NMDA Receptor Dynamics After Brain Injury

脑损伤后 NMDA 受体动态

• 批准号: 7990396
• 负责人: ANAT BIEGON
• 金额: $ 37.05万
• 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 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7990396
• 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; 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率和发病率的主要原因。 尝试用谷氨酸 NMDA 受体 (NMDAR) 拮抗剂治疗意外脑损伤 在几项主要临床试验中未能对结果产生任何改善。这些试验预测 假设头部受伤后的神经功能缺陷至少部分是由于 NMDAR 过度激活和“兴奋性毒性”。 拟议研究背后的工作假设有三个方面： 1. 头部受伤后 NMDAR 的过度激活是短暂的，并会导致长期功能减退； 2. 脑损伤后的认知缺陷是大脑活动不足而非过度激活的结果 NMDA 受体。 3. NMDAR的延迟激活可能会加速脑损伤后功能的恢复。 第二个假设假设某些大脑区域；例如海马体；本质上是 比其他人更容易受到脑损伤。我们建议在封闭的小鼠中测试这些假设 头部受伤；钝性头部创伤的动物模型。 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 天的时间范围内使用 使用依赖性配体 MK801 的定量放射自显影。 NMDAR 的生理相关性 hyepr 激活和低激活将使用电生理学（长期增强）进行测量。 将在受伤后 14 天和 60 天使用两项不同的任务测试认知缺陷；物体 给予完全激动剂NMDA的动物的识别测试和莫里斯水迷宫 不同时间点和频率的部分 NMDAR 激动剂 d-环丝氨酸或拮抗剂 MK801 受伤后。最后，几种可能的机制对 NMDAR 动态变化的贡献 1. 剂量反应与动力学之间关系的研究 NMDAR 激活和功能反应的剂量和持续时间 2. 操纵测定条件 3. 对 NMDAR 的必需 NR1 单位和 NR2 亚单位进行免疫组织化学染色。 拟议的研究重点是 NMDAR 的命运，这种分子被认为在 脑损伤的病理学。脑损伤是一个重大的公共卫生问题，因为它与死亡有关 很大一部分受害者长期残疾，其中大多数是年轻人。结果 可以解释 NMDAR 拮抗剂在临床试验中的失败并提出新的治疗策略 脑损伤。

项目成果

Regional sensitivity to neuroinflammation: in vivo and in vitro studies.

• DOI: 10.1002/syn.20889
• 发表时间: 2011-07
• 期刊: SYNAPSE
• 影响因子: 2.3
• 作者: Liraz-Zaltsman, Sigal;Alexandrovich, Alexander G.;Trembovler, Victoria;Fishbein, Ianai;Yaka, Rami;Shohami, Esther;Biegon, Anat
• 通讯作者: Biegon, Anat

A new look at glutamate and ischemia: NMDA agonist improves long-term functional outcome in a rat model of stroke.

• DOI: 10.2217/fnl.11.55
• 发表时间: 2011-11-01
• 期刊: Future neurology
• 影响因子: 1.3
• 作者: Dhawan J;Benveniste H;Luo Z;Nawrocky M;Smith SD;Biegon A
• 通讯作者: Biegon A

Critical role of the embryonic mid-hindbrain organizer in the behavioral response to amphetamine and methylphenidate.

• DOI: 10.1016/j.neuroscience.2009.07.040
• 发表时间: 2009-11-10
• 期刊: NEUROSCIENCE
• 影响因子: 3.3
• 作者: Tilleman, H.;Kofman, O.;Nashelsky, L.;Livneh, U.;Roz, N.;Sillaber, I.;Biegon, A.;Rehavi, M.;Brodski, C.
• 通讯作者: Brodski, C.

Transient focal ischemia results in persistent and widespread neuroinflammation and loss of glutamate NMDA receptors.

• DOI: 10.1016/j.neuroimage.2010.02.073
• 发表时间: 2010-06
• 期刊: NEUROIMAGE
• 影响因子: 5.7
• 作者: Dhawan, Jasbeer;Benveniste, Helene;Nawrocky, Marta;Smith, S. David;Biegon, Anat
• 通讯作者: Biegon, Anat

D-cycloserine improves functional outcome after traumatic brain injury with wide therapeutic window.

• DOI: 10.1016/j.ejphar.2009.11.066
• 发表时间: 2010-03-10
• 期刊: European journal of pharmacology
• 影响因子: 5
• 作者: Adeleye A;Shohami E;Nachman D;Alexandrovich A;Trembovler V;Yaka R;Shoshan Y;Dhawan J;Biegon A
• 通讯作者: Biegon A