NAAG peptidase inhibitor increases dialysate NAAG and reduces glutamate, aspartate and GABA levels in the dorsal hippocampus following fluid percussion injury in the rat

Chunlong Zhong, Xueren Zhao, Ken C. Van, Tomasz Bzdega, Aoife Smyth, Jia Zhou, Alan P. Kozikowski, Jiyao Jiang, William T. O'Connor, Robert F. Berman, Joseph H. Neale, Bruce G. Lyeth

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Traumatic brain injury (TBI) produces a rapid and excessive elevation in extracellular glutamate that induces excitotoxic brain cell death. The peptide neurotransmitter N-acetylaspartylglutamate (NAAG) is reported to suppress neurotransmitter release through selective activation of presynaptic group II metabotropic glutamate receptors. Therefore, strategies to elevate levels of NAAG following brain injury could reduce excessive glutamate release associated with TBI. We hypothesized that the NAAG peptidase inhibitor, ZJ-43 would elevate extracellular NAAG levels and reduce extracellular levels of amino acid neurotransmitters following TBI by a group II metabotropic glutamate receptor (mGluR)-mediated mechanism. Dialysate levels of NAAG, glutamate, aspartate and GABA from the dorsal hippocampus were elevated after TBI as measured by in vivo microdialysis. Dialysate levels of NAAG were higher and remained elevated in the ZJ-43 treated group (50 mg/kg, i.p.) compared with control. ZJ-43 treatment also reduced the rise of dialysate glutamate, aspartate, and GABA levels. Co-administration of the group II mGluR antagonist, LY341495 (1 mg/kg, i.p.) partially blocked the effects of ZJ-43 on dialysate glutamate and GABA, suggesting that NAAG effects are mediated through mGluR activation. The results are consistent with the hypothesis that inhibition of NAAG peptidase may reduce excitotoxic events associated with TBI.

Original languageEnglish (US)
Pages (from-to)1015-1025
Number of pages11
JournalJournal of Neurochemistry
Volume97
Issue number4
DOIs
StatePublished - May 2006
Externally publishedYes

Fingerprint

Glutamate Carboxypeptidase II
Percussion
Dialysis Solutions
Protease Inhibitors
Aspartic Acid
gamma-Aminobutyric Acid
Rats
Glutamic Acid
Hippocampus
Brain
Metabotropic Glutamate Receptors
Fluids
Wounds and Injuries
Neurotransmitter Agents
LY 341495
Chemical activation
Excitatory Amino Acid Antagonists
Brain Death
Microdialysis
Brain Injuries

Keywords

  • Gamma-aminobutyric acid
  • Glutamate
  • Metabotropic glutamate receptor
  • Microdialysis
  • N-acetylaspartylglutamate
  • Traumatic brain injury

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

NAAG peptidase inhibitor increases dialysate NAAG and reduces glutamate, aspartate and GABA levels in the dorsal hippocampus following fluid percussion injury in the rat. / Zhong, Chunlong; Zhao, Xueren; Van, Ken C.; Bzdega, Tomasz; Smyth, Aoife; Zhou, Jia; Kozikowski, Alan P.; Jiang, Jiyao; O'Connor, William T.; Berman, Robert F.; Neale, Joseph H.; Lyeth, Bruce G.

In: Journal of Neurochemistry, Vol. 97, No. 4, 05.2006, p. 1015-1025.

Research output: Contribution to journalArticle

Zhong, Chunlong ; Zhao, Xueren ; Van, Ken C. ; Bzdega, Tomasz ; Smyth, Aoife ; Zhou, Jia ; Kozikowski, Alan P. ; Jiang, Jiyao ; O'Connor, William T. ; Berman, Robert F. ; Neale, Joseph H. ; Lyeth, Bruce G. / NAAG peptidase inhibitor increases dialysate NAAG and reduces glutamate, aspartate and GABA levels in the dorsal hippocampus following fluid percussion injury in the rat. In: Journal of Neurochemistry. 2006 ; Vol. 97, No. 4. pp. 1015-1025.
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AU - Zhong, Chunlong

AU - Zhao, Xueren

AU - Van, Ken C.

AU - Bzdega, Tomasz

AU - Smyth, Aoife

AU - Zhou, Jia

AU - Kozikowski, Alan P.

AU - Jiang, Jiyao

AU - O'Connor, William T.

AU - Berman, Robert F.

AU - Neale, Joseph H.

AU - Lyeth, Bruce G.

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AB - Traumatic brain injury (TBI) produces a rapid and excessive elevation in extracellular glutamate that induces excitotoxic brain cell death. The peptide neurotransmitter N-acetylaspartylglutamate (NAAG) is reported to suppress neurotransmitter release through selective activation of presynaptic group II metabotropic glutamate receptors. Therefore, strategies to elevate levels of NAAG following brain injury could reduce excessive glutamate release associated with TBI. We hypothesized that the NAAG peptidase inhibitor, ZJ-43 would elevate extracellular NAAG levels and reduce extracellular levels of amino acid neurotransmitters following TBI by a group II metabotropic glutamate receptor (mGluR)-mediated mechanism. Dialysate levels of NAAG, glutamate, aspartate and GABA from the dorsal hippocampus were elevated after TBI as measured by in vivo microdialysis. Dialysate levels of NAAG were higher and remained elevated in the ZJ-43 treated group (50 mg/kg, i.p.) compared with control. ZJ-43 treatment also reduced the rise of dialysate glutamate, aspartate, and GABA levels. Co-administration of the group II mGluR antagonist, LY341495 (1 mg/kg, i.p.) partially blocked the effects of ZJ-43 on dialysate glutamate and GABA, suggesting that NAAG effects are mediated through mGluR activation. The results are consistent with the hypothesis that inhibition of NAAG peptidase may reduce excitotoxic events associated with TBI.

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