Zhang Ruyi, Lei Jianzhen, Chen Luyao, Wang Yanan, Yang Guocui, Yin Zhimin, Luo Lan
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China.
Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing 210046, China.
Antioxidants (Basel). 2022 Aug 25;11(9):1653. doi: 10.3390/antiox11091653.
Ferroptosis is a non-apoptotic form of cell death driven by iron-dependent lipid peroxidation. Recent evidence indicates that inhibiting ferroptosis could alleviate cerebral ischemia/reperfusion (CIR) injury. γ-glutamylcysteine (γ-GC), an intermediate of glutathione (GSH) synthesis, can upregulate GSH in brains. GSH is the co-factor of glutathione peroxidase 4 (GPX4), which is the negative regulator of ferroptosis. In this study, we explored the effect of γ-GC on CIR-induced neuronal ferroptosis and brain injury. We found that γ-GC significantly reduced the volume of cerebral infarction, decreased the loss of neurons and alleviated neurological dysfunction induced by CIR in rats. Further observation showed that γ-GC inhibited the CIR-caused rupture of the neuronal mitochondrial outer membrane and the disappearance of cristae, and decreased Fe deposition and lipid peroxidation in rat cerebral cortices. Meanwhile, γ-GC altered the expression of some ferroptosis-related proteins in rat brains. Mechanistically, γ-GC increased the expression of GSH synthetase (GSS) for GSH synthesis via protein kinase C (PKC)ε-mediated activation of nuclear factor erythroid 2-related factor (Nrf2). Our findings suggest that γ-GC not only serves as a raw material but also increases the GSS expression for GSH synthesis against CIR-induced lipid peroxidation and ferroptosis. Our study strongly suggests that γ-GC has potential for treating CIR injury.
铁死亡是一种由铁依赖性脂质过氧化驱动的非凋亡性细胞死亡形式。最近的证据表明，抑制铁死亡可以减轻脑缺血/再灌注（CIR）损伤。γ-谷氨酰半胱氨酸（γ-GC）是谷胱甘肽（GSH）合成的中间体，可上调大脑中的GSH。GSH是谷胱甘肽过氧化物酶4（GPX4）的辅助因子，而GPX4是铁死亡的负调节因子。在本研究中，我们探讨了γ-GC对CIR诱导的神经元铁死亡和脑损伤的影响。我们发现，γ-GC显著减小了大鼠脑梗死体积，减少了神经元损失，并减轻了CIR诱导的神经功能障碍。进一步观察表明，γ-GC抑制了CIR导致的神经元线粒体外膜破裂和嵴消失，并减少了大鼠大脑皮质中的铁沉积和脂质过氧化。同时，γ-GC改变了大鼠脑中一些铁死亡相关蛋白的表达。机制上，γ-GC通过蛋白激酶C（PKC）ε介导的核因子红细胞2相关因子（Nrf2）激活增加了用于GSH合成的谷胱甘肽合成酶（GSS）的表达。我们的研究结果表明，γ-GC不仅作为一种原料，还通过增加GSS表达来对抗CIR诱导的脂质过氧化和铁死亡以合成GSH。我们的研究强烈表明，γ-GC具有治疗CIR损伤的潜力。
