Under physiological conditions, vitamin C is the main antioxidant found in the central nervous system and is found in two states: reduced as ascorbic acid (AA) and oxidized as dehydroascorbic acid (DHA). However, under pathophysiological conditions, AA is oxidized to DHA. The oxidation of AA and subsequent production of DHA in neurons are associated with a decrease in GSH concentrations, alterations in glucose metabolism and neuronal death. To date, the endogenous molecules that act as intrinsic regulators of neuronal necroptosis under conditions of oxidative stress are unknown. Here, we show that treatment with AA regulates the expression of pro- and antiapoptotic genes. Vitamin C also regulates the expression of RIPK1/MLKL, whereas the oxidation of AA in neurons induces morphological alterations consistent with necroptosis and MLKL activation. The activation of necroptosis by AA oxidation in neurons results in bubble formation, loss of membrane integrity, and ultimately, cellular explosion. These data suggest that necroptosis is a target for cell death induced by vitamin C.

在生理条件下，维生素C是在中枢神经系统中发现的主要抗氧化剂，并且存在两种状态：还原为抗坏血酸（AA）和氧化为脱氢抗坏血酸（DHA）。但是，在病理生理条件下，AA被氧化成DHA。AA的氧化和随后神经元中DHA的产生与GSH浓度降低，葡萄糖代谢改变和神经元死亡有关。迄今为止，在氧化应激条件下充当神经元坏死病的内在调节剂的内源性分子是未知的。在这里，我们表明，AA治疗可以调节促凋亡和抗凋亡基因的表达。维生素C还调节RIPK1 / MLKL的表达，而神经元中AA的氧化诱导与坏死病和MLKL激活相一致的形态学改变。通过神经元中AA氧化激活坏死病，会导致气泡形成，膜完整性丧失，并最终导致细胞爆炸。这些数据表明坏死病是维生素C诱导的细胞死亡的靶标。