第三军医大学大坪医院野战外科研究所分子生物学中心通过6年攻关，解开了腺苷在颅脑创伤中既可产生神经保护，又可加重颅脑损害的双重作用之谜，为临床治疗颅脑创伤提供了新的理论依据和策略。相关论文发表在国际神经科学领域权威期刊《神经科学杂志》上。
颅脑创伤的损害分为原发性和继发性两种，其中前者不可逆，而后者可以逆转，但国际上尚无有效药物进行治疗。腺苷作为腺嘌呤核苷酸的代谢产物，也是较为重要的神经递质及调质，已知的A1、A2A、A2B和A3是腺苷的4种受体，其中A2A受体的活化在神经系统中具有保护和加重损伤两种效应，对预后起着决定性作用。到底是什么因素在其中起着控制作用？逆转效应又在何时出现？这些问题多年来一直困扰国际学术界，同时也制约了腺苷调节剂在脑中枢神经系统损伤中的临床应用。
大坪医院野战外科研究所、分子生物学中心主任周元国带领的课题组，采用基因敲除及分别应用A2A腺苷受体激动剂和拮抗剂的研究方式，通过体内外系列实验，发现腺苷A2A受体活化后，可以通过调节谷氨酸释放、炎性反应及钙离子内流手段，在多种脑中枢神经损伤模型中，发挥保护神经或加重神经损伤的双向作用。而脑内谷氨酸浓度，则是调控腺苷受体A2A活化后效应走向的决定因素。
这一研究结果，不仅揭开了A2A受体发挥双向作用的机制，同时证实了可以人为地调控腺苷的逆转损害及强化抗损伤作用的方向，为临床中使用A2A受体调节药物，治疗各种脑损伤提供了理论依据；使根据谷氨酸浓度、选择使用激动剂或拮抗剂治疗脑损伤的方法成为可能，对临床实际应用腺苷及其受体调节剂具有重大意义。（生物谷Bioon.com）
生物谷推荐原文出处：
The Journal of Neuroscience doi:10.1523/JNEUROSCI.0268-10.2010
Local Glutamate Level Dictates Adenosine A2A Receptor Regulation of Neuroinflammation and Traumatic Brain Injury
Shuang-Shuang Dai,1,3 Yuan-Guo Zhou,1 Wei Li,1 Jian-Hong An,1 Ping Li,1 Nan Yang,1 Xing-Yun Chen,1 Ren-Ping Xiong,1 Ping Liu,1 Yan Zhao,1 Hai-Ying Shen,1,2 Pei-Fang Zhu,1 and Jiang-Fan Chen2
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-, 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.
