Local Glutamate Level Dictates Adenosine A2AReceptor Regulation of Neuroinflammation and Traumatic Brain Injury
| Autor: | Wei Li, Xing-Yun Chen, Ping Li, Yan Zhao, Yuan-Guo Zhou, Nan Yang, Hai-Ying Shen, Pei-Fang Zhu, Ren-Ping Xiong, Jiang-Fan Chen, Shuang-Shuang Dai, Liu Ping, Jian-Hong An |
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| Rok vydání: | 2010 |
| Předmět: |
Agonist
Receptor Adenosine A2A medicine.drug_class Glutamic Acid Adenosine A2A receptor Brain damage Pharmacology Neuroprotection Mice medicine Animals Cells Cultured Neuroinflammation Inflammation Mice Knockout Neurons biology Chemistry General Neuroscience Glutamate receptor Articles Adenosine Mice Inbred C57BL Nitric oxide synthase Biochemistry Brain Injuries biology.protein Inflammation Mediators medicine.symptom medicine.drug |
| Zdroj: | The Journal of Neuroscience. 30:5802-5810 |
| ISSN: | 1529-2401 0270-6474 |
| DOI: | 10.1523/jneurosci.0268-10.2010 |
| Popis: | 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 A2Areceptor (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. |
| Databáze: | OpenAIRE |
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