DEXAMETHASONE AND STROKE--EFFECTS ON BRAIN TRANSPORT AND METABOLISM

地塞米松和中风——对大脑运输和代谢的影响

• 批准号: 2348459
• 金额: --
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2348459
• 关键词: blood brain barrier; brain cell; brain circulation; brain metabolism; cerebral ischemia /hypoxia; dexamethasone; disease /disorder model; drug related diabetes mellitus; glucose transport; hemodynamics; hormone regulation /control mechanism; hyperglycemia; hyperinsulinism; laboratory rat; lactic acidosis; microcirculation; northern blottings; oxygen consumption; stroke; tissue /cell culture; transport proteins; western blottings

The proposed studies addresses the following question: does dexamethasone influence stroke injury by altering brain glucose transport or microvascular fuel metabolism? Dexamethasone treatment can markedly worsen stroke damage in rats and has variable efficacy in ameliorating human stroke damage. We plan to employ DEX as a tool to study regulation of glucose entry into brain. It may augment ischemic damage by causing both hyperglycemia and hyperinsulinemia, conditions common in Type II diabetes. Glucose becomes toxic during stroke by increasing brain lactic acid levels. Thus, both hyperglycemia and induction of brain hexose transport may aggravate stroke-related cerebral lactic acidosis. Altered energy metabolism by the brain's microvasculature may also influence stroke damage through vascular dysfunction. Novel causes for dexamethasone-dependent stroke injury are to be tested, based on three proposed hypotheses: 1) Chronic dexamethasone administration modifies blood-brain glucose transport; 2) Dexamethasone also alters glucose transport by brain parenchymal cells; and 3) Exposure of brain microvessels to dexamethasone may impair brain microvessel energy metabolism. Each of these hypotheses pertains to altered tolerance to cerebral ischemia. To evaluate these hypotheses, studies will be performed with the following aims: 1) Determine the influence of dexamethasone on brain hexose transport in vivo; 2) Characterize hexose transport by brain microvessels and parenchyma in vitro after dexamethasone exposure; 3) Evaluate possible molecular mechanisms whereby dexamethasone modulates glucose transport; 4) Determine whether dexamethasone changes fuel metabolism in the brain microvasculature in a manner which lessens tolerance to ischemia or fuel deprivation.

拟议的研究解决了以下问题：地塞米松是否存在 通过改变脑葡萄糖的转运或 微血管燃料代谢？ 地塞米松治疗可能明显恶化 大鼠中风损伤，并在改善人类方面具有可变的功效 中风伤害。 我们计划采用DEX作为研究调节的工具 葡萄糖进入大脑。 这可能会通过造成两者来增加缺血性损害 高血糖和高胰岛素血症，在II型糖尿病中常见的疾病。 通过增加脑乳酸水平，葡萄糖在中风过程中变得有毒。 因此，高血糖和脑己糖转运的诱导均可 加重中风相关的脑乳酸性酸中毒。 能量改变 大脑微脉管系统的代谢也可能影响中风损伤 通过血管功能障碍。 依赖地塞米松的中风损伤的新原因将被测试， 基于提出的三个假设：1）慢性地塞米松 给药可修饰血脑葡萄糖的转运； 2）地塞米松 还会改变脑实质细胞的葡萄糖转运； 3）暴露 大脑微血管对地塞米松可能会损害大脑微血管能量 代谢。 这些假设中的每一个都涉及改变的公差 脑缺血。 为了评估这些假设，将对以下研究进行研究 目的：1）确定地塞米松对脑己糖的影响 体内运输； 2）用脑微血管表征己糖传输 地塞米松暴露后体外实质性实质； 3）评估可能 地塞米松调节葡萄糖转运的分子机制； 4） 确定地塞米松是否改变了大脑中的燃料代谢 微脉管系统以减少缺血或燃料的耐受性的方式 剥夺。