Metabotropic Glu Receptors in Traumatic Brain Injury

外伤性脑损伤中的代谢型谷氨酸受体

• 批准号: 7036210
• 负责人: BRUCE G. LYETH
• 金额: $ 37.6万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-07-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7036210
• 关键词: behavior test; biological models; brain injury; glutamate receptor; immunocytochemistry; laboratory rat; memory; microdialysis; neuroprotectants; neurotoxins; pathologic process; psychomotor function; receptor binding

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is a significant health problem that results in more than 230,000 hospitalizations and 50,000 deaths per year in the USA. The objectives of this research are to determine mechanisms of acute neuronal and astrocyte protection following traumatic brain injury related to metabotropic glutamate receptor activation by the peptide N-acetylaspartylglutamate (NAAG). This application examines an abundant peptide, NAAG, found in brain that acts as a potent and selective agonist of subtype 3 mGLuR (mGluRS). NAAG is released by neurons and hydrolysed into NAA and glutamate by a specific peptidase released by astrocytes. We hypothesize that NAAG can play a significant role in modulating glutamate excitotoxicity if its rapid hydrolysis can be inhibited. We hypothesize that NAAG could confer protection in the traumatized brain by several mechanisms. First, NAAG reduces excessive glutamate release by activation of presynaptic mGluRS autoreceptors. Also, by inhibiting the hydrolysis of NAAG into NAA and glutamate a secondary source of synaptic glutamate could be diminished. Second, activation of mGLuRS on astrocytes increases the expression of glutamate transporters thereby facilitating removal of excess glutamate from the synapse. Third, the NAAG hydrolysis product, NAA, could contribute to Na+ overload in astrocytes as a result of NAA-Na+ co-transport into astrocytes. Overload of [Na+]i can initiate astrocyte pathology that subsequently impacts negatively on surrounding neurons. This application examines a novel strategy for reducing glutamate excitotoxicity following TBI in rats by inhibiting the breakdown of NAAG by administering a novel NAAG peptidase inhibitor. This strategy is hypothesized to increase levels of NAAG and thus reduce excitotoxicity by a combination of the mechanisms listed above. This research will provide new and important insights into glutamate excitotoxicity and examine important dynamics of neuron-astrocyte interactions in TBI pathophysiology. This research will also provide clinically relevant information about potential pharmacological agents for the treatment of human head injury.

描述（由申请人提供）：创伤性脑损伤 (TBI) 是一种严重的健康问题，在美国每年导致超过 230,000 人住院治疗和 50,000 人死亡。本研究的目的是确定与肽 N-乙酰天冬氨酰谷氨酸 (NAAG) 激活代谢型谷氨酸受体相关的创伤性脑损伤后急性神经元和星形胶质细胞保护的机制。该应用检查了大脑中发现的一种丰富的肽 NAAG，它充当亚型 3 mGLuR (mGluRS) 的有效选择性激动剂。 NAAG 由神经元释放，并被星形胶质细胞释放的特定肽酶水解为 NAA 和谷氨酸。我们假设，如果能够抑制 NAAG 的快速水解，NAAG 可以在调节谷氨酸兴奋毒性中发挥重要作用。我们假设 NAAG 可以通过多种机制为受创伤的大脑提供保护。首先，NAAG 通过激活突触前 mGluRS 自身受体来减少过量的谷氨酸释放。此外，通过抑制 NAAG 水解为 NAA 和谷氨酸，可以减少突触谷氨酸的次要来源。其次，星形胶质细胞上 mGLuRS 的激活增加了谷氨酸转运蛋白的表达，从而促进从突触中去除过量的谷氨酸。第三，由于 NAA-Na+ 共转运到星形胶质细胞中，NAAG 水解产物 NAA 可能导致星形胶质细胞中的 Na+ 超载。 [Na+]i 过载会引发星形胶质细胞病理，随后对周围神经元产生负面影响。本申请研究了一种通过施用新型 NAAG 肽酶抑制剂抑制 NAAG 分解来减少大鼠 TBI 后谷氨酸兴奋毒性的新策略。假设该策略通过结合上述机制来增加 NAAG 的水平，从而减少兴奋性毒性。这项研究将为谷氨酸兴奋毒性提供新的重要见解，并研究 TBI 病理生理学中神经元-星形胶质细胞相互作用的重要动态。这项研究还将提供有关治疗人类头部损伤的潜在药物的临床相关信息。