Novel Treatment Strategies Targeting Myelin and Oligodendrocyte Dysfunction in Schizophrenia

Gouvêa-Junqueira, Danielle; Falvella, Ana Caroline Brambilla; Antunes, André Saraiva Leão Marcelo; Seabra, Gabriela; Brandão‐Teles, Caroline; Martins‐de‐Souza, Daniel; Crunfli, Fernanda

doi:10.3389/fpsyt.2020.00379

Cited by 44 publications

(21 citation statements)

References 225 publications

(266 reference statements)

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“…CNPase and MBP are markers of OL differentiation and maturity, respectively. OLIG2, which is essential for cell fate choices, is a transcription factor in OLs ( Gouvea-Junqueira et al, 2020 ). The expression levels of CNPase/OLIG2 and MBP/OLIG2 in the brains of mice in each group were detected by immunofluorescence to evaluate the differentiation and maturation of OPCs.…”

Section: Resultsmentioning

confidence: 99%

Effect and Mechanism of Catalpol on Remyelination via Regulation of the NOTCH1 Signaling Pathway

Sun

Zha

et al. 2021

Front. Pharmacol.

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Promoting the differentiation of oligodendrocyte precursor cells (OPCs) is important for fostering remyelination in multiple sclerosis. Catalpol has the potential to promote remyelination and exert neuroprotective effects, but its specific mechanism is still unclear. Recent studies have shown that the NOTCH1 signaling pathway is involved in mediating OPC proliferation and differentiation. In this study, we elucidated that catalpol promoted OPC differentiation in vivo and vitro and explored the regulatory role of catalpol in specific biomolecular processes. Following catalpol administration, better and faster recovery of body weight and motor balance was observed in mice with cuprizone (CPZ)-induced demyelination. Luxol fast blue staining (LFB) and transmission electron microscopy (TEM) showed that catalpol increased the myelinated area and improved myelin ultrastructure in the corpus callosum in demyelinated mice. In addition, catalpol enhanced the expression of CNPase and MBP, indicating that it increased OPC differentiation. Additionally, catalpol downregulated the expression of NOTCH1 signaling pathway-related molecules, such as JAGGED1, NOTCH1, NICD1, RBPJ, HES5, and HES1. We further demonstrated that in vitro, catalpol enhanced the differentiation of OPCs into OLs and inhibited NOTCH1 signaling pathway activity. Our data suggested that catalpol may promote OPC differentiation and remyelination through modulation of the NOTCH1 pathway. This study provides new insight into the mechanism of action of catalpol in the treatment of multiple sclerosis.

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Section: Resultsmentioning

confidence: 99%

Effect and Mechanism of Catalpol on Remyelination via Regulation of the NOTCH1 Signaling Pathway

Sun

Zha

et al. 2021

Front. Pharmacol.

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“…Several pathways regulate OL differentiation and myelination in the CNS [ 223 ]. The phosphatidylinositol-3-phosphate kinase (PI3K)/Akt/mTOR pathway controls the initiation of myelination in the CNS through mTORC1 signaling [ 224 ].…”

Section: Molecular Mechanisms Of Oxidative Stress In the Pathogenementioning

confidence: 99%

Oxidative Stress-Related Mechanisms in Schizophrenia Pathogenesis and New Treatment Perspectives

Ermakov

Dmitrieva

Parshukova

et al. 2021

Oxidative Medicine and Cellular Longevity

107

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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.

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“…As a consequence, neuronal membranes properties are also potentially altered and may jeopardise the efficiency of the electrical signal transmission [119]. Acting on myelin dysfunction and its associations with NMDA receptors and oxidative stress is one of the therapeutic hypotheses currently studied for the treatment of schizophrenia [120].…”

Section: The Role Of Omega-3 In Myelin Constitution and Functionmentioning

confidence: 99%

Shared Biological Pathways between Antipsychotics and Omega-3 Fatty Acids: A Key Feature for Schizophrenia Preventive Treatment?

Frajerman

Scoriels

Kébir

et al. 2021

IJMS

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Schizophrenia typically emerges during adolescence, with progression from an ultra-high risk state (UHR) to the first episode of psychosis (FEP) followed by a chronic phase. The detailed pathophysiology of schizophrenia and the factors leading to progression across these stages remain relatively unknown. The current treatment relies on antipsychotics, which are effective for FEP and chronic schizophrenia but ineffective for UHR patients. Antipsychotics modulate dopaminergic and glutamatergic neurotransmission, inflammation, oxidative stress, and membrane lipids pathways. Many of these biological pathways intercommunicate and play a role in schizophrenia pathophysiology. In this context, research of preventive treatment in early stages has explored the antipsychotic effects of omega-3 supplementation in UHR and FEP patients. This review summarizes the action of omega-3 in various biological systems involved in schizophrenia. Similar to antipsychotics, omega-3 supplementation reduces inflammation and oxidative stress, improves myelination, modifies the properties of cell membranes, and influences dopamine and glutamate pathways. Omega-3 supplementation also modulates one-carbon metabolism, the endocannabinoid system, and appears to present neuroprotective properties. Omega-3 has little side effects compared to antipsychotics and may be safely prescribed for UHR patients and as an add-on for FEP patients. This could to lead to more efficacious individualised treatments, thus contributing to precision medicine in psychiatry.

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Novel Treatment Strategies Targeting Myelin and Oligodendrocyte Dysfunction in Schizophrenia

Cited by 44 publications

References 225 publications

Effect and Mechanism of Catalpol on Remyelination via Regulation of the NOTCH1 Signaling Pathway

Effect and Mechanism of Catalpol on Remyelination via Regulation of the NOTCH1 Signaling Pathway

Oxidative Stress-Related Mechanisms in Schizophrenia Pathogenesis and New Treatment Perspectives

Shared Biological Pathways between Antipsychotics and Omega-3 Fatty Acids: A Key Feature for Schizophrenia Preventive Treatment?

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