions; Plasma; Population; Proteins; Publications; Publishing; Reactive Oxygen Species; Recovery; Reperfusion Injury; Reporting; Research; Risk; Risk Factors; Signal Pathway; Small Interfering RNA; Smoker; Smoking; Stains; Stress; Stroke; System; Therapeutic; Therapeutic Agents; Thrombomodulin; Time; Tobacco smoke; Tobacco smoking behavior; Toxic effect; Withdrawal; Woman; Work; artery occlusion; blood-based biomarker; brain endothelial cell; brain tissue; cerebrovascular; chronic stroke; comorbidity; electronic liquid; environmental tobacco smoke exposure; fluoro jade; high risk; high risk population; improved; in vivo; inhibitor/antagonist; ischemic injury; male; mortality; neuroprotection; nuclear factor-erythroid 2; oxidative damage; post stroke; preclinical study; prevent; prophylactic; response; restoration; stroke outcome; stroke risk; stroke therapy; treatment group; vaper; vaping; vapor; vascular endothelial dysfunction; vascular inflammation

Abstract: Recently published in vitro and in vivo findings strongly suggest that blood-brain barrier (BBB) impairment and increased risk for stroke by tobacco smoke (TS) develop largely in response to common key modulators such oxidative stress (OS), inflammation and alterations of the endogenous antioxidative response system (ARE) regulated by the nuclear factor erythroid 2-related factor (Nrf2). Preclinical studies have also shown that nicotine (the principal e-liquid's ingredient used in e-cigarettes) can also cause OS, exacerbation of cerebral ischemia and secondary brain injury. Preliminary data from our laboratories provides evidence that likewise to TS; chronic e-Cigarette (e-Cig) vaping can promote loss of BBB integrity and vascular inflammation as well as act as a risk factor for the onset of stroke and worsening of post- ischemic brain injury. In addition, recent reports have shown that metformin (MF) treatment before and after ischemic injury reduce stress and inhibit inflammatory responses. Preliminary data provided in this grant suggests that MF promotes Nrf2-mediated counteractive mechanisms which drastically reduce TS toxicity at the brain and cerebrovascular levels while protecting BBB integrity. We provide additional in vivo evidence showing that MF can effectively reduce the oxidative and inflammatory risk for stroke and attenuate post-ischemic brain injury promoted by TS and e-Cig vaping. We propose that MF could be repurposed to prevent/reduce BBB damage and subsequent stroke injury by TS and e-Cig exposure in chronic smokers/vapors. Thus, the objectives of our study are: 1) Assess and validate the brain microvascular molecular mechanisms by which MF can protect the BBB from TS/e-Cig including ischemic/reperfusion (IR) injury. We will unravel the molecular target through which MF can positively impact the BBB and reduce the burden of ischemic stroke and cerebrovascular impairments in chronic smokers and vapors. 2) Evaluate in vivo the effect of prophylactic versus therapeutic (post-ischemic) administration of metformin in reducing TS/e-Cig - promoted cerebrovascular impairment and/or post-ischemic neuronal damage. In vivo investigations will define a mechanism of BBB transport and CNS entry for MF along with major ischemic injury endpoints; including infarction and edema volume, histological endpoints and behavioral recovery after stroke. Ultimately, we will characterize MF's efficacy and therapeutic time window for stroke treatment in mice exposed to TS or e-Cig vapor.

翻译后摘要：最近发表的体外和体内研究结果强烈表明，血脑屏障（BBB） 烟草烟雾（TS）损害和中风风险增加主要是对常见的 关键调节剂，如氧化应激（OS）、炎症和内源性抗氧化酶的改变， 反应系统（ARE）由核因子红细胞2相关因子（Nrf 2）调节。临床前研究 还表明尼古丁（电子烟中使用的主要电子液体成分）也会导致OS， 加重脑缺血和继发性脑损伤。我们实验室的初步数据 提供的证据表明，与TS类似，长期电子烟（e-Cig）vaping可促进BBB完整性的丧失 和血管炎症，并作为中风发作和中风后恶化的危险因素。 缺血性脑损伤此外，最近的报告显示，二甲双胍（MF）治疗前后 局部缺血损伤减少应激并抑制炎症反应。本补助金提供的初步数据 表明MF促进Nrf 2介导的对抗机制，其显著降低TS毒性 同时保护血脑屏障的完整性。我们提供额外的体内 有证据表明，MF可以有效降低中风的氧化和炎症风险， 减轻TS和电子烟雾化促进的缺血后脑损伤。我们认为MF可能是 重新用于预防/减少TS和电子烟暴露导致的BBB损伤和随后的卒中损伤， 长期吸烟者/烟雾。因此，我们的研究目标是： 1)评估和验证MF保护脑微血管的分子机制。 来自TS/电子烟的BBB，包括缺血/再灌注（IR）损伤。我们将通过 MF可以积极影响BBB，减轻缺血性卒中和脑血管疾病的负担， 慢性吸烟者和蒸汽的损害。 2)在体内评价预防性相对于治疗性（缺血后）施用以下化合物的效果： 二甲双胍减少TS/电子烟促进的脑血管损伤和/或缺血后神经元损伤 损害体内研究将确定MF沿着的BBB转运和CNS进入的机制， 主要缺血性损伤终点;包括梗死和水肿体积、组织学终点和 中风后的行为恢复。最终，我们将描述MF的疗效和治疗时间窗 用于暴露于TS或电子烟蒸汽的小鼠的中风治疗。