Mechanisms of Blood-brain Barrier Disruption in Type II Diabetes



 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.