Technological Development Center, Division of Biotechnology, Neurobiotechology Research Group, Federal University of Pelotas, Pelotas, RS, Brazil.
Technological Development Center, Division of Biotechnology, Cancer Biotechnology Laboratory, Federal University of Pelotas, Pelotas, RS, Brazil.
Neurochem Res. 2021 Mar;46(3):535-549. doi: 10.1007/s11064-020-03190-0. Epub 2021 Feb 6.
Extensive data have reported the involvement of oxidative stress in the pathogenesis of neuropsychiatric disorders, prompting the pursuit of antioxidant molecules that could become adjuvant pharmacological agents for the management of oxidative stress-associated disorders. The 3-[(4-chlorophenyl)selanyl]-1-methyl-1H-indole (CMI) has been reported as an antioxidant and immunomodulatory compound that improves depression-like behavior and cognitive impairment in mice. However, the exact effect of CMI on specific brain cells is yet to be studied. In this context, the present study aimed to evaluate the antioxidant activity of CMI in HO-induced oxidative stress on human dopaminergic neuroblastoma cells (SH-SY5Y) and to shed some light into its possible mechanism of action. Our results demonstrated that the treatment of SH-SY5Y cells with 4 µM CMI protected them against HO (343 μM)-induced oxidative stress. Specifically, CMI prevented the increased number of reactive oxygen species (ROS)-positive cells induced by HO exposure. Furthermore, CMI treatment increased the levels of reduced glutathione in SH-SY5Y cells. Molecular docking studies demonstrated that CMI might interact with enzymes involved in glutathione metabolism (i.e., glutathione peroxidase and glutathione reductase) and HO scavenging (i.e., catalase). In silico pharmacokinetics analysis predicted that CMI might be well absorbed, metabolized, and excreted, and able to cross the blood-brain barrier. Also, CMI was not considered toxic overall. Taken together, our results suggest that CMI protects dopaminergic neurons from HO-induced stress by lowering ROS levels and boosting the glutathione system. These results will facilitate the clinical application of CMI to treat nervous system diseases associated with oxidative stress.
大量数据报道氧化应激参与神经精神疾病的发病机制，促使人们寻求抗氧化分子，这些分子可能成为治疗与氧化应激相关疾病的辅助药物。3-[(4-氯苯基)硒基]-1-甲基-1H-吲哚（CMI）已被报道为一种具有抗氧化和免疫调节作用的化合物，可改善抑郁样行为和认知障碍小鼠。然而，CMI 对特定脑细胞的确切作用尚未研究。在这种情况下，本研究旨在评估 CMI 在 HO 诱导的人多巴胺能神经母细胞瘤细胞（SH-SY5Y）氧化应激中的抗氧化活性，并探讨其可能的作用机制。我们的研究结果表明，用 4 μM CMI 处理 SH-SY5Y 细胞可防止 HO（343 μM）诱导的氧化应激。具体而言，CMI 可防止 HO 暴露引起的 ROS 阳性细胞数量增加。此外，CMI 处理可增加 SH-SY5Y 细胞中还原型谷胱甘肽的水平。分子对接研究表明，CMI 可能与参与谷胱甘肽代谢的酶（即谷胱甘肽过氧化物酶和谷胱甘肽还原酶）和 HO 清除（即过氧化氢酶）相互作用。基于计算机的药代动力学分析预测 CMI 可能具有良好的吸收、代谢和排泄能力，并且能够穿过血脑屏障。此外，CMI 总体上不被认为有毒。总之，我们的研究结果表明，CMI 通过降低 ROS 水平和增强谷胱甘肽系统来保护多巴胺能神经元免受 HO 诱导的应激。这些结果将促进 CMI 在治疗与氧化应激相关的神经系统疾病中的临床应用。
