NAAG Peptidase Inhibitor Prodrug, PGI-02776, Improves Motor And Cognitive Behavior In Experimental TBI

Over 1.7 million people suffer from Traumatic Brain Injury (TBI) annually in the United States. Hypoxia, a secondary injury, is frequently associated with TBI. TBI+hypoxia causes cell death through excitotoxicity, an excessive release of glutamate. Cell death correlates with poor motor and cognitive outcome following injury.  N-acetylaspartylglutamate (NAAG), a peptide neurotransmitter, is released with glutamate following injury and activates presynaptic group II metabotropic glutamate receptors inhibiting further glutamate release. Hydrolysis of NAAG into NAA and glutamate by glutamate carboxypeptidase reduces presynaptic inhibition and increases glutamate concentrations resulting in enhanced excitotoxicity.  We hypothesize that PGI-02776, a NAAG peptidase inhibitor, will prevent hydrolysis of NAAG, reduce excitotoxicity, and increase motor and cognitive performance in rats following TBI+hypoxia. Using a lateral fluid percussion (LFP) device we induced moderate TBI in rats followed immediately by 30 min of hypoxia. PGI-02776 was administered intraperitoneally immediately after hypoxia. Animals were analyzed on the beam walk and Morris water maze (MWM) to test motor and cognitive behavior respectively. CA2-3 pyramidal cells in the dorsal hippocampus were quantified using stereology. We observed a significant decrease in cell death in TBI+hypoxia rats treated with PGI-02776 and improved performance on the beam walk and MWM when compared to TBI+hypoxia rats treated with saline. In conclusion, PGI-02776 played a vital role in improving motor and cognitive behavior in a rodent model of TBI+hypoxia. Our goal is to translate these data into a clinical trial to determine whether PGI-02776 can reduce the number of people suffering from disabilities related to TBI.