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.

脑损伤是工业化世界中年轻人厌恶和发病率的主要原因。 试图用谷氨酸NMDA受体（NMDAR）拮抗剂治疗意外脑损伤的尝试 在几项主要的临床试验中，无法改善结果的任何改善。这些试验是预测的 关于头部损伤后神经系统缺陷至少部分的假设是 NMDAR和“兴奋性毒性”的过度激活。 拟议的研究背后的工作假设是三个方面： 1。头部损伤后NMDAR的过度激活寿命短，并让位于长时间功能障碍； 2。脑损伤后的认知缺陷是未能激活而不是过度活化的结果 NMDA受体。 3。延迟NMDAR的激活可能会加速脑损伤后功能的恢复。 次要假设假设某些大脑区域。例如海马；是天生的 比其他人更容易受到脑损伤。我们建议在关闭的小鼠中检验这些假设 头部受伤；钝头创伤的动物模型。 NMDAR可用性的区域变化和 功能（激活）状态将在受伤后5分钟到60天内测量 使用依赖性配体MK801的定量放射自显影。 NMDAR的生理相关性 将使用电生理学（长期增强）来测量渗流激活和低激活。 认知缺陷将在受伤后14和60天使用两种不同的任务进行测试；对象 识别测试和用全部激动剂NMDA施用的动物中的莫里斯水迷宫， 部分NMDAR激动剂D-Cycloserine或拮抗剂MK801在各个时间点和频率下 受伤后。最后，几种可能的机制对NMDAR的动态变化的贡献 脑损伤后，将通过1。剂量反应和动力学研究 NMDAR激活和功能疗法的剂量和持续时间2。操纵测定条件3。 强制性NR1单元和NMDAR的NR2亚基的免疫 - 历史化学染色。 拟议的研究重点是NMDAR的命运，NMDAR的命运是一个据信在 脑损伤的病理。脑损伤是一个主要的公共卫生问题，因为它与死亡有关 以及大部分是年轻人的受害者中的长期残疾。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。