title: Local glutamate level dictates adenosine A2A receptor regulation of neuroinflammation and traumatic brain injury.
abstract: During brain injury, extracellular adenosine and glutamate levels increase rapidly and dramatically. We hypothesized that local glutamate levels in the brain dictates the adenosine-adenosine A(2A) receptor (A(2A)R) effects on neuroinflammation and brain damage outcome. Here, we showed that, in the presence of low concentrations of glutamate, the A(2A)R agonist 3-[4-[2-[[6-amino-9-[(2R,3R,4S,5S)-5-(ethylcarbamoyl)-3,4-dihydroxy-oxolan-2-yl]purin-2-yl]amino]ethyl]phenyl]propanoic acid (CGS21680) inhibited lipopolysaccharide (LPS)-induced nitric oxide synthase (NOS) activity of cultured microglial cells, an effect that was dependent on the protein kinase A (PKA) pathway. However, in high concentrations of glutamate, CGS21680 increased LPS-induced NOS activity in a protein kinase C (PKC)-dependent manner. Thus, increasing the local level of glutamate redirects A(2A)R signaling from the PKA to the PKC pathway, resulting in a switch in A(2A)R effects from antiinflammatory to proinflammatory. In a cortical impact model of traumatic brain injury (TBI) in mice, brain water contents, behavioral deficits, and expression of tumor necrosis factor-alpha, interleukin-1 mRNAs, and inducible NOS were attenuated by administering CGS21680 at post-TBI time when brain glutamate levels were low, or by administering the A(2A)R antagonist ZM241385 [4-(2-{[5-amino-2-(2-furyl)[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-yl]amino}ethyl)phenol] at post-TBI time when brain glutamate levels were elevated. Furthermore, pre-TBI treatment with the glutamate release inhibitor (S)-4C3HPG [(S)-4-carboxy-3-hydroxyphenylglycine] converted the debilitating effect of CGS21680 administered at post-TBI time with high glutamate level to a neuroprotective effect. This further indicates that the switch in the effect of A(2A)R activation in intact animals from antiinflammatory to proinflammatory is dependent on glutamate concentration. These findings identify a novel role for glutamate in modulation of neuroinflammation and brain injury via the adenosine-A(2A)R system.
authors.affiliation: Molecular Biology Center, State Key Laboratory of Trauma, Burn, and Combined Injury, Research Institute of Surgery and Daping Hospital, Third Military Medical University, Chongqing 400042, China.
authors.forename: Shuang-Shuang
authors.initials: SS
authors.lastname: Dai
authors.forename: Yuan-Guo
authors.initials: YG
authors.lastname: Zhou
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Jian-Hong
authors.initials: JH
authors.lastname: An
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.forename: Nan
authors.initials: N
authors.lastname: Yang
authors.forename: Xing-Yun
authors.initials: XY
authors.lastname: Chen
authors.forename: Ren-Ping
authors.initials: RP
authors.lastname: Xiong
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.forename: Hai-Ying
authors.initials: HY
authors.lastname: Shen
authors.forename: Pei-Fang
authors.initials: PF
authors.lastname: Zhu
authors.forename: Jiang-Fan
authors.initials: JF
authors.lastname: Chen
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000134:cerebrospinal fluid / Q000378:metabolism* / Q000473:pathology*; D002478:Cells, Cultured; D018698:Glutamic Acid / Q000134:cerebrospinal fluid / Q000378:metabolism / Q000502:physiology*; D007249:Inflammation / Q000134:cerebrospinal fluid / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000134:cerebrospinal fluid / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D043705:Receptor, Adenosine A2A / Q000502:physiology*
chemical_list: D018836:Inflammation Mediators; D043705:Receptor, Adenosine A2A; D018698:Glutamic Acid
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