Investigating Oatp-Mediated Delivery of Statins to the Brain in Males and Females: Relevance to Neuroprotective Treatment for Ischemic Stroke

研究 Oatp 介导的他汀类药物向男性和女性大脑的递送：与缺血性中风神经保护治疗的相关性

• 批准号: 10682409
• 负责人: Erica Iris Williams
• 金额: $ 4.77万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-22 至 2024-10-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10682409
• 关键词: Acute; Affect; Age; Age Years; Alteplase; Animals; Behavioral; Biological; Blood; Blood - brain barrier anatomy; Brain; Brain Ischemia; Cause of Death; Cerebral Infarction; Cerebral cortex; Clinical; Coenzyme A; Cognitive; Confocal Microscopy; Data; Development; Drug Transport; Edema; Effectiveness; FDA approved; Female; Fibrinolytic Agents; Goals; Gonadal Steroid Hormones; Hemorrhage; Hour; In Situ; Ischemic Stroke; Laboratories; Male Castration; Marketing; Measures; Mechanics; Mediating; Menopause; Methodology; Methods; Middle Cerebral Artery Occlusion; Modeling; Motor; Neurocognitive; Neurocognitive Deficit; Neurologic; Neurological outcome; Neuroprotective Agents; OATP Transporters; Operative Surgical Procedures; Organic Anion Transporters; Outcome; Oxidoreductase; Performance; Perfusion; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacotherapy; Phase III Clinical Trials; Pravastatin; Property; Public Health; Rattus; Recovery of Function; Reperfusion Injury; Research Design; Risk; Role; Severities; Sex Differences; Sprague-Dawley Rats; Stroke; Stroke prevention; Testing; Therapeutic; Time; Tissues; United States; United States National Institutes of Health; Variant; Western Blotting; Woman; Work; age group; atorvastatin; behavior test; cognitive performance; endovascular thrombectomy; experience; experimental study; fexofenadine; improved; indexing; inhibitor; male; men; molecular marker; morris water maze; neurological recovery; neuroprotection; novel; object recognition; pharmacologic; post stroke; preclinical study; protective effect; protein expression; sex; stroke incidence; stroke outcome; stroke patient; stroke therapy; therapeutic effectiveness; therapeutically effective; treatment strategy; uptake

PROJECT SUMMARY Stroke is the fifth leading cause of death in the United States. Approved stroke therapies are limited by narrow treatment windows, the risk of hemorrhagic transformation, and reperfusion injury. Therefore, there is a critical need for neuroprotective drugs that can improve post-stroke neurological performance. Currently, 3-hydroxy-3- methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (i.e., statins) are given to stroke patients due to their proven utility in improving cognitive and motor outcomes. Studies in our laboratory have uncovered a specific biological mechanism that enables statins to be effective drugs for stroke treatment: transport across the blood- brain barrier (BBB) via the endogenous uptake transporter organic anion transporting polypeptide 1a4 (Oatp1a4). We have shown, for the first time, that Oatp-mediated transport is required for atorvastatin to reduce cerebral infarction volume and improve sensorimotor performance at 24 h following transient middle cerebral artery occlusion (tMCAO). We also observed increased atorvastatin uptake in female rats subjected to tMCAO as compared with their age-matched male counterparts; however, it is unknown if these differences in Oatp- mediated transport at the BBB cause variations in atorvastatin’s ability to prevent stroke progression and/or worsening of neurocognitive deficits in the acute/subacute period. Our goals are to assess the role of sex as a biological variable on statin transport in the ischemic brain and to determine how these differences affect statin efficacy as stroke therapeutics. The central hypotheses of this F31 application are i) that functional expression of Oatp1a4 at the BBB is different in males as compared to females following tMCAO; and ii) that statin neuroprotective properties and/or their effects on post-stroke neurological outcomes are influenced by sex-dependent differences in BBB Oatp1a4 activity. Two aims will test these hypotheses: Aim 1: Investigate sex-dependent differences in Oatp1a4-mediated transport of statins at the BBB in stroke. We will perform our studies in male and female SD rats using the tMCAO model. Oatp1a4 localization and protein expression will be assessed using confocal microscopy and western blotting, respectively. Blood-to- brain transport of statins will be measured using in situ brain perfusion, a state-of-the-art methodology to study drug transport at the BBB. Aim 2: Evaluate sex-dependent differences in statin-associated neuroprotection and functional neurological recovery in stroke. In tMCAO operated male and female SD rats, we will use confocal microscopy and western blot analysis to examine molecular biomarkers associated with neuroprotection. We will also assess motor and cognitive performance in tMCAO-animals using robust behavioral tests (i.e., rotarod analysis, Morris Water Maze, Novel Object Recognition test). Overall, this project will provide critical mechanistic data on efficacy of statins as neuroprotective drugs for stroke. Furthermore, this project directly aligns with NIH goals in studying sex as a biological variable in stroke.

项目总结