Reducing Brain Hyperglycolysis: A Novel Strategy for Hyperglycemia after Stroke

 产品说明： 高血压（即，血糖升高）影响约40%的急性缺血性中风患者，而不管其是否有糖尿病史。在实验和临床研究中，高血糖症通过使异常的葡萄糖代谢和由活性氧（ROS）的过量产生引起的糖酵解过度相关的氧化损伤永久化而加重缺血性脑损伤。在临床上，为了解决中风中的高血糖症，已经实施胰岛素以使血清葡萄糖水平正常化。然而，这种治疗没有产生明确的有益结果，主要是因为持续的低血糖或血糖水平控制不充分。因此，开发一种替代的和有效的治疗高血糖症的中风是非常可取的。葡萄糖最初通过糖酵解分解代谢，随后通过有氧途径产生细胞ATP，作为神经活动的主要能量来源。在缺血中，由于缺氧，葡萄糖的氧化磷酸化受损，脑细胞试图通过增加无氧糖酵解（hyperglycolysis）来应对新的代谢挑战。厌氧糖酵解，这是非常低效的ATP生产，诱导乳酸酸中毒，从而ROS，特别是在再灌注。ROS进一步通过激活烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶（NOX）产生，NOX在缺血期间产生并通过糖酵解过度产生NADPH而增强。冬眠的动物能够适应大脑血流量的显著减少，这对非冬眠动物是有害的。类似地，中风后诱导“冬眠样”状态可能会使与血流减少或缺乏相关的脑损伤变钝。我们和其他人的实验研究已经证明了乙醇（ETOH）和吩噻嗪类神经抑制剂（氯丙嗪和异丙嗪）不仅在降低脑活动和葡萄糖代谢方面，而且在缺血性脑损伤方面具有抑制作用。这些作用提高了ETOH和吩噻嗪药物可能作为一种新的神经保护剂，其调节脑卒中后葡萄糖代谢的能力。这里提出的研究解决了这种假定的能力。在啮齿动物短暂性和永久性卒中模型中，我们将首先确定缺血后给予ETOH或氯丙嗪+异丙嗪组合是否减少脑损伤并改善功能结局（目的1）。然后，我们将测试所提出的治疗是否减少缺血半暗带和高血糖相关脑中的葡萄糖摄取、利用、代谢，从而减少糖酵解过度（目的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和NOX复合物的形成和活化来预防氧化损伤（目的3）。由于卒中后胰岛素治疗一直存在争议，因此提出的治疗方法可能通过减缓脑葡萄糖代谢和减弱糖酵解相关的NOX活性来更有效地减少高血糖增强的缺血性损伤。这种治疗价值将被开发为糖尿病和中风引起的高血糖症的有效方法。

 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.