title: NAAG peptidase inhibitor improves motor function and reduces cognitive dysfunction in a model of TBI with secondary hypoxia.
abstract: Immediately following traumatic brain injury (TBI) and TBI with hypoxia, there is a rapid and pathophysiological increase in extracellular glutamate, subsequent neuronal damage and ultimately diminished motor and cognitive function. N-acetyl-aspartyl glutamate (NAAG), a prevalent neuropeptide in the CNS, is co-released with glutamate, binds to the presynaptic group II metabotropic glutamate receptor subtype 3 (mGluR3) and suppresses glutamate release. However, the catalytic enzyme glutamate carboxypeptidase II (GCP II) rapidly hydrolyzes NAAG into NAA and glutamate. Inhibition of the GCP II enzyme with NAAG peptidase inhibitors reduces the concentration of glutamate both by increasing the duration of NAAG activity on mGluR3 and by reducing degradation into NAA and glutamate resulting in reduced cell death in models of TBI and TBI with hypoxia. In the following study, rats were administered the NAAG peptidase inhibitor PGI-02776 (10mg/kg) 30 min following TBI combined with a hypoxic second insult. Over the two weeks following injury, PGI-02776-treated rats had significantly improved motor function as measured by increased duration on the rota-rod and a trend toward improved performance on the beam walk. Furthermore, two weeks post-injury, PGI-02776-treated animals had a significant decrease in latency to find the target platform in the Morris water maze as compared to vehicle-treated animals. These findings demonstrate that the application of NAAG peptidase inhibitors can reduce the deleterious motor and cognitive effects of TBI combined with a second hypoxic insult in the weeks following injury.
authors.affiliation: Department of Neurological Surgery, University of California at Davis, One Shields Avenue, Davis, CA 95616, USA.
authors.forename: Gene G
authors.initials: GG
authors.lastname: Gurkoff
authors.forename: Jun-Feng
authors.initials: JF
authors.lastname: Feng
authors.forename: Ken C
authors.initials: KC
authors.lastname: Van
authors.forename: Ali
authors.initials: A
authors.lastname: Izadi
authors.forename: Rahil
authors.initials: R
authors.lastname: Ghiasvand
authors.forename: Kiarash
authors.initials: K
authors.lastname: Shahlaie
authors.forename: Minsoo
authors.initials: M
authors.lastname: Song
authors.forename: David A
authors.initials: DA
authors.lastname: Lowe
authors.forename: Jia
authors.initials: J
authors.lastname: Zhou
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Lyeth
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy / Q000201:enzymology*; D003072:Cognition Disorders / Q000188:drug therapy / Q000201:enzymology*; D004195:Disease Models, Animal; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors* / Q000502:physiology; D002534:Hypoxia, Brain / Q000188:drug therapy / Q000201:enzymology*; D008297:Male; D009048:Motor Skills / Q000187:drug effects* / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D018696:Neuroprotective Agents; C571450:PGI-02776; D014508:Urea; D043425:Glutamate Carboxypeptidase II
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