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NAAG peptidase inhibitor increases dialysate NAAG and reduces glutamate, aspartate and GABA levels in the dorsal hippocampus following fluid percussion injury in the rat
Author(s) -
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.
Publication year - 2006
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2006.03786.x
Subject(s) - metabotropic glutamate receptor , glutamate receptor , microdialysis , glutamate carboxypeptidase ii , neurotransmitter , metabotropic receptor , pharmacology , metabotropic glutamate receptor 2 , metabotropic glutamate receptor 1 , neuroscience , chemistry , glutamic acid , metabotropic glutamate receptor 5 , extracellular , medicine , biology , amino acid , receptor , biochemistry , central nervous system , prostate , cancer
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.