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

Jun Feng Feng, Gene G. Gurkoff, Ken C. Van, Minsoo Song, David A. Lowe, Jia Zhou, Bruce G. Lyeth

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)144-152
Number of pages9
JournalBrain Research
Volume1469
DOIs
StatePublished - Aug 21 2012

Fingerprint

Protease Inhibitors
Glutamic Acid
Glutamate Carboxypeptidase II
Dentate Gyrus
Astrocytes
Hippocampus
Wounds and Injuries
Cell Death
Metabotropic Glutamate Receptors
Prodrugs
Neuropeptides
Esters
Hypoxia
N-acetyl-1-aspartylglutamic acid
Traumatic Brain Injury
Enzymes
PGI-02776

Keywords

  • Astrocyte
  • Glutamate
  • Hippocampus
  • Hypoxia
  • N-acetylaspartylglutamate (NAAG)
  • Neuronal degeneration
  • Traumatic brain injury (TBI)

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology
  • Developmental Biology
  • Molecular Biology

Cite this

Feng, J. F., Gurkoff, G. G., Van, K. C., Song, M., Lowe, D. A., Zhou, J., & Lyeth, B. G. (2012). NAAG peptidase inhibitor reduces cellular damage in a model of TBI with secondary hypoxia. Brain Research, 1469, 144-152. https://doi.org/10.1016/j.brainres.2012.06.021

NAAG peptidase inhibitor reduces cellular damage in a model of TBI with secondary hypoxia. / Feng, Jun Feng; Gurkoff, Gene G.; Van, Ken C.; Song, Minsoo; Lowe, David A.; Zhou, Jia; Lyeth, Bruce G.

In: Brain Research, Vol. 1469, 21.08.2012, p. 144-152.

Research output: Contribution to journalArticle

Feng, Jun Feng ; Gurkoff, Gene G. ; Van, Ken C. ; Song, Minsoo ; Lowe, David A. ; Zhou, Jia ; Lyeth, Bruce G. / NAAG peptidase inhibitor reduces cellular damage in a model of TBI with secondary hypoxia. In: Brain Research. 2012 ; Vol. 1469. pp. 144-152.
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