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：
9084705
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 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9084705
关键词：
Acute Address Aerobic Affect Alternative Therapies 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 Employee Strikes Energy-Generating Resources Ethanol Generations Glucose Glucose Transporter Glycolysis Hibernation Hyperglycemia Hypoglycemia Infarction Injury Insulin Ischemia Ischemic Brain Injury Ischemic Penumbra Ischemic Stroke Lactic Acidosis Lead Metabolic Metabolism Middle Cerebral Artery Occlusion Modality Modeling NADP NADPH Oxidase National Institute of Neurological Disorders and Stroke Neurologic Neurological outcome Neuroprotective Agents Outcome Oxidases Oxidative Phosphorylation Oxidative Stress Oxygen Pathway interactions Patients Pharmaceutical Preparations Phase Phenothiazines Physically Handicapped Population Production Promethazine Rattus Reactive Oxygen Species Recording of previous events Reperfusion Therapy Reporting Research Rodent Role Serum Stroke Testing Therapeutic United States National Institutes of Health anaerobic glycolysis base blood glucose regulation brain cell clinical investigation depressive symptoms deprivation diabetic disability effective therapy functional outcomes glucose metabolism glucose uptake improved meetings metabolic rate middle cerebral artery novel novel strategies novel therapeutic intervention novel therapeutics post stroke pre-clinical prevent public health relevance relating to nervous system research study

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：高血糖（即血糖升高）会影响大约40％的急性缺血性中风患者，而不论糖尿病病史如何。在实验和临床研究中，高血糖通过使异常葡萄糖代谢和高糖基学相关的氧化物损伤因过量产生活性氧（ROS）而加剧缺血性脑损伤。在临床上，为了解决中风高血糖，已经实施了胰岛素以使血清葡萄糖水平归一化。但是，这种治疗没有明确的有益结果，这主要是由于持续性低血糖或无法充分控制的葡萄糖水平。因此，非常需要开发中风高血糖的替代疗法。葡萄糖最初是通过糖酵解分解代谢的，然后通过有氧途径通过有氧途径来产生所需的细胞ATP作为神经元活性的主要能源。在缺血中，葡萄糖的氧化物磷酸化因氧气剥夺而受到损害，但脑细胞试图通过增加厌氧性糖酵解（高糖酵解）来应对其新的代谢挑战。 ATP产生效率非常低的厌氧性糖酵解诱导乳酸性酸中毒，因此尤其是在再灌注后。 ROS是通过激活烟酰胺腺嘌呤二核苷酸（NADPH）氧化物（NOX）的激活，该氧化物（NOX）是在缺血期间产生的，并通过高糖酵解通过NADPH产生增强。已知冬眠的动物可适应大脑的血液流动的显着降低，这对非解脱动物会有害。同样，中风后诱导“冬眠状”状态可能会钝化脑损伤，与血液流量减少或缺乏有关。我们和其他人的实验研究表明，乙醇（ETOH）和苯噻嗪神经肽（氯丙嗪和异丙嗪）的抑郁作用不仅减少脑活动和葡萄糖代谢，还减少缺血性脑损伤。这些作用增加了ETOH和苯噻嗪药物可以通过调节中风后脑葡萄糖代谢的能力而成为一种新的神经保护剂的可能性。这里提出的研究涉及这种推定的能力。在啮齿动物的瞬态和永久性中风模型中，我们将首先确定ETOH或氯丙胺+异丙嗪的组合是否会减少脑损伤并改善功能结果（AIM 1）。然后，我们将测试所提出的治疗是否会减少缺血性阴茎和高血糖相关的大脑中的葡萄糖摄取，利用率，代谢，从而减少过度糖酵解（AIM 2）。我们还将确定我们的治疗是否通过改善升高的葡萄糖转运蛋白表达以及NOX复合物的形成和激活来防止氧化损伤（AIM 3）。由于中风后胰岛素治疗引起了争议，因此提出的治疗方法可能更有效地通过减慢脑葡萄糖代谢和衰减糖酵解相关的NOX活性来减少高血糖增强的缺血性损伤。然后，该治疗值将作为糖尿病和中风诱导的高血糖的有效方法发展。