NMDA Receptor Dynamics After Brain Injury

脑损伤后 NMDA 受体动态

• 批准号: 7538379
• 负责人: ANAT BIEGON
• 金额: $ 37.08万
• 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/7538379
• 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; 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; Outcome; Pathology; Phase; Physiological; Play; Procedures; Public Health; Quantitative Autoradiography; Receptor Activation; Receptor Gene; Recovery of Function; Research; Role; Staining method; Stains; Testing; Time; Traumatic Brain Injury; Work; brain tissue; desensitization; disability; excitotoxicity; functional loss; improved; injured; morris water maze; novel strategies; object recognition; receptor; receptor function; response; young adult

Brain injury is a leading cause of moratlity 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.

脑损伤是工业化国家年轻人死亡和发病的主要原因。 尝试用谷氨酸NMDA受体（NMDAR）拮抗剂治疗意外脑损伤， 在几个主要的临床试验中没有产生任何结果的改善。这些试验被预测为 假设头部受伤后的神经功能缺损至少部分是由于 NMDAR过度活化和“兴奋性毒性”。 拟议研究背后的工作假设有三个方面： 1.脑损伤后NMDAR的过度激活是短暂的，并让位于长期的功能减退; 2.脑损伤后的认知缺陷是大脑皮层激活不足，而不是过度激活的结果， NMDA受体。 3. NMDAR的延迟激活可加速脑损伤后的功能恢复。 第二种假设认为，某些大脑区域，如海马体， 比其他人更容易受到脑损伤我们建议在小鼠中测试这些假设， 头部损伤;钝性头部创伤动物模型。NMDAR可用性的区域变化， 功能（激活）状态将在损伤后5分钟至60天的时间范围内测量， 使用依赖性配体MK 801的定量放射自显影。NMDAR的生理相关性 将使用电生理学（长时程增强）测量高活化和低活化。 认知缺陷将在受伤后14天和60天使用两种不同的任务进行测试; 在给予完全激动剂NMDA的动物中， 部分NMDAR激动剂d-环丝氨酸或拮抗剂MK 801在不同时间点和频率 受伤后。最后讨论了几种可能的机制对NMDAR动态变化的贡献 脑损伤后将由1.剂量反应和动力学研究之间的关系 剂量和持续时间的NMDAR激活和功能反应2.操作测定条件3. NMDAR的专性NR 1和NR 2亚单位的免疫组织化学染色。 拟议的研究集中在NMDAR的命运上，NMDAR是一种被认为在癌症中起关键作用的分子。 脑损伤的病理学脑损伤是一个主要的公共卫生问题，因为它与死亡有关 在相当大比例的受害者中，大多数是年轻的成年人。结果 可能解释了NMDAR拮抗剂在临床试验中的失败，并提出了新的治疗策略 脑损伤