NAAG peptidase inhibitor reduces cellular damage in a model of TBI with secondary hypoxia

Traumatic brain injury (TBI) leads to a rapid and excessive glutamate elevation in the extracellular milieu, resulting in neuronal degeneration and astrocyte damage. Posttraumatic hypoxia is a clinically relevant secondary insult that increases the magnitude and duration of glutamate release following TBI. N-acetyl-aspartyl glutamate (NAAG), a prevalent neuropeptide in the CNS, suppresses presynaptic glutamate release by its action at the mGluR3 (a group II metabotropic glutamate receptor). However, extracellular NAAG is rapidly converted into NAA and glutamate by the catalytic enzyme glutamate carboxypeptidase II (GCPII) reducing presynaptic inhibition. We previously reported that the GCPII inhibitor ZJ-43 and its prodrug di-ester PGI-02776 reduce the deleterious effects of excessive extracellular glutamate when injected systemically within the first 30 min following injury. We now report that PGI-02776 (10 mg/kg) is neuroprotective when administered 30 min post-injury in a model of TBI plus 30 min of hypoxia (FiO2=11%). 24 h following TBI with hypoxia, significant increases in neuronal cell death in the CA1, CA2/3, CA3c, hilus and dentate gyrus were observed in the ipsilateral hippocampus. Additionally, there was a significant reduction in the number of astrocytes in the ipsilateral CA1, CA2/3 and in the CA3c/hilus/dentate gyrus. Administration of PGI-02776 immediately following the cessation of hypoxia significantly reduced neuronal and astrocytic cell death across all regions of the hippocampus. These findings indicate that NAAG peptidase inhibitors administered post-injury can significantly reduce the deleterious effects of TBI combined with a secondary hypoxic insult.

► TBI combined with 30 min hypoxia exacerbates neural degeneration in hippocampus.
► TBI combined with 30 min hypoxia exacerbates astrocyte cell loss hippocampus at 24 h after injury.
► PGI-02776 significantly reduced acute neuronal degeneration after TBI in rats.
► PGI-02776 significantly reduced astrocyte loss after TBI in rats.