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

基本信息

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
项目类别：
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

项目摘要

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) 造成的损伤和中风风险增加很大程度上是由于常见的关键调节剂，如氧化应激 (OS)、炎症和内源性抗氧化物质的改变反应系统（ARE）受核因子红细胞2相关因子（Nrf2）调节。临床前研究还表明尼古丁（电子烟中使用的电子液体的主要成分）也会导致操作系统，加重脑缺血和继发性脑损伤。来自我们实验室的初步数据向 TS 提供同样的证据；长期吸电子烟 (e-Cig) 会导致血脑屏障完整性丧失和血管炎症，也是中风发作和术后病情恶化的危险因素。缺血性脑损伤。此外，最近的报告显示，二甲双胍（MF）治疗前后缺血性损伤可减轻应激并抑制炎症反应。本次赠款中提供的初步数据表明 MF 促进 Nrf2 介导的反作用机制，从而大大降低 TS 毒性在大脑和脑血管水平上，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 可以有效降低中风和炎症的氧化和炎症风险减轻 TS 和电子烟引起的缺血后脑损伤。我们建议 MF 可以是重新用于预防/减少 TS 和电子烟暴露造成的 BBB 损伤和随后的中风损伤长期吸烟者/电子烟者。因此，我们的研究目标是： 1）评估和验证MF保护大脑微血管的分子机制 TS/e-Cig 的 BBB 包括缺血/再灌注 (IR) 损伤。我们将通过以下方式解开分子靶标 MF可对血脑屏障产生积极影响，减轻缺血性中风和脑血管负担长期吸烟者和吸烟者的损害。 2) 评估体内预防性与治疗性（缺血后）给药的效果二甲双胍可减少 TS/电子烟促进脑血管损伤和/或缺血后神经元损伤损害。体内研究将定义 MF 的 BBB 运输和中枢神经系统进入机制主要缺血性损伤终点；包括梗塞和水肿体积、组织学终点和中风后的行为恢复。最终，我们将描述 MF 的功效和治疗时间窗口用于治疗暴露于 TS 或电子烟蒸汽的小鼠的中风。