G6PD plays a neuroprotective role in brain ischemia through promoting pentose phosphate pathway

摘要

Abstract 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. Graphical abstract Display Omitted Highlights ? Overexpression of G6PD reduced the infarct volume, neurological score, brain edema. ? Overexpression of G6PD improved long-term survival and functional recovery. ? Overexpression of G6PD decreased oxidative damage in vitro and in vivo . ? Overexpression of G6PD decreased ROS through producing NADPH. ? G6PD may be considered a potential therapeutic target for ischemic brain injury.