From Mitochondrial Function to Neuroprotection-an Emerging Role for Methylene Blue

Abstract

Methylene blue (MB) is a well-established drug with a long history of use, owing to its diverse range of use and its minimal side effect profile. MB has been used classically for the treatment of malaria, methemoglobinemia, and carbon monoxide poisoning, as well as a histological dye. Its role in the mitochondria, however, has elicited much of its renewed interest in recent years. MB can reroute electrons in the mitochondrial electron transfer chain directly from NADH to cytochrome c, increasing the activity of complex IV and effectively promoting mitochondrial activity while mitigating oxidative stress. In addition to its beneficial effect on mitochondrial protection, MB is also known to have robust effects in mitigating neuroinflammation. Mitochondrial dysfunction has been identified as a seemingly unifying pathological phenomenon across a wide range of neurodegenerative disorders, which thus positions methylene blue as a promising therapeutic. In both in vitro and in vivo studies, MB has shown impressive efficacy in mitigating neurodegeneration and the accompanying behavioral phenotypes in animal models for such conditions as stroke, global cerebral ischemia, Alzheimer's disease, Parkinson's disease, and traumatic brain injury. This review summarizes recent work establishing MB as a promising candidate for neuroprotection, with particular emphasis on the contribution of mitochondrial function to neural health. Furthermore, this review will briefly examine the link between MB, neurogenesis, and improved cognition in respect to age-related cognitive decline.

Keywords: Cognitive enhancement; Methylene blue; Neurodegenerative disorders; Neurogenesis; Neuroprotection.

Conflict of interest statement

Conflict of interest

The authors confirm that their contributions to this article are free from conflict of interest.

Figures

Figure 1

Chemical structure of methylene blue and leucomethylene blue.

Figure 2. Diagram of MB as an alternative mitochondrial electron transporter

Electrons in the mitochondrial electron transfer chain are transferred from complex I – complex IV, providing the transmembrane potential to drive production of ATP by complex V. Electron leakage from complex I and complex III acts as the main cellular source of ROS production. MB has been demonstrated as an alternative mitochondrial electron transporter to reroute electrons directly from complex I to complex III, avoiding electrons leakage and subsequent ROS production. This significantly facilitates complex IV activity, increasing mitochondrial respiration

Figure 3. MB in neurodegeneration

MB can protect against neuronal apoptosis by suppressing mitochondrial dysfunction and subsequent oxidative damage and ATP decline. MB supports neurogenesis by ameliorating neuroinflammation and promoting neurite outgrowth and synaptogenesis. In this manner, MB can prevent neuronal damage and may facilitate neuronal repair.