TY - JOUR
T1 - NAAG peptidase inhibitor increases dialysate NAAG and reduces glutamate, aspartate and GABA levels in the dorsal hippocampus following fluid percussion injury in the rat
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.
PY - 2006/5
Y1 - 2006/5
N2 - 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.
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.
KW - Gamma-aminobutyric acid
KW - Glutamate
KW - Metabotropic glutamate receptor
KW - Microdialysis
KW - N-acetylaspartylglutamate
KW - Traumatic brain injury
UR - http://www.scopus.com/inward/record.url?scp=33646078096&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33646078096&partnerID=8YFLogxK
U2 - 10.1111/j.1471-4159.2006.03786.x
DO - 10.1111/j.1471-4159.2006.03786.x
M3 - Article
C2 - 16606367
AN - SCOPUS:33646078096
SN - 0022-3042
VL - 97
SP - 1015
EP - 1025
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
IS - 4
ER -