Neuropeptide Modulation of Glutamate Excitotoxicity in Experimental Traumatic Brain Injury

Abstract:

Traumatic brain injury (TBI) remains one of the leading causes of death and disability globally. In the United States, an estimated 1.7 million persons sustain TBI resulting in 275,000 hospitalizations and 52,000 deaths each year. TBI produces a rapid and excessive increase of glutamate into the extracellular milieu, which promotes excitotoxicity and neuronal degeneration resulting in cognitive deficits. N-acetylaspartylglutamate (NAAG) is a prevalent peptide neurotransmitter in the vertebrate nervous system that is released along with glutamate. NAAG modulates (reduces) excessive glutamate release by inhibitory actions at pre-synaptic metabotropic autoreceptors. We are examining the therapeutic potential of selective NAAG peptidase inhibitors in a rat model of experimental TBI. Experimental evidence will be presented examining the mechanistic and functional effects of NAAG peptidase inhibition in the traumatically injured rodent brain, with discussion of the implications for the acute treatment of human TBI.