Methylene blue (MB) is a well-established drug with a long history of use, valued for its diverse applications and minimal side effect profile . Classically, MB has been used to treat malaria , methemoglobinemia , and carbon monoxide poisoning , as well as as a histological stain. More recently, however, its role in mitochondria has attracted considerable interest. MB may divert electrons in the mitochondrial electron transport chain directly from NADH to cytochrome c , thereby increasing the activity of complex IV and promoting mitochondrial activity while mitigating oxidative stress. In addition to its protective effect on mitochondria, MB may attenuate neuroinflammatory processes. Mitochondrial dysfunction has been identified as a unifying pathological phenomenon in a variety of neurodegenerative diseases , making MB a promising therapeutic agent.
According to in vitro and in vivo studies, MB may demonstrate impressive efficacy in mitigating neurodegeneration and associated behavioral phenotypes in animal models of diseases such as stroke , global cerebral ischemia, Alzheimer's disease , Parkinson's disease , and traumatic brain injury . This review summarizes recent work that may establish MB as a promising candidate for neuroprotection , with particular emphasis on the contribution of mitochondrial function to neuronal health. Furthermore, this study briefly examines the relationship between MB, neurogenesis , and improved cognition in relation to age-related cognitive decline.

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

Methylene blue (MB) is the first fully synthetic compound introduced into medicine over 120 years ago as a treatment for malaria . MB is approved for the treatment of methemoglobinemia but also shows promising results as a neuroprotective agent in models of Alzheimer's , Parkinson's , and Huntington's diseases , traumatic brain injury , amyotrophic lateral sclerosis , and depressive disorders . The aim of this study, however, is not so much to highlight the therapeutic effects of MB in the treatment of various neurodegenerative diseases , but rather to investigate the mechanisms of its direct or indirect influence on signaling pathways. MB might act as an alternative electron transporter in the mitochondrial respiratory chain when the electron transport chain is dysfunctional. It also exhibits anti-inflammatory and anti-apoptotic effects, inhibits monoamine oxidase (MAO) and nitric oxide synthase (NOS) , activates signaling pathways involved in the renewal of the mitochondrial pool (mitochondrial biogenesis and autophagy), and prevents the aggregation of misfolded proteins. A comprehensive understanding of all aspects of MB's direct and indirect influence, not just some of its effects, could advance further research on this compound, including its clinical applications.

Source: Molecular Mechanisms of the Neuroprotective Effect of Methylene Blue

Methylene blue (MB) is valued for its diverse medical applications and is well-suited for the treatment of methemoglobinemia and ifosfamide-induced encephalopathy . In recent years, interest in MB as an antimalarial agent and potential treatment option for neurodegenerative diseases such as Alzheimer's disease has increased. Reports demonstrate antidepressant and anxiolytic potential of MB in preclinical models, as well as promising results from clinical trials in schizophrenia and bipolar disorder . MB is a known inhibitor of monoamine oxidase A (MAO-A) , which is an established target for antidepressant effects. Furthermore, MB non-selectively inhibits nitric oxide synthase (NOS) and guanylate cyclase . Dysfunction of the nitric oxide (NO) -cyclic guanosine monophosphate (cGMP) signaling pathway is closely linked to the neurobiology of mood, anxiety, and psychotic disorders, while inhibition of NOS and/or guanylate cyclase is associated with antidepressant activity. These effects could significantly contribute to the psychotropic activity of MB. Furthermore, these disorders are characterized by mitochondrial dysfunction and redox imbalance. By acting as an alternative electron acceptor /donor, MB restores mitochondrial function, improves neuronal energy production, and inhibits superoxide generation, which could also contribute to its therapeutic activity. MB may be a particularly relevant strategy in depression combined with neurodegenerative diseases such as Alzheimer's and Parkinson's . By considering their physicochemical and pharmacokinetic properties, MB analogues may offer therapeutic potential as novel multi-target strategies in the treatment of depression . In addition, analogues with low MAOI activity may offer equivalent or improved efficacy with a lower risk of side effects.

Source: Methylene blue and its analogues as antidepressant compounds

Oxidative stress1 is the main cause of skin aging , which includes wrinkles, pigmentation , and impaired wound healing ability . The application of antioxidants in skin care is recognized as an effective method to delay the skin aging process. Methylene blue (MB), a traditional mitochondria -targeting antioxidant , showed potent effects in scavenging reactive oxygen species (ROS) in cultured human skin fibroblasts obtained from healthy donors and patients with progeria , a genetic premature aging disease. Compared with other commonly used antioxidants , both general and mitochondria -targeting, it was found that MB could more effectively stimulate the proliferation of skin fibroblasts and delay cellular senescence . A skin irritation test on an in vitro reconstructed 3D model of human skin showed that MB is safe for long-term use even at high concentrations and does not cause irritation. The application of MB to this 3D skin model further demonstrated that MB could improve skin viability, promote wound healing , increase skin hydration, and enhance dermis thickness. Gene expression analysis showed that MB treatment altered the expression of several extracellular matrix proteins in the skin, including upregulation of elastin and collagen 2A1, two essential components for healthy skin. MB can circumvent complex I/III activity in mitochondria and mitigate oxidative stress to some extent. This review summarizes the latest studies on the applications of MB in the treatment of age-related conditions, including neurodegeneration , memory loss , skin aging, and the premature aging disease progeria.

Source 1: Anti-Aging Potentials of Methylene Blue for Human Skin Longevity Source 2: The Potentials of Methylene Blue as an Anti-Aging Drug

This randomized , controlled acute intervention study investigated the effect of methylene blue (MB) on endotoxic shock. Anesthetized, healthy dogs received endotoxin alone or in combination with increasing doses of MB. The study found that low and moderate doses of MB could significantly increase arterial blood pressure but had no effect on cardiac index . MB resulted in a dose-dependent increase in systemic and pulmonary arterial pressure and vascular resistance. However, at higher doses, MB worsened systemic hypotension, myocardial depression, and pulmonary hypertension. Interestingly, MB selectively increased blood flow in mesenteric and femoral arteries, while renal blood flow remained unaffected. The study suggests that MB has complex dose-dependent effects on hemodynamic parameters and regional blood flow during endotoxic shock, which could potentially impact its application in critical care.

Source: Effects of methylene blue on oxygen availability and regional blood flow during endotoxic shock

Methylene blue (MB) and its compounds are being investigated for their potential to treat Alzheimer's disease (AD), a widespread neuropathological disorder characterized by the gradual loss of cognitive abilities and the development of severe dementia . The prevalence of AD is projected to increase significantly due to the aging population. Histopathologically, AD is characterized by the presence of intracellular neurofibrillary tangles (NFTs) and extracellular amyloid plaques in the brain. Methylene blue, a thiophene dye with FDA approval for the treatment of several diseases, demonstrates easy crossing of the blood-brain barrier and may have potential therapeutic potential in central nervous system disorders. The literature review includes randomized clinical trials investigating the potential benefits of MB in the treatment of AD. The results of the studies show that MB administration has demonstrated improvements in cognitive function, reductions in the accumulation of beta-amyloid plaques, improvements in memory and cognitive function in animals, and antioxidant properties that may mitigate oxidative stress and inflammation in the brain. This review evaluates the most recent research on the use of MB for the treatment of AD.

The relationship between methylene blue and Alzheimer's disease has recently attracted increasing scientific attention due to the suggestion that MB could slow the progression of this disease. Indeed, in addition to its well-characterized inhibitory effects on the cGMP signaling pathway, MB influences numerous cellular and molecular events closely linked to the progression of AD. Recent studies show that MB could reduce the formation of amyloid plaques and neurofibrillary tangles and partially repair impairments in mitochondrial function and cellular metabolism. Furthermore, MB influences various neurotransmitter systems ( cholinergic , serotonergic, and glutamatergic ), which may play an important role in the pathogenesis of AD and other cognitive disorders. The combination of the various effects of MB on these cellular functions could potentially mediate beneficial effects of MB. This has led to attempts to develop novel MB-based treatment modalities for AD. This review summarizes the effects of MB on neurotransmitter systems as well as on several cellular and molecular targets and discusses their relevance to AD.

Source 1: Exploring Methylene Blue and Its Derivatives in Alzheimer's Treatment: A Comprehensive Review of Randomized Control Trials
Source 2: Methylene blue and Alzheimer's disease