A2: PROJ 3: MECHANISMS OF ACIDOSIS ENHANCED ISCHEMIC BRAIN DAMAGE: DRUG

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。糖尿病加重了脑缺血引起的脑损伤。这一重要的临床相关现象的潜在机制还知之甚少。本项目的目的是确定线粒体和线粒体启动的细胞死亡途径在高血糖脑缺血中的作用。过去5年的研究结果表明：1)酸中毒和高糖均可导致高血糖/糖尿病对缺血神经元的损害；2)糖尿病患者脑缺血导致线粒体形态发生改变。这包括卒中后再灌流早期线粒体严重肿胀和线粒体基质蛋白的释放；3)糖尿病诱导促炎细胞因子白介素1(IL-1)和细胞间黏附分子-1(ICAM-1)等神经炎性分子的表达；4)糖尿病缺血增加自由基的产生，激活线粒体介导的细胞死亡途径，导致核碎裂和细胞死亡；5)高血糖对脑缺血的损害不仅对神经元，而且对星形胶质细胞；6)在正常血糖和/或高血糖受试者中，保护线粒体、清除自由基或抑制神经炎症的药物可以保护大脑免受缺血损伤。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Diabetes exaggerates brain damage induced by cerebral ischemia. The underlying mechanisms for this important, clinically relevant phenomenon are poorly understood. The objective of this project is to identify the role of mitochondria and mitochondrial-initiated cell death pathways in hyperglycemic ischemia. The results obtained from past 5 years showed that that 1) both acidosis and high glucose contribute to the detrimental effects of hyperglycemia/diabetes on ischemic neurons; 2) cerebral ischemia in diabetics results in alteration of mitochondrial morphology. This includes severe mitochondrial swelling and release of mitochondrial matrix proteins at the early reperfusion phase after stroke; 3) diabetes induces expression of neuro-inflammatory molecules such as the pro-inflammatory cytokine interleukin-1 (IL-1) and intercellular adhesive molecule-1 (ICAM-1); 4) diabetic ischemia enhances production of free radicals, and activates the mitochondrion-mediated cell death pathway, resulting in nuclear fragmentation and cell death; 5) the detrimental effects of hyperglycemia on ischemic brain are not only to neurons but to astrocytes as well; 6) pharmacological agents that preserve mitochondria, scavenge free radicals or suppress neuro-inflammation protect the brain from ischemic injury in normoglycemic and/or hyperglycemic subjects.