Council for Nutritional and Environmental Medicine (CONEM), Toften 24, 8610, Mo i Rana, Norway.
Department of Pharmacology, Faculty of Medicine, Ovidius University of Constanta, Campus, 900470, Constanta, Romania.
Pharmacol Res. 2021 Apr;166:105437. doi: 10.1016/j.phrs.2021.105437. Epub 2021 Jan 22.
This paper reviews the potential role of glutathione (GSH) in autism spectrum disorder (ASD). GSH plays a key role in the detoxification of xenobiotics and maintenance of balance in intracellular redox pathways. Recent data showed that imbalances in the GSH redox system are an important factor in the pathophysiology of ASD. Furthermore, ASD is accompanied by decreased concentrations of reduced GSH in part caused by oxidation of GSH into glutathione disulfide (GSSG). GSSG can react with protein sulfhydryl (SH) groups, thereby causing proteotoxic stress and other abnormalities in SH-containing enzymes in the brain and blood. Moreover, alterations in the GSH metabolism via its effects on redox-independent mechanisms are other processes associated with the pathophysiology of ASD. GSH-related regulation of glutamate receptors such as the N-methyl-D-aspartate receptor can contribute to glutamate excitotoxicity. Synergistic and antagonistic interactions between glutamate and GSH can result in neuronal dysfunction. These interactions can involve transcription factors of the immune pathway, such as activator protein 1 and nuclear factor (NF)-κB, thereby interacting with neuroinflammatory mechanisms, ultimately leading to neuronal damage. Neuronal apoptosis and mitochondrial dysfunction are recently outlined as significant factors linking GSH impairments with the pathophysiology of ASD. Moreover, GSH regulates the methylation of DNA and modulates epigenetics. Existing data support a protective role of the GSH system in ASD development. Future research should focus on the effects of GSH redox signaling in ASD and should explore new therapeutic approaches by targeting the GSH system.
本文综述了谷胱甘肽 (GSH) 在自闭症谱系障碍 (ASD) 中的潜在作用。GSH 在解毒外来物质和维持细胞内氧化还原途径平衡方面发挥着关键作用。最近的数据表明，GSH 氧化还原系统的失衡是 ASD 病理生理学的一个重要因素。此外，ASD 伴随着还原型 GSH 浓度的降低，部分原因是 GSH 氧化成谷胱甘肽二硫化物 (GSSG)。GSSG 可以与蛋白质巯基 (SH) 基团反应，从而导致脑和血液中含 SH 的酶的蛋白毒性应激和其他异常。此外，通过对氧化还原独立机制的影响，GSH 代谢的改变是与 ASD 病理生理学相关的其他过程。GSH 对谷氨酸受体（如 N-甲基-D-天冬氨酸受体）的调节作用可导致谷氨酸兴奋性毒性。谷氨酸和 GSH 的协同和拮抗相互作用可导致神经元功能障碍。这些相互作用可以涉及免疫途径的转录因子，如激活蛋白 1 和核因子 (NF)-κB，从而与神经炎症机制相互作用，最终导致神经元损伤。神经元凋亡和线粒体功能障碍最近被概述为将 GSH 损伤与 ASD 病理生理学联系起来的重要因素。此外，GSH 调节 DNA 的甲基化并调节表观遗传学。现有数据支持 GSH 系统在 ASD 发展中的保护作用。未来的研究应侧重于 GSH 氧化还原信号在 ASD 中的作用，并应通过靶向 GSH 系统探索新的治疗方法。
