大腦中產(chǎn)生的氣體分子一氧化氮能夠?qū)ι窠?jīng)元造成損傷。當(dāng)大腦產(chǎn)生太多一氧化氮時(shí),它導(dǎo)致中風(fēng)和諸如阿爾茨海默病之類的神經(jīng)退化性疾病加重和惡化。在一項(xiàng)新的研究中，來(lái)自美國(guó)桑福德-伯納姆醫(yī)學(xué)研究所（Sanford-Burnham Medical Research Institute）發(fā)現(xiàn)一氧化氮不僅對(duì)神經(jīng)元造成損傷，而且它也關(guān)閉大腦修復(fù)機(jī)制。相關(guān)研究結(jié)果于2013年2月4日在線發(fā)表在PNAS期刊上。

論文通信作者Stuart A. Lipton博士說(shuō)，“在這項(xiàng)研究中,我們發(fā)現(xiàn)關(guān)于在多種疾病中大腦內(nèi)自然化學(xué)反應(yīng)如何能夠?qū)е麓竽X損傷——記憶和認(rèn)知功能喪失——的新線索。”這項(xiàng)發(fā)現(xiàn)提示著如果人們能夠找到一種方法來(lái)逆轉(zhuǎn)一氧化氮對(duì)神經(jīng)元中特定酶的影響，那么就可能能夠開發(fā)新的策略來(lái)治療中風(fēng)和其他疾病。

學(xué)習(xí)和記憶部分上受到大腦中NMDA谷氨酸受體的控制。這些受體與神經(jīng)細(xì)胞膜上調(diào)節(jié)鈣離子和鈉離子進(jìn)出神經(jīng)元的孔相結(jié)合。當(dāng)這些NMDA受體遭受過(guò)度激活時(shí)，它們觸發(fā)一氧化氮產(chǎn)生。接著，一氧化氮通過(guò)S-亞硝基化（S-nitrosylation）反應(yīng)附著到其他的蛋白上。當(dāng)這些S-亞硝基化的蛋白參與細(xì)胞存活和壽命時(shí)，一氧化氮能夠?qū)е履X細(xì)胞提前死亡，而腦細(xì)胞提前死亡是神經(jīng)退化性疾病的一個(gè)特征。

在這項(xiàng)研究中,研究人員利用體外培養(yǎng)的神經(jīng)元和活的中風(fēng)模式小鼠來(lái)研究一氧化氮與協(xié)助修復(fù)神經(jīng)元損傷的蛋白之間的關(guān)系。他們發(fā)現(xiàn)一氧化氮與酶SHP-2發(fā)生反應(yīng)來(lái)抑制保護(hù)性的被稱作ERK1/2信號(hào)通路的分子級(jí)聯(lián)事件。因此，一氧化氮不僅對(duì)神經(jīng)元造成損傷，而且它也阻斷大腦進(jìn)行自我修復(fù)的能力。

Overproduction of nitric oxide (NO) can cause neuronal damage, contributing to the pathogenesis of several neurodegenerative diseases and stroke (i.e., focal cerebral ischemia). NO can mediate neurotoxic effects at least in part via protein S-nitrosylation, a reaction that covalently attaches NO to a cysteine thiol (or thiolate anion) to form an S-nitrosothiol. Recently, the tyrosine phosphatase Src homology region 2-containing protein tyrosine phosphatase-2 (SHP-2) and its downstream pathways have emerged as important mediators of cell survival. Here we report that in neurons and brain tissue NO can S-nitrosylate SHP-2 at its active site cysteine, forming S-nitrosylated SHP-2 (SNO–SHP-2). We found that NMDA exposure in vitro and transient focal cerebral ischemia in vivo resulted in increased levels of SNO–SHP-2. S-Nitrosylation of SHP-2 inhibited its phosphatase activity, blocking downstream activation of the neuroprotective physiological ERK1/2 pathway, thus increasing susceptibility to NMDA receptor-mediated excitotoxicity. These findings suggest that formation of SNO–SHP-2 represents a key chemical reaction contributing to excitotoxic damage in stroke and potentially other neurological disorders.