Glutamate affects the production of epoxyeicosanoids within the brain: The up-regulation of brain CYP2J through the MAPK-CREB signaling pathway. (15th April 2017)

• Record Type: Journal Article
• Authors: Liu, Mingzhou; Zhu, Quanfei; Wu, Jinhua; Yu, Xuming; Hu, Mingbai; Xie, Xianfei; Yang, Zheqiong; Yang, Jing; Feng, Yu-Qi; Yue, Jiang
• Is Part Of: Toxicology. Volume 381(2017)
• Page Start: 31
• Page End: 38
• Publication Date: 2017-04-15
• Subjects: AA arachidonic acid -- CYP cytochrome P450 -- ChIP chromatin immunoprecipitation -- COX cyclooxygenases -- LOX lipoxygenases -- LC–MS/MS liquid chromatograph-mass spectrometer -- PCA principal component analysis -- PLS-DA partial least-squares-discriminant analysis -- LSD least significance difference -- mGlu5 receptor metabotropic glutamate receptor subtype 5 -- EETs epoxyeicosatrienoic acids -- DHETs dihydroxyeicosatrienoic acids -- CREB cAMP response element-binding protein -- MAPK mitogen-activated protein kinases -- MPEP 2-methyl-6-(phenylethynyl)-pyridine -- FC frontal cortex -- HC hippocampus -- BS brain stem -- CB cerebellum; Glutamate -- Epoxyeicosanoids -- CYP2J -- Brain -- CREB; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2017.02.008
• Languages: English
• ISSNs: 0300-483X

Abstract

Abstract: Glutamate is the major excitatory neurotransmitter in the brain, and chronic glutamate excitotoxicity has been thought to be involved in numerous neurodegenerative diseases. We investigated the effects of glutamate at concentrations lower than the usual extrasynaptic concentrations on the production of epoxyeicosanoids mediated by brain CYP2J. Glutamate increased CYP2J2 mRNA levels in astrocytes in a dose-dependent manner, while an antagonist of the metabotropic glutamate receptor subtype 5 (mGlu5 receptor) attenuated the glutamate-induced increases in CYP2J2 levels by glutamate. Glutamate increased the binding of cAMP response element-binding protein (CREB) with the CYP2J2 promoter, and the inhibition of the MAPK signaling pathway (ERK1/2, p38, and JNK) decreased the binding of CREB with the CYP2J2 promoter following the glutamate treatment. CREB activated the CYP2J2 promoter located at −1522 to −1317 bp, and CREB overexpression significantly increased CYP2J2 mRNA levels. The CYP2J2 and mGlu5 mRNA levels were higher in the frontal cortex, hippocampus, cerebellum, and brainstem in adult rats that received a subcutaneous injection of monosodiuml -glutamate at 1, 3, 5, and 7 days of age. The data from the partial least-squares-discriminant analysis showed the epoxyeicosanoid profile of the hippocampus from the cerebellum, brain stem, and frontal cortex. The sum of the epoxyeicosatrienoic acids (EETs) and dihydroxyeicosatrienoic acids (DHETs) was increased by 1.16-fold, 1.18-fold, and 1.19-fold in the frontal cortex, cerebellum, and brain stem, respectively, in rats treated with monosodiuml -glutamate compared with the control group. The results suggest that brain CYP2J levels and CYP2J-mediated epoxyeicosanoid production can be regulated by extrasynaptic glutamate. The glutamate receptors expressed in astrocytes may mediate the regulation of drug-metabolizing enzymes and the metabolome of endogenous substances by glutamate.