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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

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posted on 2015-09-23, 14:10 authored by Chunlong Zhong, Xueren Zhao, Ken C. Van, Tomasz Bzdega, Aoife Smyth, Zia Zhou, Alan P. Kozikowski, Jiyao Jiang, William T. O'Connor, Robert F. Berman, Joseph H. Neale, Bruce G. Lyeth
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 IIlhih itor. ZJ-43 would elevate extracellul~lr NAAG levels and reduce ext",cellular levels of amino acid neurotransmitters following Tl3l by a Group II metabotropic glutamate receptor (mGluR)-mcdiated mechanism. Dialysate levels ofNAAG, glutamate, aspartate and GABA from the dorsal hippocampus were elevated after TBI as measured by ill vivo microdialysis. Dialysate levels ofNAAG were higher and remained elevated in the ZJ-43 treated group (50 mg/kg, i.p.) compared to control. ZJ-43 treatment also reduced the rise of dialysate glutamate, aspartate, and GAB A levels. Co-administration of the Group II mGluR antagonist, L Y34 1495 (I 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 ofNAAG peptidase may reduce excitotoxic events associated with TBI.

History

Publication

Journal of Neurochemistry;97 (4), pp. 1015-1025

Publisher

Wiley

Note

peer-reviewed

Other Funding information

National Neuroscience Network (Ireland), EI, SFI

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This is the author's version of the following article: NAAG peptidase inhibitor increases dialysate NAAG and reduces glutamate, aspartate and GABA levels in the dorsal hippocampus following fluid percussion injury in the ratThe definitive version is available at http://dx.doi.org/10.1111/j.1471-4159.2006.03786.x

Language

English

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