NMDA Receptor Dynamics After Brain Injury

脑损伤后 NMDA 受体动态

• 批准号: 7196146
• 负责人: ANAT BIEGON
• 金额: $ 36.52万
• 依托单位: BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-06 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7196146
• 关键词: Ablation; Acute; Agonist; Animal Model; Animals; Autoradiography; Biochemical; Biological Assay; Brain; Brain Injuries; Brain region; Catheters; Cessation of life; Clinical Trials; Closed head injuries; Cognitive deficits; Condition; Craniocerebral Trauma; Cycloserine; Dose; Electrophysiology (science); Event; Excision; Failure; Frequencies; Gene Expression; Glutamates; Hippocampus (Brain); Human; Injury; Kinetics; Life; Ligands; Long-Term Effects; Long-Term Potentiation; Longitudinal Studies; MK801; Measures; Mediating; Memory; Modeling; Monitor; Morbidity - disease rate; Morphology; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NMDA receptor antagonist; NR1 gene; Neurologic; Neurologic Dysfunctions; Neurons; Neurosurgical Procedures; Numbers; Outcome; Pathology; Phase; Physiological; Play; Procedures; Public Health; Quantitative Autoradiography; Range; Receptor Activation; Receptor Gene; Recovery of Function; Research; Role; Staining method; Stains; Testing; Time; Traumatic Brain Injury; Work; brain tissue; day; desensitization; disability; excitotoxicity; functional loss; human NR1 protein; improved; injured; morris water maze; mortality; novel strategies; object recognition; receptor; receptor function; response; young adult

DESCRIPTION (provided by applicant): Brain injury is a leading cause of mortality and morbidity among young people in the industrialized world. Attempts to treat accidental brain injuries with glutamate NMDA receptor (NMDAR) antagonists have failed to produce any improvement in outcome in several major clinical trials. These trials were predicated on the hypothesis that neurological deficits after head injury are, at least in part, the result of hyperactivation of NMDAR and "excitotoxicity". The working hypothesis behind the proposed studies is three fold: 1. Hyperactivation of NMDAR after head injury is short lived and gives way to prolonged hypofunction; 2. The cognitive deficits after brain injury are a results of underactivation, rather than overactivation, of NMDA receptors. 3. Delayed activation of NMDAR may accelerate recovery of function after brain injury. A secondary hypothesis postulates that some brain regions; such as the hippocampus; are inherently more vulnerable to brain injury than others. We propose to test these hypotheses in mice with closed head injury; an animal model of blunt head trauma. Regional changes in NMDAR availablility and functional (activational) state will be measured at times ranging from 5 min to 60 days after injury using quantitative autoradiography of the use-dependent ligand MK801. Physiological correlates of NMDAR hyepr-activation and hypo-activation will be measured using electrophysiology (Long term potentiation). Cognitive deficits will be tested 14 and 60 days after the injury using two different tasks; the object recognition test and the Morris water maze in animals administered with the full agonist NMDA , the partial NMDAR agonist d-Cycloserine or the antagonist MK801 at various time points and frequencies after the injury. Finally the contribution of several likely mechanisms to the dynamic changes in NMDAR after brain injury will be investigated by 1. Dose response and kinetic studies of the relationship between dose and duration of NMDAR activation and functional respone 2. Manipulating assay conditions 3. immuno-histochemical staining for the obligatory NR1 unit and the NR2 subunits of NMDAR. The proposed research focuses on the fate of NMDAR, a molecule believed to play a key role in the pathology of brain injury. Brain injury is a major public health problem since it is associated with death and long-term disability in a significant proportion of victims, who are mostly young adults. The results may explain the failure of NMDAR antagonists in clinical trials and suggest novel strategies for treatment of brain injury.

描述（由申请人提供）：脑损伤是工业化世界中年轻人死亡和发病的主要原因。在几个主要的临床试验中，用谷氨酸NMDA受体（NMDAR）拮抗剂治疗意外脑损伤的尝试未能产生任何改善的结果。这些试验是基于这样的假设，即脑损伤后的神经功能缺陷至少部分是NMDAR过度激活和“兴奋性毒性”的结果。提出的研究背后的工作假设有三个方面：1。头部损伤后NMDAR的过度激活是短暂的，让位给长期的功能减退；2. 脑损伤后的认知缺陷是NMDA受体激活不足而不是过度激活的结果。3. NMDAR的延迟激活可能加速脑损伤后功能的恢复。第二种假设假设大脑的某些区域；比如海马体；天生就比其他人更容易受到脑损伤。我们建议在闭合性脑损伤小鼠中验证这些假设；钝性头部创伤动物模型。NMDAR可用性和功能（激活）状态的区域变化将在损伤后5分钟至60天内使用使用依赖性配体MK801的定量放射自显影术进行测量。NMDAR高激活和低激活的生理相关性将通过电生理学（长期增强）来测量。认知缺陷将在受伤后14天和60天通过两项不同的任务进行测试；在损伤后不同时间点和频率分别给予NMDA完全激动剂、NMDA部分激动剂d-环丝氨酸或MK801拮抗剂的动物进行物体识别试验和Morris水迷宫。最后，本文将探讨几种可能的机制对脑损伤后NMDAR动态变化的贡献。NMDAR激活与功能反应的剂量反应及剂量与持续时间关系的动力学研究操作分析条件免疫组化染色检测NMDAR的专性NR1和NR2亚基。这项研究的重点是NMDAR的命运，这是一种被认为在脑损伤病理中起关键作用的分子。脑损伤是一个重大的公共卫生问题，因为它与很大一部分受害者（大多数是年轻人）的死亡和长期残疾有关。该结果可以解释NMDAR拮抗剂在临床试验中的失败，并为脑损伤治疗提供新的策略。