PT  - JOURNAL ARTICLE
AU  - Shuang-Shuang Dai
AU  - Yuan-Guo Zhou
AU  - Wei Li
AU  - Jian-Hong An
AU  - Ping Li
AU  - Nan Yang
AU  - Xing-Yun Chen
AU  - Ren-Ping Xiong
AU  - Ping Liu
AU  - Yan Zhao
AU  - Hai-Ying Shen
AU  - Pei-Fang Zhu
AU  - Jiang-Fan Chen
TI  - Local Glutamate Level Dictates Adenosine A<sub>2A</sub> Receptor Regulation of Neuroinflammation and Traumatic Brain Injury
AID  - 10.1523/JNEUROSCI.0268-10.2010
DP  - 2010 Apr 21
TA  - The Journal of Neuroscience
PG  - 5802--5810
VI  - 30
IP  - 16
4099  - http://www.jneurosci.org/content/30/16/5802.short
4100  - http://www.jneurosci.org/content/30/16/5802.full
SO  - J. Neurosci.2010 Apr 21; 30
AB  - 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 A2A receptor (A2AR) effects on neuroinflammation and brain damage outcome. Here, we showed that, in the presence of low concentrations of glutamate, the A2AR 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 A2AR signaling from the PKA to the PKC pathway, resulting in a switch in A2AR 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-α, 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 A2AR 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 A2AR 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–A2AR system.