Diabetes mellitus is associated with deterioration of the brain's microvasculature and the blood-brain barrier (BBB) that it forms. The BBB prevents the unrestricted leakage of plasma proteins into the brain. The vascular BBB is physically formed by specially modified brain endothelial cells (BECs), but other cell types interact with it to form the neurovascular unit (NVU). Pericytes in particular are important in maintaining BBB function in the face of glycemic insult. We have shown in vitro that the insulin transporter is lost in the face of high glucose concentrations unless BECs are co-cultured with pericytes;astrocyte co-culture does not preserve BEC insulin transporter function. However, pericytes are themselves susceptible to glucose toxicity and the accompanying oxidative stress. Work with retinal pericytes and the blood-retinal barrier (BRB) shows that hyperglycemia induces apoptosis in retinal pericytes;with pericyte loss the BRB deteriorates. Mitochondrial carbonic anhydrases (CAs) are important in the generation of reactive oxygen species (ROS) and the subsequent oxidative stress that arises and is accelerated during hyperglycemia. In brief, mitochondrial CAs generate mitochondrial bicarbonate that is necessary for the oxidative catabolism of glucose, the major source of ROS. Hyperglycemia accelerates this process, increasing production of ROS. Blocking mitochondrial CAs shuttles pyruvate through anaerobic metabolism and so prevents excessive ROS production. We hypothesize that inhibition of mitochondrial carbonic anhydrases (CAs) will protect pericytes and BECs from ROS induced apoptosis and slow the development of disruption of the BBB in STZ-induced diabetes. Wewill test this hypothesis in two specific aims. SA1 will measure oxidative stress induced by high glucose media and the resulting mitochondrial leakage and apoptosis in primary cultures of brain pericytes and BEC isolated from mitochondrial CA KO &WT mice and in pericytes and BEC that overexpress CA or are treated with clinically used CA inhibitors. SA 2 will measure in diabetic and control mice BBB disruption and oxidative stress in BEC from CA KO mice, WT mice, and mice treated with the CA inhibitors of SA1.
We will investigate a mechanism that could explain why diabetics develop problems with the small vessels of the brain and drugs that could reverse those problems. If successful, a major complication of diabetes might be treatable with a class of drugs already on the market.
|Price, Tulin O; Sheibani, Nader; Shah, Gul N (2017) Regulation of high glucose-induced apoptosis of brain pericytes by mitochondrial CA VA: A specific target for prevention of diabetic cerebrovascular pathology. Biochim Biophys Acta 1863:929-935|
|Banks, William A; Abrass, Christine K; Hansen, Kim M (2016) Differentiating the Influences of Aging and Adiposity on Brain Weights, Levels of Serum and Brain Cytokines, Gastrointestinal Hormones, and Amyloid Precursor Protein. J Gerontol A Biol Sci Med Sci 71:21-9|
|Salameh, Therese S; Shah, Gul N; Price, Tulin O et al. (2016) Blood-Brain Barrier Disruption and Neurovascular Unit Dysfunction in Diabetic Mice: Protection with the Mitochondrial Carbonic Anhydrase Inhibitor Topiramate. J Pharmacol Exp Ther 359:452-459|
|Banks, W A (2015) The blood-brain barrier in neuroimmunology: Tales of separation and assimilation. Brain Behav Immun 44:1-8|
|Price, Tulin O; Farr, Susan A; Niehoff, Michael L et al. (2015) Protective Effect of Topiramate on Hyperglycemia-Induced Cerebral Oxidative Stress, Pericyte Loss and Learning Behavior in Diabetic Mice. Int Libr Diabetes Metab 1:6-12|
|Patrick, Ping; Price, Tulin O; Diogo, Ana L et al. (2015) Topiramate Protects Pericytes from Glucotoxicity: Role for Mitochondrial CA VA in Cerebromicrovascular Disease in Diabetes. J Endocrinol Diabetes 2:|
|Dohi, Kenji; Kraemer, Brian C; Erickson, Michelle A et al. (2014) Molecular hydrogen in drinking water protects against neurodegenerative changes induced by traumatic brain injury. PLoS One 9:e108034|
|Shah, Gul N; Rubbelke, Timothy S; Hendin, Joshua et al. (2013) Targeted mutagenesis of mitochondrial carbonic anhydrases VA and VB implicates both enzymes in ammonia detoxification and glucose metabolism. Proc Natl Acad Sci U S A 110:7423-8|
|Shah, Gul N; Price, Tulin O; Banks, William A et al. (2013) Pharmacological inhibition of mitochondrial carbonic anhydrases protects mouse cerebral pericytes from high glucose-induced oxidative stress and apoptosis. J Pharmacol Exp Ther 344:637-45|
|Shah, Gul N; Morofuji, Yoichi; Banks, William A et al. (2013) High glucose-induced mitochondrial respiration and reactive oxygen species in mouse cerebral pericytes is reversed by pharmacological inhibition of mitochondrial carbonic anhydrases: Implications for cerebral microvascular disease in diabetes. Biochem Biophys Res Commun 440:354-8|
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