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

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定是研究者机构。糖尿病加重脑缺血引起的脑损伤。这种重要的临床相关现象的潜在机制知之甚少。本项目的目的是确定线粒体和胰岛细胞启动的细胞死亡途径在高血糖缺血中的作用。近5年来的研究结果表明：1）酸中毒和高糖均参与了高血糖/糖尿病对缺血神经元的不利影响; 2）糖尿病患者脑缺血导致线粒体形态学改变。这包括中风后早期再灌注阶段严重的线粒体肿胀和线粒体基质蛋白的释放; 3）糖尿病诱导神经炎性分子如促炎细胞因子白细胞介素-1（IL-1）和细胞间粘附分子-1（ICAM-1）的表达; 4）糖尿病性缺血增强自由基的产生，并激活cadion介导的细胞死亡途径，导致核碎裂和细胞死亡; 5）高血糖症对缺血性脑的有害作用不仅对神经元而且对星形胶质细胞也是有害的; 6）保护线粒体、线粒体自由基或抑制神经炎症的药理学试剂保护正常血糖和/或高血糖受试者的脑免受缺血性损伤。

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.