Laboratory of Repair Enzymes, Institute of Chemical Biology and Fundamental Medicine, Siberian Division of Russian Academy of Sciences, Novosibirsk 630090, Russia.
Laboratory of Molecular Genetics and Biochemistry, Mental Health Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk 634014, Russia.
Oxid Med Cell Longev. 2021 Jan 23;2021:8881770. doi: 10.1155/2021/8881770. eCollection 2021.
Schizophrenia is recognized to be a highly heterogeneous disease at various levels, from genetics to clinical manifestations and treatment sensitivity. This heterogeneity is also reflected in the variety of oxidative stress-related mechanisms contributing to the phenotypic realization and manifestation of schizophrenia. At the molecular level, these mechanisms are supposed to include genetic causes that increase the susceptibility of individuals to oxidative stress and lead to gene expression dysregulation caused by abnormal regulation of redox-sensitive transcriptional factors, noncoding RNAs, and epigenetic mechanisms favored by environmental insults. These changes form the basis of the prooxidant state and lead to altered redox signaling related to glutathione deficiency and impaired expression and function of redox-sensitive transcriptional factors (Nrf2, NF-B, FoxO, etc.). At the cellular level, these changes lead to mitochondrial dysfunction and metabolic abnormalities that contribute to aberrant neuronal development, abnormal myelination, neurotransmitter anomalies, and dysfunction of parvalbumin-positive interneurons. Immune dysfunction also contributes to redox imbalance. At the whole-organism level, all these mechanisms ultimately contribute to the manifestation and development of schizophrenia. In this review, we consider oxidative stress-related mechanisms and new treatment perspectives associated with the correction of redox imbalance in schizophrenia. We suggest that not only antioxidants but also redox-regulated transcription factor-targeting drugs (including Nrf2 and FoxO activators or NF-B inhibitors) have great promise in schizophrenia. But it is necessary to develop the stratification criteria of schizophrenia patients based on oxidative stress-related markers for the administration of redox-correcting treatment.
精神分裂症在遗传到临床表现和治疗敏感性等各个层面被认为是一种高度异质的疾病。这种异质性也反映在与氧化应激相关的多种机制中，这些机制有助于精神分裂症的表型实现和表现。在分子水平上，这些机制包括增加个体对氧化应激易感性的遗传原因，以及由氧化还原敏感转录因子、非编码 RNA 和环境损伤偏好的表观遗传机制异常调节导致的基因表达失调。这些变化构成了促氧化剂状态的基础，并导致与谷胱甘肽缺乏和氧化还原敏感转录因子（Nrf2、NF-B、FoxO 等）表达和功能受损相关的氧化还原信号改变。在细胞水平上，这些变化导致线粒体功能障碍和代谢异常，从而导致异常的神经元发育、异常的髓鞘形成、神经递质异常和钙调蛋白阳性中间神经元功能障碍。免疫功能障碍也导致氧化还原失衡。在整个机体水平上，所有这些机制最终导致精神分裂症的表现和发展。在这篇综述中，我们考虑了与精神分裂症中氧化还原失衡纠正相关的氧化应激相关机制和新的治疗观点。我们认为，不仅抗氧化剂，而且氧化还原调节转录因子靶向药物（包括 Nrf2 和 FoxO 激活剂或 NF-B 抑制剂）在精神分裂症中具有很大的应用前景。但是，有必要根据与氧化应激相关的标志物为精神分裂症患者制定分层标准，以进行氧化还原纠正治疗。
