ArticleBrain research2013
NAAG peptidase inhibitor improves motor function and reduces cognitive dysfunction in a model of TBI with secondary hypoxia.
Article in Brain research, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 32 citations in OpenAlex.
- Article
- Targeting NAAG metabolism restores cognition and synaptic integrity in EcoHIV-infected mice.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Article
- Mass spectrometry-guided discovery of novel GCPII inhibitor scaffolds.Frontiers in pharmacology · 2025Article
- Inhibition of brain glutamate carboxypeptidase II (GCPII) to enhance cognitive function.Advances in pharmacology (San Diego, Calif.) · 2025Review
- Metabolome-Wide Mendelian Randomization Assessing the Causal Role of Serum and Cerebrospinal Metabolites in Traumatic Brain Injury.Biomedicines · 2024Article
- Neuropharmacological insight into preventive intervention in posttraumatic epilepsy based on regulating glutamate homeostasis.CNS neuroscience & therapeutics · 2023Review
- Inhibition of glutamate-carboxypeptidase-II in dorsolateral prefrontal cortex: potential therapeutic target for neuroinflammatory cognitive disorders.Molecular psychiatry · 2022Article
- The regulatory role of NAAG-mGluR3 signaling on cortical synaptic plasticity after hypoxic ischemia.Cell communication and signaling : CCS · 2022Article
- Review
- Phosphonates and Phosphonate Prodrugs in Medicinal Chemistry: Past Successes and Future Prospects.Frontiers in chemistry · 2022Review
- Sustained Hippocampal Synaptic Pathophysiology Following Single and Repeated Closed-Head Concussive Impacts.Frontiers in cellular neuroscience · 2021Article
- Recovery of Theta Frequency Oscillations in Rats Following Lateral Fluid Percussion Corresponds With a Mild Cognitive Phenotype.Frontiers in neurology · 2020Article
- Metabolite differences between glutamate carboxypeptidase II gene knockout mice and their wild-type littermates after traumatic brain injury: a 7-teslaBMC neuroscience · 2018Article
- The therapeutic and diagnostic potential of the prostate specific membrane antigen/glutamate carboxypeptidase II (PSMA/GCPII) in cancer and neurological disease.British journal of pharmacology · 2016Review
- Inhibition of SRC family kinases protects hippocampal neurons and improves cognitive function after traumatic brain injury.Journal of neurotrauma · 2014Article
- A guide to the metabolic pathways and function of metabolites observed in human brain 1H magnetic resonance spectra.Neurochemical research · 2014Review
- N-Acetylaspartate reductions in brain injury: impact on post-injury neuroenergetics, lipid synthesis, and protein acetylation.Frontiers in neuroenergetics · 2013Review
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.