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Molecular Mechanisms of the Neuroprotective Effect of Methylene Blue

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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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  1. Voronezh State University, 394018, Voronezh, Russia

    Artem P. Gureev, Irina S. Sadovnikova & Vasily N. Popov

  2. Voronezh State University of Engineering Technologies, 394036, Voronezh, Russia

    Artem P. Gureev & Vasily N. Popov

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  1. Artem P. Gureev
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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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