Reducing Brain Hyperglycolysis: A Novel Strategy for Hyperglycemia after Stroke

 说明： 高血糖(即血糖升高)影响大约40%的急性缺血性中风患者，而不考虑糖尿病病史。在实验和临床研究中，高血糖通过维持异常的葡萄糖代谢和过度产生活性氧自由基(ROS)引起的高糖酵解相关的氧化损伤来加重缺血性脑损伤。在临床上，为了解决中风的高血糖问题，胰岛素已经被用来使血糖水平正常化。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、有效的治疗卒中高血糖的方法是非常必要的。葡萄糖最初被糖酵解分解，然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。在缺血状态下，虽然葡萄糖的氧化磷酸化因缺氧而受损，但脑细胞试图通过增加无氧糖酵解(高糖酵解)来应对新的代谢挑战。厌氧糖酵解导致乳酸酸中毒，导致ROS，特别是在再灌流时。ROS的进一步产生是通过激活烟酰胺腺嘌呤二核苷酸磷酸(NADPH)氧化酶(NOX)，该酶在缺血时产生，并通过高糖酵解增加NADPH的产生。众所周知，冬眠动物会适应流向大脑的血液显著减少，这对非冬眠动物是有害的。类似地，中风后诱导的“冬眠”状态可能会减轻与血流减少或缺乏相关的脑损伤。我们和其他人的实验研究表明，乙醇(Etoh)和吩噻嗪类神经镇静剂(氯丙嗪和异丙嗪)不仅可以降低脑活动和葡萄糖代谢，而且还可以降低缺血性脑损伤。这些效应增加了乙醇和吩噻嗪类药物可能作为一种新的神经保护剂的可能性，因为它们能够调节中风后的大脑葡萄糖代谢。这里拟议的研究涉及这一假定的能力。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乙醇或氯丙嗪+异丙嗪联合应用是否减少了脑损伤并改善了功能结果(目标1)。然后，我们将测试建议的疗法是否减少了缺血半暗带和高血糖相关脑的葡萄糖摄取、利用、代谢和高糖酵解(目标2)。我们还将确定我们的疗法是否通过改善葡萄糖转运体的高表达和NOX复合体的形成和激活来防止氧化损伤(目标3)。由于卒中后胰岛素治疗一直存在争议，建议的治疗方法可能通过减缓大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所致的缺血性损伤。这种治疗价值将被开发为治疗糖尿病和中风引起的高血糖的有效方法。

 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.