Post-injury administration of NAAG peptidase inhibitor prodrug, PGI-02776, in experimental TBI

Abstract Traumatic brain injury (TBI) leads to a rapid and excessive increase in glutamate concentration in the extracellular milieu, which is strongly associated with excitotoxicity and neuronal degeneration. N -acetylaspartylglutamate (NAAG), a prevalent peptide neurotransmitter in the vertebrate nervous system, is released along with glutamate and suppresses glutamate release by actions at pre-synaptic metabotropic glutamate autoreceptors. Extracellular NAAG is hydrolyzed to N -acetylaspartate and glutamate by peptidase activity. In the present study PGI-02776, a newly designed di-ester prodrug of the urea-based NAAG peptidase inhibitor ZJ-43, was tested for neuroprotective potential when administered intraperitoneally 30 min after lateral fluid percussion TBI in the rat. Stereological quantification of hippocampal CA2–3 degenerating neurons at 24 h post injury revealed that 10 mg/kg PGI-02776 significantly decreased the number of degenerating neurons (p