第三軍醫(yī)大學(xué)大坪醫(yī)院野戰(zhàn)外科研究所分子生物學(xué)中心通過6年攻關(guān),，解開了腺苷在顱腦創(chuàng)傷中既可產(chǎn)生神經(jīng)保護,，又可加重顱腦損害的雙重作用之謎，為臨床治療顱腦創(chuàng)傷提供了新的理論依據(jù)和策略,。相關(guān)論文發(fā)表在國際神經(jīng)科學(xué)領(lǐng)域權(quán)威期刊《神經(jīng)科學(xué)雜志》上,。
顱腦創(chuàng)傷的損害分為原發(fā)性和繼發(fā)性兩種,，其中前者不可逆,，而后者可以逆轉(zhuǎn),，但國際上尚無有效藥物進行治療。腺苷作為腺嘌呤核苷酸的代謝產(chǎn)物,，也是較為重要的神經(jīng)遞質(zhì)及調(diào)質(zhì),，已知的A1,、A2A,、A2B和A3是腺苷的4種受體,，其中A2A受體的活化在神經(jīng)系統(tǒng)中具有保護和加重損傷兩種效應(yīng)，對預(yù)后起著決定性作用,。到底是什么因素在其中起著控制作用,？逆轉(zhuǎn)效應(yīng)又在何時出現(xiàn)？這些問題多年來一直困擾國際學(xué)術(shù)界,，同時也制約了腺苷調(diào)節(jié)劑在腦中樞神經(jīng)系統(tǒng)損傷中的臨床應(yīng)用,。
大坪醫(yī)院野戰(zhàn)外科研究所、分子生物學(xué)中心主任周元國帶領(lǐng)的課題組,，采用基因敲除及分別應(yīng)用A2A腺苷受體激動劑和拮抗劑的研究方式,，通過體內(nèi)外系列實驗，發(fā)現(xiàn)腺苷A2A受體活化后,，可以通過調(diào)節(jié)谷氨酸釋放,、炎性反應(yīng)及鈣離子內(nèi)流手段，在多種腦中樞神經(jīng)損傷模型中,，發(fā)揮保護神經(jīng)或加重神經(jīng)損傷的雙向作用,。而腦內(nèi)谷氨酸濃度，則是調(diào)控腺苷受體A2A活化后效應(yīng)走向的決定因素,。
這一研究結(jié)果,，不僅揭開了A2A受體發(fā)揮雙向作用的機制，同時證實了可以人為地調(diào)控腺苷的逆轉(zhuǎn)損害及強化抗損傷作用的方向,，為臨床中使用A2A受體調(diào)節(jié)藥物,，治療各種腦損傷提供了理論依據(jù)；使根據(jù)谷氨酸濃度,、選擇使用激動劑或拮抗劑治療腦損傷的方法成為可能,，對臨床實際應(yīng)用腺苷及其受體調(diào)節(jié)劑具有重大意義。（生物谷Bioon.com）
生物谷推薦原文出處：
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.
