Abstract
Methylene blue (MB) is the first fully synthetic compound that had found its way into medicine over 120 years ago as a treatment against malaria. MB has been approved for the treatment of methemoglobinemia, but there are premises for its repurposing as a neuroprotective agent based on the efficacy of this compound demonstrated in the models of Alzheimer’s, Parkinson’s, and Huntington’s diseases, traumatic brain injury, amyotrophic lateral sclerosis, depressive disorders, etc. However, the goal of this review was not so much to focus on the therapeutic effects of MB in the treatment of various neurodegeneration diseases, but to delve into the mechanisms of direct or indirect effect of this drug on the signaling pathways. MB can act as an alternative electron carrier in the mitochondrial respiratory chain in the case of dysfunctional electron transport chain. It also displays the anti-inflammatory and anti-apoptotic effects, inhibits monoamine oxidase (MAO) and nitric oxide synthase (NOS), activates signaling pathways involved in the mitochondrial pool renewal (mitochondrial biogenesis and autophagy), and prevents aggregation of misfolded proteins. Comprehensive understanding of all aspects of direct and indirect influence of MB, and not just some of its effects, can help in further research of this compound, including its clinical applications.
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Abbreviations
- AMPK:
-
AMP-activated protein kinase
- ARE:
-
antioxidant response element
- cGMP:
-
cyclic guanosine monophosphate
- CRH:
-
corticotropin-releasing hormone
- ETC:
-
electron transport chain
- GSK3β:
-
glycogen synthase kinase-3 beta
- HTT:
-
huntingtin
- Keap1:
-
Kelch-like ECH-associated protein 1
- MAO:
-
monoamine oxidase
- MB:
-
methylene blue
- mTORC1:
-
mammalian target of rapamycin complex 1
- NF-κB:
-
nuclear factor kappa-B
- NOS:
-
nitric oxide synthase
- Nrf2:
-
nuclear factor erythroid 2-related factor 2
- PGC-1α:
-
peroxisome proliferator-activated receptor gamma coactivator 1-alpha
- PI3K:
-
phosphoinositide 3-kinase
- PMCA:
-
plasma membrane Ca2+-ATPase
- ROS:
-
reactive oxygen species
- sGC:
-
soluble guanylate cyclase
- SOD1:
-
superoxide dismutase 1
- STAT:
-
signal transducer and transcription activator
- TNF-α:
-
tumor necrosis factor
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Funding
This work was supported by the Ministry of Science and Higher Education of the Russian Federation under the State assignment for universities in the field of scientific activity for 2020-2022 (project FZGU-2020-0044), scholarships of the President of the Russian Federation for young scientists and graduate students (SP-2802.2021.4), and a grant from the President of the Russian Federation for state support of young Russian scientists and state support for leading scientific schools (NSh-1375.2022.5).
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Artem P. Gureev – writing the text, Irina S. Sadovnikova – search and annotation of articles, preparation of drawings, Vasily N. Popov – concept and administration.
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Gureev, A.P., Sadovnikova, I.S. & Popov, V.N. Molecular Mechanisms of the Neuroprotective Effect of Methylene Blue. Biochemistry Moscow 87, 940–956 (2022). https://doi.org/10.1134/S0006297922090073
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DOI: https://doi.org/10.1134/S0006297922090073