Metabotropic Glu Receptors in Traumatic Brain Injury

创伤性脑损伤（TBI）是一个严重的健康问题，导致超过230，000例 住院和50，000人死亡每年在美国。本研究的目的是确定 创伤性脑损伤后急性神经元和星形胶质细胞保护机制的研究 通过肽N-乙酰基谷氨酸盐（NAAG）的代谢型谷氨酸盐受体活化。 本申请研究了大脑中发现的一种丰富的肽NAAG，它作为一种有效的选择性的 亚型3 mGluR（mGluRS）的激动剂。NAAG由神经元释放并水解成NAA， 由星形胶质细胞释放的特定肽酶释放谷氨酸。我们假设NAAG可以发挥重要的作用， 在调节谷氨酸兴奋性毒性中的作用，如果其快速水解可以被抑制。我们假设NAAG 可以通过几种机制保护受创伤的大脑。首先，NAAG减少了过度的 通过激活突触前mGluRS自身受体释放谷氨酸。此外，通过抑制 NAAG转化为NAA和谷氨酸，这是突触谷氨酸的次要来源。第二、 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 从突触中清除多余的谷氨酸。第三，NAAG水解产物NAA可能有助于 NAA-Na+共转运进入星形胶质细胞导致星形胶质细胞Na+超载。[Na+]i的过载可以 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 研究了一种新的策略，用于减少大鼠TBI后谷氨酸兴奋性毒性，通过抑制 通过施用新的NAAG肽酶抑制剂来分解NAAG。这一策略被假设为 增加NAAG水平，从而通过上述机制的组合降低兴奋性毒性。 这项研究将提供新的和重要的见解谷氨酸兴奋毒性和检查重要的 TBI病理生理学中神经元-星形胶质细胞相互作用的动力学。这项研究还将提供临床 关于用于治疗人类头部损伤的潜在药理学试剂的相关信息。

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.