Metabotropic Glu Receptors in Traumatic Brain 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23万人住院治疗和5万人死亡。本研究的目的是确定n -乙酰天冬氨酸（NAAG）肽激活代谢性谷氨酸受体对创伤性脑损伤后急性神经元和星形胶质细胞的保护机制。本应用程序研究了一种丰富的肽，NAAG，发现于大脑中，作为3型mGLuR （mGluRS）亚型的有效和选择性激动剂。NAAG由神经元释放，并被星形胶质细胞释放的特定肽酶水解成NAA和谷氨酸。我们假设NAAG在调节谷氨酸兴奋毒性中发挥重要作用，如果它的快速水解可以被抑制。我们假设NAAG可以通过几种机制在创伤的大脑中提供保护。首先，NAAG通过激活突触前mGluRS自身受体来减少过量的谷氨酸释放。同时，通过抑制NAAG水解为NAA和谷氨酸，可以减少突触谷氨酸的次级来源。其次，星形胶质细胞上的mGLuRS的激活增加了谷氨酸转运蛋白的表达，从而促进了突触中过量谷氨酸的清除。第三，NAAG水解产物NAA可能导致星形胶质细胞内Na+超载，这是NAA-Na+在星形胶质细胞内共转运的结果。过量的[Na+]i可引发星形细胞病理，随后对周围神经元产生负面影响。本应用研究了一种通过施用一种新型NAAG肽酶抑制剂来抑制大鼠脑外伤后谷氨酸兴奋性毒性的新策略。这一策略被假设为增加NAAG水平，从而通过上述机制的组合减少兴奋性毒性。这项研究将为谷氨酸兴奋毒性研究提供新的重要见解，并研究脑外伤病理生理中神经元-星形胶质细胞相互作用的重要动力学。本研究还将为治疗人类头部损伤的潜在药理学药物提供临床相关信息。

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.