G6PD plays a neuroprotective role in brain ischemia through promoting pentose phosphate pathway
G6PD plays a neuroprotective role in brain ischemia through promoting pentose phosphate pathway
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G6PD通过促进戊糖磷酸途径在脑缺血中发挥神经保护作用
DOI：
10.1016/j.freeradbiomed.2017.08.011
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发表时间：
2017-11-01
影响因子：
7.4
通讯作者：
Qin, Zheng-Hong
中科院分区：
文献类型：
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作者：
Cao, Lijuan;Zhang, Dingmei;Qin, Zheng-Hong
TIGAR调节的磷酸戊糖途径(PPP)在脑缺血/再灌流过程中对神经元的存活起着关键作用。葡萄糖-6-磷酸脱氢酶(G6PD)是PPP中的限速酶，因此我们推测它通过产生NADPH在抗氧化防御中发挥重要作用。本研究采用体内和体外缺血性卒中模型，探讨G6PD在脑缺血/再灌注性神经元损伤中的调节和作用。结果表明，脑缺血再灌流后G6PD的mRNA和蛋白水平明显升高。在体内，慢病毒介导的G6PD在小鼠体内的过表达显著减轻了缺血/再灌注损伤后的神经元损伤，而慢病毒介导的G6PD基因敲除则加剧了这种损伤。体外培养的原代神经元过表达G6PD可减轻缺氧缺糖/复氧(OGD/R)状态下神经元的损伤，而G6PD的过表达则加重神经元的损伤。G6PD的过表达增加了NADPH和还原型谷胱甘肽(RGSH)的水平，并改善了ROS诱导的大分子损伤。相反，G6PD基因的敲除在小鼠和初级神经元中执行相反的效果。补充外源性NADPH可减轻G6PD基因敲除的不利影响，而进一步增强G6PD过表达在缺血损伤中的有利作用。因此，我们的结果提示G6PD通过增加PPP来保护缺血性脑损伤。因此，G6PD有可能成为治疗缺血性脑损伤的潜在靶点。
TIGAR-regulated pentose phosphate pathway (PPP) plays a critical role in the neuronal survival during cerebral ischemia/reperfusion. Glucose-6-phosphate dehydrogenase (G6PD) is a rate-limiting enzyme in PPP and thus, we hypothesized that it plays an essential role in anti-oxidative defense through producing NADPH. The present study investigated the regulation and the role of G6PD in ischemia/reperfusion-induced neuronal injury with in vivo and in vitro models of ischemic stroke. The results showed that the levels of G6PD mRNA and protein were increased after ischemia/reperfusion. In vivo, lentivirus-mediated G6PD overexpression in mice markedly reduced neuronal damage after ischemia/reperfusion insult, while lentivirus-mediated G6PD knockdown exacerbated it. In vitro, overexpression of G6PD in cultured primary neurons decreased neuronal injury under oxygen and glucose deprivation/reoxygenation (OGD/R) condition, whereas knockdown of G6PD aggravated it. Overexpression of G6PD increased levels of NADPH and reduced form of glutathione (rGSH), and ameliorated ROS-induced macromolecular damage. On the contrary, knockdown of G6PD executed the opposite effects in mice and in primary neurons. Supplementation of exogenous NADPH alleviated the detrimental effects of G6PD knockdown, whereas further enhanced the beneficial effects of G6PD overexpression in ischemic injury. Therefore, our results suggest that G6PD protects ischemic brain injury through increasing PPP. Thus G6PD may be considered as potential therapeutic target for treatment of ischemic brain injury.