title: NAAG peptidase inhibitor increases dialysate NAAG and reduces glutamate, aspartate and GABA levels in the dorsal hippocampus following fluid percussion injury in the rat.
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.
authors.affiliation: Department of Neurological Surgery, University of California at Davis, Davis, California 95616-8797, USA.
authors.forename: Chunlong
authors.initials: C
authors.lastname: Zhong
authors.forename: Xueren
authors.initials: X
authors.lastname: Zhao
authors.forename: Ken C
authors.initials: KC
authors.lastname: Van
authors.forename: Tomasz
authors.initials: T
authors.lastname: Bzdega
authors.forename: Aoife
authors.initials: A
authors.lastname: Smyth
authors.forename: Jia
authors.initials: J
authors.lastname: Zhou
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
authors.forename: Jiyao
authors.initials: J
authors.lastname: Jiang
authors.forename: William T
authors.initials: WT
authors.lastname: O'Connor
authors.forename: Robert F
authors.initials: RF
authors.lastname: Berman
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Neale
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Lyeth
mesh_terms: D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D001930:Brain Injuries / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology; D004151:Dipeptides / Q000819:agonists* / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D017551:Microdialysis; D009410:Nerve Degeneration / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D004151:Dipeptides; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D009498:Neurotoxins; D017470:Receptors, Glutamate; C027172:isospaglumic acid; D001224:Aspartic Acid; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D043425:Glutamate Carboxypeptidase II