Reducing Brain Hyperglycolysis: A Novel Strategy for Hyperglycemia after Stroke

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 DESCRIPTION: Hyperglycemia (i.e., elevated blood glucose) affects approximately 40% of acute ischemic stroke patients, regardless of a diabetes history. In experimental and clinical studies, hyperglycemia exacerbates ischemic brain injury by perpetuating aberrant glucose metabolism and hyperglycolysis-associated oxidative injury from excessive production of reactive oxygen species (ROS). Clinically, to address hyperglycemia in stroke, insulin has been implemented to normalize serum glucose levels. However no clear beneficial outcome has resulted from such treatment, mainly because of persistent hypoglycemia or inadequately controlled glucose levels. Therefore development of an alternative and effective therapy for hyperglycemia in stroke is highly desirable. Glucose is initially catabolized by glycolysis, and subsequently through the aerobic pathway to produce cellular ATP needed as the primary energy source for neural activity. In ischemia while oxidative phosphorylation of glucose is impaired due to oxygen deprivation, brain cells attempt to meet their new metabolic challenge by increasing anaerobic glycolysis (hyperglycolysis). Anaerobic glycolysis, which is very inefficient in ATP production, induces lactic acidosis thus ROS, especially upon reperfusion. ROS is further produced by activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX), which is generated during ischemia and enhanced by NADPH production through hyperglycolysis. Hibernating animals are known to adapt to a significant decrease of blood flow to the brain, which would be deleterious to a non-hibernating animal. Similarly, induction of a "hibernation-like" status after stroke may blunt brain damage associated with decreased or absence of blood flow. Experimental studies by us and others have demonstrated depressive roles of ethanol (ETOH) and phenothiazine neuroleptics (Chlorpromazine and Promethazine) in decreasing not only brain activity and glucose metabolism, but also ischemic brain damage. These effects raise the possibility that ETOH and phenothiazine drugs might serve as a novel neuroprotectant by its ability to regulate brain glucose metabolism after stroke. The proposed studies here address this putative capability. In rodent transient and permanent stroke models, we will first establish whether post-ischemia administration of ETOH or Chlorpromazine+Promethazine combination reduces brain injury and improve functional outcome (Aim 1). We will then test whether the proposed therapy reduces glucose uptake, utilization, metabolism and thus hyperglycolysis, in ischemic penumbra and hyperglycemia-associated brain (Aim 2). We will also determine whether our therapy prevents oxidative injury by ameliorating elevated glucose transporter expression and NOX complex formation and activation (Aim 3). Because post-stroke insulin treatment has been controversial, the proposed treatments may be more effective in reducing hyperglycemia-enhanced ischemic injury by both slowing cerebral glucose metabolism and attenuating glycolysis-associated NOX activity. This therapeutic value would then be developed as an effective approach in diabetic and stroke-induced hyperglycemia.