Abstract
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-κB, 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-κB 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.
Highlights
Schizophrenia is a complex and heterogeneous mental disorder
The most reliable proof of predominance of prooxidant processes is the increase of thiobarbituric acid reactive substances in drug-naïve first-episode psychosis, stable medicated outpatients, and chronic inpatients, which is confirmed by the results of meta-analysis [40, 46]
The heterogeneity of schizophrenia is reflected in the diversity of oxidative stress-related mechanisms that contribute to the disease
Summary
Schizophrenia is a complex and heterogeneous mental disorder. The heterogeneity of schizophrenia is associated with a wide range of causative biological pathways. The factor that unites these biological pathways is oxidative stress (OS). There is still no definite opinion on whether OS is the primary cause of the disease, or it occurs secondarily under the influence of environmental factors or long-term treatment. It is generally accepted that OS plays an essential role in the pathogenesis of schizophrenia. In the first part of this comprehensive review, we will analyze the various mechanisms of schizophrenia pathogenesis associated with oxidative stress. We will consider the effect of antipsychotic therapy on the parameters of redox balance, as well as review the prospects for the use of antioxidant therapy, and propose new therapeutic strategies for redox correction based on transcription factor-targeting drugs
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