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.