Metabotropic Glu Receptors in Traumatic Brain Injury

描述(申请人提供)：创伤性脑损伤(TBI)是一个严重的健康问题，在美国每年导致超过230,000人住院和50,000人死亡。本研究旨在探讨N-乙酰天冬氨酸氨基转移酶(NAAG)激活代谢型谷氨酸受体对创伤性脑损伤后神经细胞和星形胶质细胞的保护作用机制。这项应用研究了在大脑中发现的一种丰富的多肽NAAG，它是3型mGluR(MGluRs)的有效和选择性激动剂。NAAG是由神经元释放的，由星形胶质细胞释放的一种特定的多肽酶将其分解为NAA和谷氨酸。我们假设，NAAG在调节谷氨酸的兴奋性毒性方面可以发挥重要作用，如果它的快速水解能够被抑制的话。我们假设NAAG可以通过几种机制在受伤的大脑中提供保护。首先，NAAG通过激活突触前mGluRs自身受体来减少谷氨酸的过度释放。此外，通过抑制NAAG水解成NAA和谷氨酸，突触谷氨酸的第二来源可能会减少。其次，星形胶质细胞上mGluRs的激活增加了谷氨酸转运体的表达，从而促进了突触中多余的谷氨酸的去除。第三，由于NAA-Na+共转运到星形胶质细胞，NAAG的水解物NAA可能导致星形胶质细胞的Na+超载。[Na+]i超负荷可引发星形胶质细胞病理，从而对周围神经元产生负面影响。这项申请研究了一种新的策略，通过给予一种新的NAAG肽酶抑制剂来抑制NAAG的分解，从而减少大鼠脑损伤后的谷氨酸兴奋性毒性。这一策略被认为是通过上述机制的组合来增加NAAG的水平，从而减少兴奋性毒性。这项研究将为谷氨酸的兴奋性毒性提供新的和重要的见解，并研究脑损伤病理生理学中神经元-星形胶质细胞相互作用的重要动力学。这项研究还将提供有关治疗人类头部损伤的潜在药理药物的临床相关信息。

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.