Mechanisms of Blood-brain Barrier Disruption in Type II Diabetes

 描述(由申请人提供)：所有形式的糖尿病都以慢性高血糖为特征，导致许多微血管和大血管病变的发展。视网膜、肾小球和周围神经存在明显的微血管病变，导致失明、终末期肾病和各种衰弱的神经病变。此外，糖尿病患者患心肌梗死的风险更高， 中风和截肢，因为加速的大血管疾病影响到向这些区域供应血液的动脉。糖尿病还与脑微血管改变有关，导致血脑屏障(BBB)功能障碍和破坏。这些变化与认知功能的下降有关。血脑屏障是脑和血液之间的调节界面，防止血浆蛋白不受限制地泄漏到中枢神经系统(CNS)，发挥营养、体内平衡和沟通的作用。在糖尿病中，血脑屏障损伤与氧化应激(OxST)和活性氧(ROS)增加有关。这是由于高血糖引起的葡萄糖氧化代谢增加所致。使用线粒体碳酸酐酶抑制剂(MCAI)减少碳酸氢盐(HCO3-)的产生限制了氧化代谢和ROS的产生，ROS的产生驱动丙酮酸进行有氧糖酵解以产生ATP而不产生ROS。我们小组的初步研究表明，i)STZ诱导的糖尿病导致BBB破坏，ii)超微结构研究显示维持BBB的两种细胞-脑周细胞丢失和星形胶质细胞回缩，以及iii)线粒体碳酸酐酶抑制剂托吡酯的治疗减弱了这种影响。在我们使用STZ诱导的I型糖尿病小鼠模型的研究中，胰岛素和瘦素水平较低，血脑屏障中断发生在五个大脑区域：额叶皮质、枕叶皮质、顶叶皮质、中脑和丘脑。相比之下，在饮食诱导肥胖(DIO)的II型糖尿病模型中，在胰岛素和瘦素水平较高的CD-1近交系小鼠中，血脑屏障的破坏没有在这五个区域发生，但在海马体和纹状体发生了。我们假设，瘦素或胰岛素在血脑屏障发挥保护作用，除非在已知它们诱导神经发生的区域，如海马体，从而增加新陈代谢。这项研究的成功完成将为研究II型糖尿病脑微血管的恶化提供有价值的见解。这里收集的数据将为NIH R01拨款申请提供初步数据，以加深我们对该领域的理解。

 DESCRIPTION (provided by applicant): All forms of diabetes mellitus are characterized by chronic hyperglycemia resulting in the development of a number of microvascular and macrovascular pathologies. Microvascular pathologies are apparent in the retina, renal glomerulus, and peripheral nerve, resulting in blindness, end-stage renal disease, and a variety of debilitating neuropathies. Also, diabetic patients are at higher risk for myocardial infarction, stroke, and limb amputation because of accelerated macrovascular disease affecting arteries that supply blood to these regions. Diabetes is also associated with changes in brain microvasculature leading to dysfunction and disruption of the blood-brain barrier (BBB). These changes are correlated with a decline in cognitive function. The BBB is a regulatory interface between brain and blood, preventing the unrestricted leakage of plasma proteins into the central nervous system (CNS) and performing nutritive, homeostatic, and communication roles. In diabetes BBB damage is associated with increased oxidative stress (OxSt) and reactive oxygen species (ROS). This occurs because of the increased oxidative metabolism of glucose caused by hyperglycemia. Decreasing the production of bicarbonate (HCO3-) with the use of a mitochondrial carbonic anhydrase inhibitor (mCAI) limits oxidative metabolism and the production of ROS, which drives pyruvate to undergo aerobic glycolysis to produce ATP without producing ROS. Preliminary studies by our group have demonstrated that i) STZ-induced diabetes results in BBB disruption, ii) ultrastructural studies show a loss of brain pericytes and retraction of astrocytes, the two cell types that maintain the BBB, and iii) treatment with topiramate, a mitochondrial carbonic anhydrase inhibitor, attenuated the effects. In our studies using an STZ- induced mouse model of Type I diabetes, where insulin and leptin levels are low, BBB disruption occurred in five brain regions: frontal cortex, occipital cortex, parietal cortex, midbrain, and thalamus. In contrast, preliminary results in a diet induced obesity (DIO) model of Type II diabetes in the outbred strain of CD-1 mice, where insulin and leptin levels are high, BBB disruption did not occur in those five regions but did occur in the hippocampus and striatum. We hypothesize that either leptin or insulin exerted protective effects at the BBB except in those regions where they are known to induce neurogenesis, such as the hippocampus, and hence increased metabolism. Successful completion of this study will provide valuable insight into studying the deterioration of brain microvasculature in type II diabetes mellitus. Data collected here will provide preliminary data for an NIH R01 grant application to further our understanding of this field.