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.

摘要：最近出版的体外和体内发现强烈表明血脑屏障（BBB） 烟草烟雾（TS）的损害和中风的风险增加很大程度上是响应共同的 关键调节剂此类氧化应激（OS），内源性抗氧化剂的炎症和改变 响应系统（由核因子2相关因子（NRF2）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）也可能导致OS， 大脑缺血和继发性脑损伤加剧。我们实验室的初步数据 提供对TS的证据；慢性电子烟（E-CIG）蒸发可以促进BBB完整性的丧失 和血管炎症，并充当中风发作的危险因素 缺血性脑损伤。此外，最近的报告表明，二甲双胍（MF）治疗 缺血性损伤会减轻压力并抑制炎症反应。本赠款中提供的初步数据 建议MF促进NRF2介导的反活性机制，从而大大降低TS毒性 在保护BBB完整性的同时，在大脑和脑血管水平上。我们提供其他体内 证据表明，MF可以有效地降低中风的氧化和炎症风险 通过TS和E-CIG蒸发促进的衰减后缺血后脑损伤。我们建议MF可能是 重新利用以防止/减少TS和E-cig暴露在 长期吸烟者/蒸气。因此，我们研究的目标是： 1）评估和验证MF可以保护的脑微血管分子机制 来自TS/E-CIG的BBB包括缺血/再灌注（IR）损伤。我们将通过 哪些MF可以积极影响BBB并减轻缺血性中风和脑血管的负担 长期吸烟者和蒸气的损害。 2）在体内评估预防性与治疗性（后缺血）给药的影响 减少TS/E-CIG的二甲双胍 - 促进脑血管障碍和/或缺血后神经元 损害。体内调查将定义BBB运输的机制和MF的CNS进入 主要缺血性损伤终点；包括梗塞和水肿量，组织学终点和 中风后的行为恢复。最终，我们将表征MF的功效和治疗时间窗口 用于暴露于TS或E-CIG蒸气的小鼠中的中风治疗。