Local Glutamate Level Dictates Adenosine A2AReceptor Regulation of Neuroinflammation and Traumatic Brain Injury

• DOI: 10.1523/jneurosci.0268-10.2010
• Publication Date: 2010-04-21T17:08:39Z
• Authors: Shuang-Shuang Dai; Yuan-Guo Zhou; Wei Li; Jian-Hong An; Ping Li; Nan Yang; Xing-Yun Chen; Ren-Ping Xiong; Ping Liu; Yan Zhao; Hai-Ying Shen; Pei-Fang Zhu; Jiang-Fan Chen
• Keywords: Inflammation; Mice, Knockout; Neurons; 0301 basic medicine; Receptor, Adenosine A2A; Glutamic Acid; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Brain Injuries; Animals; Inflammation Mediators; Cells, Cultured

During brain injury, extracellular adenosine and glutamate levels increase rapidly dramatically. We hypothesized that local in the dictates adenosine–adenosine A 2A receptor (A R) effects on neuroinflammation damage outcome. Here, we showed that, presence of low concentrations glutamate, R agonist 3-[4-[2-[[6-amino-9-[(2 ,3 ,4 S ,5 )-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 cultured microglial cells, an effect was dependent protein kinase (PKA) pathway. However, high CGS21680 increased LPS-induced NOS a C (PKC)-dependent manner. Thus, increasing level redirects signaling from PKA to PKC pathway, resulting switch antiinflammatory proinflammatory. In cortical impact model traumatic injury (TBI) mice, water contents, behavioral deficits, expression tumor necrosis factor-α, interleukin-1 mRNAs, inducible were attenuated by administering at post-TBI time when low, or 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] elevated. Furthermore, pre-TBI treatment with release inhibitor ( )-4C3HPG [( )-4-carboxy-3-hydroxyphenylglycine] converted debilitating administered neuroprotective effect. This further indicates activation intact animals proinflammatory is concentration. These findings identify novel role for modulation via adenosine–A system.