REVIEW: Molecular Mechanisms of the Neuroprotective Effect of Methylene Blue

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Artem P. Gureev^1,2,a*, Irina S. Sadovnikova¹, and Vasily N. Popov^1,2

¹Voronezh State University, 394018 Voronezh, Russia

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

^* To whom correspondence should be addressed.

Received May 3, 2022; Revised July 7, 2022; Accepted July 15, 2022

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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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KEY WORDS: methylene blue, neurodegeneration, Alzheimer’s disease, tau protein, alternative electron transport, Nrf2/ARE signaling pathway, apoptosis, autophagy, inflammation, monoamine oxidase, NO synthase

DOI: 10.1134/S0006297922090073

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