The long-term goal of this project is to improve neurological health of diabetics by decreasing the severity and incidence of cerebral ischemia in diabetics. Cerebral ischemia and heart disease are the most serious complications of diabetes, accounting for more than 84% of the mortality among diabetics. Epidemiological studies of cerebral ischemia suggest that diabetes increases both the risk of incidence and exacerbates the consequences of cerebral ischemia. Hyperglycemia is one of the contributing factors. In clinical studies, intensive anti-diabetic therapy was able to delay the onset and slow the progression of secondary complications of diabetes. The major side-effect of intensive diabetic therapy is hypoglycemia. Several reports described hypoglycemic episodes in type 1 and type 2 diabetics receiving intensive therapy. Using the streptozotocin-diabetic rat, we observed that recurrent hypoglycemia (RH) renders the insulin-treated diabetic (ITD) rat brain more sensitive to global cerebral ischemia and results in greater brain damage. Presently, we are proposing to investigate the mechanism by which RH increases ischemic damage in ITD. In preliminary studies we observed that the intra-ischemic extracellular pH drop was enhanced, and the levels of glucose transporters (GLUTs) 1 and 3 were increased in the hippocampus of ITD rats subjected to RH. We hypothesize that in the insulin-treated diabetic brain, increased glucose transporter levels following RH lead to increased intra-ischemic acidosis, sensitizing the brain towards the enhancement of cerebral ischemia-induced damage. The following specific objectives are proposed to test the central hypothesis: 1) To determine how RH increases cerebral ischemic damage in ITD rats;2) To determine the mechanism by which the larger intra-ischemic pH drop in RH-exposed ITD rats increases cerebral ischemic damage;and 3) To determine the mechanism by which RH increases GLUT1 and GLUT3 levels in the hippocampus of ITD rats. We expect these studies to provide insight into the mechanism by which RH increases ischemic damage in diabetics. Understanding this mechanism will help improve outcome following cerebral ischemia.
Diabetes is a risk factor for cerebral ischemia and heart disease. A major side effect of intensive therapy for diabetics is intermittent low blood glucose levels (hypoglycemia). Our results indicate that intermittent hypoglycemic episodes preceding an ischemic attack result in increased brain damage in diabetics. We propose to determine the mechanisms by which hypoglycemic episodes cause increased susceptibility to cerebral ischemic damage in diabetics.
|Thompson, John W; Narayanan, Srinivasan V; Koronowski, Kevin B et al. (2015) Signaling pathways leading to ischemic mitochondrial neuroprotection. J Bioenerg Biomembr 47:101-10|
|Rehni, Ashish K; Nautiyal, Neha; Perez-Pinzon, Miguel A et al. (2015) Hyperglycemia / hypoglycemia-induced mitochondrial dysfunction and cerebral ischemic damage in diabetics. Metab Brain Dis 30:437-47|
|Koronowski, Kevin B; Dave, Kunjan R; Saul, Isabel et al. (2015) Resveratrol Preconditioning Induces a Novel Extended Window of Ischemic Tolerance in the Mouse Brain. Stroke 46:2293-8|
|Cohan, Charles H; Neumann, Jake T; Dave, Kunjan R et al. (2015) Effect of cardiac arrest on cognitive impairment and hippocampal plasticity in middle-aged rats. PLoS One 10:e0124918|
|Lin, Hung Wen; Gresia, Victoria L; Stradecki, Holly M et al. (2014) Protein kinase C delta modulates endothelial nitric oxide synthase after cardiac arrest. J Cereb Blood Flow Metab 34:613-20|
|Della-Morte, David; Palmirotta, Raffaele; Rehni, Ashish K et al. (2014) Pharmacogenomics and pharmacogenetics of thiazolidinediones: role in diabetes and cardiovascular risk factors. Pharmacogenomics 15:2063-82|
|Lin, Hung Wen; Saul, Isabel; Gresia, Victoria L et al. (2014) Fatty acid methyl esters and Solutol HS 15 confer neuroprotection after focal and global cerebral ischemia. Transl Stroke Res 5:109-17|
|Neumann, Jake T; Cohan, Charles H; Dave, Kunjan R et al. (2013) Global cerebral ischemia: synaptic and cognitive dysfunction. Curr Drug Targets 14:20-35|
|Narayanan, Srinivasan V; Dave, Kunjan R; Perez-Pinzon, Miguel A (2013) Ischemic preconditioning and clinical scenarios. Curr Opin Neurol 26:1-7|
|Thompson, John W; Dave, Kunjan R; Young, Juan I et al. (2013) Ischemic preconditioning alters the epigenetic profile of the brain from ischemic intolerance to ischemic tolerance. Neurotherapeutics 10:789-97|
Showing the most recent 10 out of 12 publications