Elevated homocysteine (Hcy) levels have been implicated in neurodevelopmental and neurodegenerative disorders. Induction of oxidative stress and apoptosis has been reported as major mechanism in Hcy-induced neurotoxicity. Hydrogen sulfide (H₂S), as an antioxidant molecule has been reported to exhibit novel protective effect against Hcy-induced cell damage. However, the mechanisms involved in protective effect of H₂S against Hcy-induced toxicity in neurons have not been fully elucidated. Herein, effect of sodium hydrogen sulfide (NaHS, a source of H₂S) on Hcy-induced neurotoxicity was studied on Neuro-2a (N2a) cells in vitro and in animals subjected to hyperhomocysteinemia. DCFH-DA staining revealed that NaHS effectively attenuated Hcy-induced oxidative damage by reducing intracellular reactive oxygen species (ROS) generation. JC-1 staining and western blot results showed that NaHS pre-treatment prevented Hcy-induced mitochondrial dysfunctions and mitochondria-mediated apoptosis. MTT assay, cell cycle analysis, ethidium bromide/acridine orange (EB/AO) and Hoechst staining results demonstrated that NaHS significantly alleviated Hcy-induced cytotoxicity in N2a cells by preventing oxidative damage. Importantly, the results from agarose gel electrophoresis, comet and TUNEL assay indicated that NaHS also prevented neurodegeneration by reducing DNA damage and apoptotic cell death in animals with hyperhomocysteinemia. Taken together, the results demonstrate that the protective potential of H₂S against Hcy-induced neurotoxicity is mediated by preventing oxidative DNA damage and mitochondrial dysfunctions. The findings validate that H₂S is a promising therapeutic molecule in neurodegenerative conditions associated with hyperhomocysteinemia.

高半胱氨酸（Hcy）水平升高与神经发育和神经退行性疾病有关。据报道，氧化应激的诱导和细胞凋亡是Hcy诱导的神经毒性的主要机制。硫化氢（H ₂ S），作为一种抗氧化剂分子，据报道对Hcy诱导的细胞损伤表现出新颖的保护作用。但是，尚未完全阐明H ₂ S对Hcy诱导的神经元毒性的保护作用的机制。本文在体外对Neuro-2a（N2a）细胞研究了硫化氢钠（NaHS，H ₂ S的来源）对Hcy诱导的神经毒性的影响。以及遭受高同型半胱氨酸血症的动物。DCFH-DA染色显示，NaHS通过减少细胞内活性氧（ROS）的生成有效地减弱了Hcy诱导的氧化损伤。JC-1染色和蛋白质印迹结果表明，NaHS预处理可预防Hcy诱导的线粒体功能障碍和线粒体介导的细胞凋亡。MTT分析，细胞周期分析，溴化乙锭/ ac啶橙（EB / AO）和Hoechst染色结果表明，NaHS通过防止氧化损伤显着减轻了Hcy诱导的N2a细胞毒性。重要的是，琼脂糖凝胶电泳，彗星和TUNEL分析的结果表明，NaHS还可以通过减少高同型半胱氨酸血症动物的DNA损伤和凋亡细胞死亡来预防神经变性。在一起通过防止氧化性DNA损伤和线粒体功能障碍来介导₂ H对Hcy诱导的神经毒性的作用。这些发现证实，在与高同型半胱氨酸血症相关的神经退行性疾病中，H ₂ S是一种有前途的治疗分子。