Balanced, polyvalent antiglutamatergic action as a novel approach to efficacious

平衡的多价抗谷氨酸作用作为一种有效的新方法

• 批准号: 7532037
• 负责人: ANATOLY E MARTYNYUK
• 金额: $ 19.23万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-26 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7532037
• 关键词: Acids; Acute; Adverse effects; Amino Acids; Animals; Antioxidants; Brain; Capillary Electrophoresis; Cardiovascular system; Central Nervous System Diseases; Cerebrum; Chemosensitization; Chronic; Class; Clinical Trials; Depressed mood; Detection; Epilepsy; Epileptogenesis; Equilibrium; Event; Excitatory Amino Acid Antagonists; Fluorescence; Glutamate Receptor; Glutamates; Hand; Impairment; Infarction; Ischemic-Hypoxic Encephalopathy; Kainic Acid Receptors; Lasers; Liquid Chromatography; Literature; Measurement; Mediating; Mental Depression; Microdialysis; Middle Cerebral Artery Occlusion; Modeling; N-Methylaspartate; Neurodegenerative Disorders; Neurons; Neurotransmitters; Pharmacologic Substance; Physiological; Physiology; Play; Process; Property; Public Health; Range; Rattus; Reactive Oxygen Species; Renal function; Role; Safety; Signal Transduction; Site; Stroke; Symptoms; System; Testing; Therapeutic; Tyrosine; artery occlusion; attenuation; base; concept; excitotoxicity; glutamate receptor subunit 3; in vivo; kainate; liquid chromatography mass spectrometry; middle cerebral artery; neuroprotection; novel; novel strategies; patch clamp; post stroke; postsynaptic; presynaptic; tandem mass spectrometry; uptake

DESCRIPTION (provided by applicant): Excessively activated ionotropic glutamate receptors of both the N-methyl-D-aspartate (NMDA) and (RS)-amino-3-hydroxy-5-methyl-4-isoxazolepropioinic acid (AMPA)/kainate subtypes initiate numerous events leading to neuronal damage in a wide range of pathophysiological states, including acute hypoxic-ischemic brain injury, epilepsy and many chronic neurodegenerative diseases. Also, glutamate is a major excitatory neurotransmitter that plays a critical role in normal brain physiology. Therefore it is not surprising that many previous highly selective and potent glutamate receptor antagonists, usually specific to NMDARs, failed clinical trials, primarily because of side effects they produced. These adverse effects may occur because of: 1) impairment of essential physiological function of NMDARs by NMDA antagonists; 2) intact excitotoxicity mediated by AMPA/kainate receptors; 3) increase in glutamate release caused by NMDA antagonists. Current study tests the novel concept that antiglutamatergic agents with polyvalent actions at pre and postsynaptic sites and moderate potency have the potential to overcome these limitations by producing efficacious neuroprotection still enabling a level of balanced glutamate receptor activity required for physiological brain functions and thus avoiding significant side effects. 3, 5-dibromo-Dtyrosine (3,5-DBr-D-Tyr), by depressing NMDA and AMPA/kainate receptors and glutamate release in combination with its antioxidant properties, may represent such agents. We will investigate the cellular mechanisms of 3, 5-DBr-D-Tyr action in neuronal cultures using patch-clamp, liquid chromatography/tandem mass spectrometry and glutamate uptake measurements. The neuroprotective properties of 3, 5-DBr-D-Tyr will be studied in vivo using a rat model of stroke caused by transient middle cerebral artery occlusion (MCAO). Microdialysis with capillary electrophoresis and laser-induced fluorescence detection will be used to elucidate the antiglutamatergic and antioxidant properties of 3, 5-DBr-D-Tyr. In order to access safety of 3, 5-DBr-D-Tyr, cardiovascular parameters, processing of sensorimotor information, renal function and histopathological changes in the brain of treated animals will be evaluated. Aim #1: To characterize the cellular mechanisms of 3, 5-DBr-D-Tyr action in the brain. Aim #2: To determine efficacy and safety of the neuroprotective action of 3, 5-DBr-D-Tyr in vivo in the rat transient MCAO model of stroke and to elucidate underlying mechanisms. PUBLIC HEALTH RELEVANCE: Glutamate receptors represent an obvious target for potential pharmaceutical agents aiming at ameliorating symptoms of a wide range of CNS disorders. Many previous highly selective and potent glutamate receptor antagonists failed clinical trials, primarily because of side effects they produced. This study tests the novel concept that antiglutamatergic agents with polyvalent actions and moderate potency have the potential to overcome these limitations by producing efficacious neuroprotection and still enabling a level of balanced glutamate receptor activity required for physiological brain functions and thus avoiding significant side effects.

描述（由申请人提供）：N-甲基-D-天冬氨酸（NMDA）和（RS）-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）/红藻氨酸亚型的离子型谷氨酸受体过度激活引发多种事件，导致多种病理生理状态下的神经元损伤，包括急性缺氧缺血性脑损伤、癫痫和许多慢性神经退行性疾病。此外，谷氨酸是一种主要的兴奋性神经递质，在正常大脑生理学中发挥着关键作用。因此，许多先前的高选择性和强效谷氨酸受体拮抗剂（通常针对 NMDAR）未能通过临床试验也就不足为奇了，这主要是因为它们产生的副作用。这些不良反应的发生可能是因为： 1) NMDA 拮抗剂损害 NMDAR 的基本生理功能； 2) 由AMPA/红藻氨酸受体介导的完整兴奋毒性； 3) NMDA拮抗剂引起的谷氨酸释放增加。目前的研究测试了一个新概念，即在突触前和突触后位点具有多价作用且效力中等的抗谷氨酸能药物有可能克服这些局限性，通过产生有效的神经保护作用，仍然能够实现生理脑功能所需的平衡谷氨酸受体活性水平，从而避免显着的副作用影响。 3, 5-二溴-D酪氨酸 (3,5-DBr-D-Tyr) 通过抑制 NMDA 和 AMPA/红藻氨酸受体以及谷氨酸释放及其抗氧化特性，可能是此类药物的代表。我们将使用膜片钳、液相色谱/串联质谱法和谷氨酸摄取测量来研究 3, 5-DBr-D-Tyr 在神经元培养物中作用的细胞机制。将使用短暂性大脑中动脉闭塞 (MCAO) 引起的中风大鼠模型在体内研究 3, 5-DBr-D-Tyr 的神经保护特性。毛细管电泳微透析和激光诱导荧光检测将用于阐明 3, 5-DBr-D-Tyr 的抗谷氨酸和抗氧化特性。为了了解 3, 5-DBr-D-Tyr 的安全性，将对治疗动物的心血管参数、感觉运动信息处理、肾功能和大脑组织病理学变化进行评估。目标#1：表征 3, 5-DBr-D-Tyr 在大脑中作用的细胞机制。目标#2：确定 3, 5-DBr-D-Tyr 在大鼠短暂性中风 MCAO 模型中的体内神经保护作用的有效性和安全性，并阐明潜在机制。公共卫生相关性：谷氨酸受体代表了旨在改善多种中枢神经系统疾病症状的潜在药物的明显靶点。之前许多高选择性和强效的谷氨酸受体拮抗剂都未能通过临床试验，主要是因为它们产生的副作用。这项研究测试了一个新概念，即具有多价作用和中等效力的抗谷氨酸能药物有可能通过产生有效的神经保护作用来克服这些局限性，并仍然实现生理脑功能所需的平衡谷氨酸受体活性水平，从而避免显着的副作用。