Diabetes mellitus (DM) is the sixth and stroke is the third leading cause of death in the United States. Although both experimental and clinical data have shown that diabetic hyperglycemia (HG) augments brain damage due to cerebral ischemia, the molecular mechanisms underlying this important, clinically relevant phenomenon are poorly defined. Preliminary studies suggest that HG enhances the superoxide production of mitochondrial origin and causes mitochondria! functional and morphological alterations in the early stage of reperfusion following a transient cerebral ischemia. HG-enhanced reactive oxygen species (ROS) formation may be caused by increased proton potential across the inner mitochondrial membrane due to excessive extrusion of protons donated from NADH and FADH2 through glucose metabolism. Mitochondrial uncoupling proteins (UCPs) dissipate the mitochondrial proton gradient by transporting H+ across the inner membrane, thereby stabilizing the mitochondrial membrane potential and reducing the formation of ROS. However, existing eveidence provids conflicting results to whether UCP2 is neuroprotective or neurodestructive. Our Central Hypothesis is that diabetic hyperglycemia enhances brain damage during stroke by overproducing ROS from the mitochondrial electron transport chain (ETC) due to increased extrusion of protons that perturbs AM^m. Accordingly, if the membrane potential is stabilized by upregulation of UCP2 the formation of ROS may be reduced and the diabetes-exacerbated stroke damage may be prevented. Using in vitro neuronal cultures that simulate in vivo diabetic and ischemic stroke conditions and an in vivo stroke model in Tg-UCP2, KO-UCP2 and genetic background matched C57BL/6J mice under both non- DM and DM conditions, the objectives of this study are to: 1) determine the pathways leading to ROS production after in vitro oxygen deprivation (OD) in cultured neurons mimicking in vivo diabetes and stroke conditions, 2) determine if deletion of the UCP2 gene augments and overexpression of UCP2 prevents HG- enhanced brain damage using both in vitro and in vivo ischemia models, and 3) determine the pathways by which UCP2 exerts its protective effects. Our successful achievement of this goal should significantly contribute to the current understanding of this clinical problem and may lead to the development of new therapeutic approaches, e.g. via manipulation of UCPs expression in the brain as a treatment for the disease

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK075476-06
Application #
8079675
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Jones, Teresa L Z
Project Start
2007-07-01
Project End
2014-06-30
Budget Start
2011-07-01
Budget End
2014-06-30
Support Year
6
Fiscal Year
2011
Total Cost
$229,368
Indirect Cost
Name
North Carolina Central University
Department
Type
Organized Research Units
DUNS #
783691801
City
Durham
State
NC
Country
United States
Zip Code
27707
Ma, Wanrui; Jing, Li; Valladares, Alexandra et al. (2015) Silver nanoparticle exposure induced mitochondrial stress, caspase-3 activation and cell death: amelioration by sodium selenite. Int J Biol Sci 11:860-7
Li, Haining; Chen, Guisheng; Ma, Wanrui et al. (2014) Water-soluble coenzyme q10 inhibits nuclear translocation of apoptosis inducing factor and cell death caused by mitochondrial complex I inhibition. Int J Mol Sci 15:13388-400
Pan, Juan; Zhang, Lingwu; Wang, Feng et al. (2013) Amygdala Kindling Alters Estrus Cycle and Ovarian Morphology in the Rat. Int J Sci 2:12-21
Jing, Li; Mai, Li; Zhang, Jian-Zhong et al. (2013) Diabetes inhibits cerebral ischemia-induced astrocyte activation - an observation in the cingulate cortex. Int J Biol Sci 9:980-8
Mehta, Suresh L; Mendelev, Natalia; Kumari, Santosh et al. (2013) Overexpression of human selenoprotein H in neuronal cells enhances mitochondrial biogenesis and function through activation of protein kinase A, protein kinase B, and cyclic adenosine monophosphate response element-binding protein pathway. Int J Biochem Cell Biol 45:604-11
Jing, Li; He, Qingping; Zhang, Jian-Zhong et al. (2013) Temporal profile of astrocytes and changes of oligodendrocyte-based myelin following middle cerebral artery occlusion in diabetic and non-diabetic rats. Int J Biol Sci 9:190-9
Kumari, Santosh; Anderson, Lavita; Farmer, Stephanie et al. (2012) Hyperglycemia alters mitochondrial fission and fusion proteins in mice subjected to cerebral ischemia and reperfusion. Transl Stroke Res 3:296-304
Kumari, Santosh; Mehta, Suresh L; Li, P Andy (2012) Glutamate induces mitochondrial dynamic imbalance and autophagy activation: preventive effects of selenium. PLoS One 7:e39382
Haines, Bryan; Li, P Andy (2012) Overexpression of mitochondrial uncoupling protein 2 inhibits inflammatory cytokines and activates cell survival factors after cerebral ischemia. PLoS One 7:e31739
Mehta, Suresh L; Kumari, Santosh; Mendelev, Natalia et al. (2012) Selenium preserves mitochondrial function, stimulates mitochondrial biogenesis, and reduces infarct volume after focal cerebral ischemia. BMC Neurosci 13:79

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