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230，000例住院治疗和50，000例死亡。本研究的目的是确定急性神经元和星形胶质细胞的保护机制创伤性脑损伤相关的代谢型谷氨酸受体激活的肽N-乙酰基谷氨酸（NAAG）。本申请检查了在脑中发现的丰富肽NAAG，其充当亚型3 mGLuR（mGluRS）的有效和选择性激动剂。NAAG由神经元释放，并由星形胶质细胞释放的特异性肽酶水解成NAA和谷氨酸。我们假设，NAAG可以发挥重要作用，在调节谷氨酸兴奋性毒性，如果它的快速水解可以被抑制。我们推测NAAG可以通过几种机制保护创伤后的大脑。首先，NAAG通过激活突触前mGluRS自身受体减少过量谷氨酸释放。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的活化增加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，NAAG水解产物NAA可作为NAA-Na+共转运进入星形胶质细胞的结果而导致星形胶质细胞中的Na+过载。[Na+]i的过载可以引发星形胶质细胞病理学，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分解来降低大鼠TBI后谷氨酸兴奋性毒性的新策略。假设该策略通过上述机制的组合增加NAAG水平，从而降低兴奋性毒性。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学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.