Department of Biochemistry, Basic Medical Science Block-II, Sector-25, Panjab University, Chandigarh, 160014, India.
Neuromolecular Med. 2018 Dec;20(4):475-490. doi: 10.1007/s12017-018-8505-y. Epub 2018 Aug 13.
Homocysteine (Hcy) is a sulfur-containing amino acid derived from methionine metabolism. Elevated plasma Hcy levels (> 15 µM) result in a condition called hyperhomocysteinemia (HHcy), which is an independent risk factor in the development of various neurodegenerative disorders. Reactive oxygen species (ROS) produced by auto-oxidation of Hcy have been implicated in HHcy-associated neurological conditions. Hydrogen sulfide (HS) is emerging as a potent neuroprotective and neuromodulator molecule. The present study was aimed to evaluate the ability of NaHS (a source of HS) to attenuate Hcy-induced oxidative stress and altered antioxidant status in animals subjected to HHcy. Impaired cognitive functions assessed by Y-maze and elevated plus maze in Hcy-treated animals were reversed on NaHS administration. Increased levels of ROS, lipid peroxidation, protein carbonyls, and 4-hydroxynonenal (4-HNE)-modified proteins were observed in the cortex and hippocampus of Hcy-treated animals suggesting accentuated oxidative stress. This increase in Hcy-induced oxidative stress was reversed following NaHS supplementation. GSH/GSSG ratio, activity of antioxidant enzymes viz; superoxide dismutase, glutathione peroxidase, glutathione reductase, and glutathione-S-transferase were decreased in Hcy-treated animals. NaHS supplementation, on the otherhand, restored redox ratio and activity of antioxidant enzymes in the brains of animals with HHcy. Further, NaHS administration normalized nuclear factor erythroid 2-related factor 2 expression and acetylcholinesterase (AChE) activity in the brain of Hcy-treated animals. Histopathological studies using cresyl violet indicated higher number of pyknotic neurons in the cortex and hippocampus of HHcy animals, which were reversed by NaHS administration. The results clearly demonstrate that NaHS treatment significantly ameliorates Hcy-induced cognitive impairment by attenuating oxidative stress, improving antioxidant status, and modulating AChE activity thereby suggesting potential of HS as a therapeutic molecule.
同型半胱氨酸（Hcy）是一种来源于蛋氨酸代谢的含硫氨基酸。血浆 Hcy 水平升高（>15μM）导致高同型半胱氨酸血症（HHcy），这是各种神经退行性疾病发展的一个独立危险因素。Hcy 自动氧化产生的活性氧（ROS）与 HHcy 相关的神经状况有关。硫化氢（HS）作为一种有效的神经保护和神经调节剂分子而出现。本研究旨在评估 NaHS（HS 的来源）减弱 HHcy 动物中 Hcy 诱导的氧化应激和改变抗氧化状态的能力。在 Hcy 处理的动物中，通过 Y 迷宫和高架十字迷宫评估受损的认知功能，在给予 NaHS 后得到逆转。在 Hcy 处理的动物的皮质和海马体中观察到 ROS、脂质过氧化、蛋白质羰基和 4-羟基壬烯醛（4-HNE）修饰蛋白的水平升高，表明氧化应激加重。NaHS 补充后，这种 Hcy 诱导的氧化应激增加得到逆转。在 Hcy 处理的动物中，GSH/GSSG 比值、抗氧化酶（超氧化物歧化酶、谷胱甘肽过氧化物酶、谷胱甘肽还原酶和谷胱甘肽-S-转移酶）的活性降低。另一方面，NaHS 补充恢复了 HHcy 动物大脑中的氧化还原比和抗氧化酶的活性。此外，NaHS 给药使 Hcy 处理动物大脑中的核因子红细胞 2 相关因子 2 表达和乙酰胆碱酯酶（AChE）活性正常化。使用甲苯胺蓝进行的组织病理学研究表明，HHcy 动物皮质和海马体中存在更多的固缩神经元，而 NaHS 给药可逆转这种情况。研究结果清楚地表明，NaHS 治疗通过减轻氧化应激、改善抗氧化状态和调节 AChE 活性，显著改善 Hcy 诱导的认知障碍，从而表明 HS 作为一种治疗分子的潜力。
