Reducing Brain Hyperglycolysis: A Novel Strategy for Hyperglycemia after Stroke

减少脑糖酵解过多：中风后高血糖的新策略

基本信息

批准号：
10101488
负责人：
YUCHUAN DING
金额：
--
依托单位：
JOHN D DINGELL VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-01 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10101488
关键词：
Acute Address Aerobic Affect Alternative Therapies Anaerobic Bacteria Animals Antipsychotic Agents Area Attenuated Blood Glucose Blood flow Brain Brain Edema Brain Injuries Cell Death Cerebrum Chlorpromazine Clinic Clinical Clinical Research Clinical Treatment Complex Development Diabetes Mellitus Disabled Persons Disease Energy-Generating Resources Ethanol Generations Glucose Glucose Transporter Glycolysis Hemorrhage Hibernation Hyperactive behavior Hyperglycemia Hypoglycemia Impairment Infarction Injury Insulin Ischemia Ischemic Brain Injury Ischemic Penumbra Ischemic Stroke Lactic Acidosis Lead Metabolic Metabolism Middle Cerebral Artery Occlusion Modality NADP NADPH Oxidase National Institute of Neurological Disorders and Stroke Neurologic Deficit Neurological outcome Neuroprotective Agents Outcome Oxidases Oxidative Phosphorylation Oxidative Stress Oxygen Pathway interactions Pharmaceutical Preparations Phase Phenothiazines Population Production Promethazine Rattus Reactive Oxygen Species Recording of previous events Reducing Agents Reperfusion Therapy Reporting Research Rodent Role Serum Stroke Testing Therapeutic United States National Institutes of Health anaerobic glycolysis brain cell clinical investigation depressive symptoms deprivation diabetic disability effective therapy experimental study functional outcomes glucose metabolism glucose uptake improved ischemic injury metabolic rate middle cerebral artery novel novel strategies novel therapeutic intervention novel therapeutics oxidative damage physically handicapped post stroke pre-clinical prevent public health relevance relating to nervous system stroke model stroke patient

项目摘要

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.

描述：无论是否有糖尿病病史，高血糖（即血糖升高）都会影响约 40% 的急性缺血性中风患者。在实验和临床研究中，高血糖会导致糖代谢异常和糖酵解过度导致的氧化损伤持续存在，从而加重缺血性脑损伤。临床上，为了解决中风中的高血糖问题，已使用胰岛素来使血糖水平正常化，但尚未产生明显的有益结果。此类治疗主要是因为持续性低血糖或血糖水平控制不当，因此非常需要开发一种针对中风高血糖的替代疗法。葡萄糖最初通过糖酵解进行分解代谢，随后通过有氧途径产生细胞所需的 ATP。在缺血中，葡萄糖的氧化磷酸化因缺氧而受损，脑细胞试图通过增加无氧来应对新的代谢挑战。糖酵解（糖酵解过度）在 ATP 产生中效率非常低，因此会引起乳酸性酸中毒，尤其是在再灌注时，通过激活缺血期间产生的烟酰胺腺嘌呤二核苷酸磷酸 (NADPH) 氧化酶 (NOX) 进一步产生 ROS。众所周知，冬眠动物会适应大脑血流量的显着减少，从而增强 NADPH 的产生。同样，中风后诱导“类似冬眠”的状态可能会减弱与血流减少或缺乏相关的脑损伤。和吩噻嗪类精神安定药（氯丙嗪和异丙嗪）不仅会降低大脑活动和葡萄糖代谢，还会导致缺血性脑损伤。这些作用增加了 ETOH 和吩噻嗪类药物的可能性。可能因其在中风后调节大脑葡萄糖代谢的能力而成为一种新型神经保护剂。在啮齿动物短暂性和永久性中风模型中，我们将首先确定是否在缺血后施用 ETOH 或氯丙嗪 + 异丙嗪组合。减少脑损伤并改善功能结果（目标 1），然后我们将测试所提出的疗法是否减少缺血半暗带和高血糖相关大脑中的葡萄糖摄取、利用、代谢，从而减少糖酵解过度。（目标 2）我们还将确定我们的治疗是否通过改善葡萄糖转运蛋白表达和 NOX 复合物的形成和激活来预防氧化损伤（目标 3），因为中风后胰岛素治疗一直存在争议，因此拟议的治疗可能更有效。通过减缓脑葡萄糖代谢和减弱糖酵解相关的 NOX 活性来减少高血糖增强的缺血性损伤，这种治疗价值将被开发为治疗糖尿病和中风诱发的有效方法。高血糖。