Local glutamate level dictates adenosine A2A receptor regulation of neuroinflammation and traumatic brain injury.
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.
Dai
Shuang-Shuang
SS
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.
Zhou
Yuan-Guo
YG
Li
Wei
W
An
Jian-Hong
JH
Li
Ping
P
Yang
Nan
N
Chen
Xing-Yun
XY
Xiong
Ren-Ping
RP
Liu
Ping
P
Zhao
Yan
Y
Shen
Hai-Ying
HY
Zhu
Pei-Fang
PF
Chen
Jiang-Fan
JF
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*
D018836:Inflammation Mediators; D043705:Receptor, Adenosine A2A; D018698:Glutamic Acid
Curr Pharm Des. 2008;14(15):1500-11
18537673
J Neurosci. 2003 Jun 15;23(12):5361-9
12832562
Cell Signal. 2003 Sep;15(9):813-27
12834807
Exp Neurol. 2009 Jan;215(1):69-76
18938161
Neurosci Lett. 2000 Aug 4;289(2):127-30
10904136
Brain Res. 2006 Feb 16;1073-1074:470-80
16443200
J Neurochem. 2005 May;93(3):595-604
15836618
Brain Res Brain Res Rev. 2000 Sep;33(2-3):258-74
11011069
Neuropsychopharmacology. 2004 Aug;29(8):1451-61
15039773
Brain Res. 2002 Oct 4;951(2):191-201
12270497
Annu Rev Immunol. 2004;22:657-82
15032592
Ann N Y Acad Sci. 2001 Jun;939:74-84
11462806
Neuroscience. 2006 Sep 15;141(4):2029-39
16777350
J Neurosci. 2002 Mar 1;22(5):1967-75
11880527
J Neurosci. 2001 May 15;21(10):RC143
11319241
J Neurochem. 2001 Nov;79(3):463-84
11701750
Br J Pharmacol. 2006 Aug;148(8):1108-15
16799650
Brain Res. 1995 Dec 24;705(1-2):79-84
8821736
J Neurosci. 2009 Nov 25;29(47):14741-51
19940169
Exp Neurol. 1996 Feb;137(2):345-9
8635550
J Biol Chem. 1997 Feb 21;272(8):4970-7
9030558
Prog Neurobiol. 1997 Jan;51(1):39-87
9044428
J Biol Chem. 1999 Dec 10;274(50):35499-504
10585422
Brain Res. 2001 Jun 8;903(1-2):177-84
11382401
J Neurosci. 1999 Nov 1;19(21):9192-200
10531422
Neuroscience. 2008 Feb 19;151(4):1198-207
18207647
J Neurochem. 2005 Apr;93(2):310-20
15816854
Brain Res. 1998 Aug 3;800(2):328-35
9685693
Trends Immunol. 2004 Jan;25(1):33-9
14698282
Br J Pharmacol. 2002 Jun;136(3):434-40
12023946
Mol Pharmacol. 2006 Apr;69(4):1311-9
16385076
Shock. 2009 Dec;32(6):578-85
19295488
J Chromatogr B Biomed Appl. 1994 Jul 1;657(1):185-91
7952066
J Neurosci. 2005 Nov 9;25(45):10414-9
16280580
Toxicol Pathol. 2001 Mar-Apr;29(2):208-23
11421488
Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11940-5
12189203
Physiol Rev. 2006 Jul;86(3):1009-31
16816144
J Appl Physiol (1985). 1994 Jan;76(1):5-13
8175547
Ann Neurol. 2001 Jun;49(6):727-35
11409424
Prog Neurobiol. 2007 Dec;83(5):310-31
18023959
Ann Neurol. 2008 Mar;63(3):338-46
18300283
Purinergic Signal. 2005 Jun;1(2):111-34
18404497
Nat Med. 2004 Oct;10(10):1081-7
15448683
Eur J Pharmacol. 1995 Dec 12;287(2):215-7
8749040
Exp Neurol. 2007 Jan;203(1):241-5
17007839
J Biol Chem. 2002 Sep 13;277(37):33930-42
12114502
J Neurochem. 2005 Nov;95(4):919-29
16092928
Neuroscience. 1998 Jul;85(1):229-37
9607714
Neurobiol Dis. 2004 Oct;17(1):77-88
15350968
Prog Neurobiol. 2007 Dec;83(5):263-76
17804147
J Neurochem. 2005 Nov;95(4):1188-200
16271052
J Neurosci Res. 2007 Apr;85(5):1077-85
17304576
J Neurochem. 2002 Jan;80(2):262-70
11902116
Neuroreport. 1999 Mar 17;10(4):687-91
10208531
Am J Physiol Heart Circ Physiol. 2007 Jun;292(6):H3079-88
17277031
Neurology. 2003 Dec 9;61(11 Suppl 6):S69-71
14663014