I will have to post the data in parts as there is a lot but here is some information to get you started.
From Mitochondrial Function to Neuroprotection-an Emerging Role for Methylene Blue
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.
https://pubmed.ncbi.nlm.nih.gov/28840449/
Top 6 Benefits of Methylene Blue + Dosage & Side Effects
At low doses, methylene blue (MB) has been shown to protect the brain from disease by acting as an electron donor to complex I-IV of the mitochondria which increases adenosine triphosphate (ATP) production. ATP is the currency of life and the energy that powers humans. If our production of ATP declines, our physical and mental performance declines. Even healthy individuals can benefit from a boost in ATP production [1].
More specifically, MB can donate electrons to coenzyme Q and possibly to cytochrome C, thus increasing cytochrome oxidase (complex IV) activity and oxygen consumption. MB also increases heme synthesis [3].
MB is also able to stimulate glucose metabolism in conditions without oxygen and increase the amount of NAD+ produced by mitochondria [4, 5].
Low dose MB also acts as an antioxidant in mitochondria. MB interacts with oxygen to form water, which would decrease the superoxide radicals produced during the process of oxidative phosphorylation. MB can also trap leaking electrons produced by mitochondrial inhibitors and preserve the metabolic rate by bypassing blocked points of electron flow, thus improving mitochondrial respiration [1].
https://selfhacked.com/blog/methylene-b ... -enhancer/
Methylene blue improves sensorimotor phenotype and decreases anxiety in parallel with activating brain mitochondria biogenesis in mid-age mice
Age-related brain dysfunctions are associated with mitochondria malfunctions and increased risk of developing neurodegenerative diseases (ND). Recently, a mitochondria-targeting drug methylene blue has been drawing considerable interest as a potential treatment for ND. We found that aged mice manifested a decrease in physical endurance, spontaneous locomotor activity, and exploration concomitant with an increase in anxiety-related behavior, as compared to adult mice. Treating mice for 60 days with MB slowed down these changes. There were no significant changes in the animals' body weight, oxygen consumption rates, or respiratory quotient index, in adult or aged MB-treated mice. However, MB treatment significantly increased the generation of reactive oxygen species in brain mitochondria. The expression of several genes relevant to mitochondria biogenesis, bioenergetics, and antioxidant defense (NRF1, MTCOX1, TFAM, and SOD2) was greatly suppressed in aged mice; it was restored by MB treatment. It seems plausible that the effects of MB could be mediated by its ability to increase H2O2 production in brain mitochondria, thereby activating Nrf2/ARE signaling pathway and mitochondria biogenesis. Our data and earlier findings support the idea that MB can be an attractive prototype drug for developing safe and efficient gerontoprotective compounds.
https://pubmed.ncbi.nlm.nih.gov/27515402/
METHYLENE BLUE: AN UNEXPECTED COGNITIVE ENHANCER
As early as 2002, Dr. Gonzalez-Lima has been studying the cognitive enhancing properties of methylene blue.
It improves the oxygen consumption of cells, increasing cellular energy, which in turn enhances memory — both long- and short-term — is neuroprotective, and is an antioxidant.
In the words of Dr. Gonzalez-Lima, there’s “no better antioxidant.” Because it accumulates in areas of cells with a high concentration of mitochondria, it stops free radicals as they are formed, preventing any oxidant damage or stress. It’s a particularly effective cognitive enhancer because methylene blue targets “respiring cells” — cells that are using more oxygen. The brain is an oxygen hog, so methylene blue collects there.
https://smartdrugsmarts.com/episodes/ep ... lene-blue/
Mitochondria as a target for neuroprotection: role of methylene blue and photobiomodulation
Mitochondrial dysfunction plays a central role in the formation of neuroinflammation and oxidative stress, which are important factors contributing to the development of brain disease. Ample evidence suggests mitochondria are a promising target for neuroprotection. Recently, methods targeting mitochondria have been considered as potential approaches for treatment of brain disease through the inhibition of inflammation and oxidative injury. This review will discuss two widely studied approaches for the improvement of brain mitochondrial respiration, methylene blue (MB) and photobiomodulation (PBM). MB is a widely studied drug with potential beneficial effects in animal models of brain disease, as well as limited human studies. Similarly, PBM is a non-invasive treatment that promotes energy production and reduces both oxidative stress and inflammation, and has garnered increasing attention in recent years. MB and PBM have similar beneficial effects on mitochondrial function, oxidative damage, inflammation, and subsequent behavioral symptoms. However, the mechanisms underlying the energy enhancing, antioxidant, and anti-inflammatory effects of MB and PBM differ. This review will focus on mitochondrial dysfunction in several different brain diseases and the pathological improvements following MB and PBM treatment.
https://translationalneurodegeneration. ... 20-00197-z
Methylene blue improves mitochondrial respiration and decreases oxidative stress in a substrate-dependent manner in diabetic rat hearts
The purpose of the present study was to characterize the effects of acute administration of methylene blue on mitochondrial respiration, H2O2 production, and calcium sensitivity in rat heart mitochondria isolated from healthy and 2 months (streptozotocin-induced) diabetic rats. Mitochondrial respiratory function was assessed by high-resolution respirometry. H2O2 production and calcium retention capacity were measured spectrofluorimetrically. The addition of methylene blue (0.1 μmol·L-1) elicited an increase in oxygen consumption of mitochondria energized with complex I and II substrates in both normal and diseased mitochondria. Interestingly, methylene blue elicited a significant increase in H2O2 release in the presence of complex I substrates (glutamate and malate), but had an opposite effect in mitochondria energized with complex II substrate (succinate). No changes in the calcium retention capacity of healthy or diabetic mitochondria were found in the presence of methylene blue. In conclusion, in cardiac mitochondria isolated from diabetic and nondiabetic rat hearts, methylene blue improved respiratory function and elicited a dichotomic, substrate-dependent effect on ROS production.
https://pubmed.ncbi.nlm.nih.gov/28738167/
Methylene blue (MB) is a dye which has been used for a long time in medicine [10,11]. When given orally, MB is well absorbed from the gastrointestinal tract and widely distributed throughout the body with maximal plasma concentrations being reached after two hours and a plasma half-life of around 20 hours; the drug is mainly excreted through the kidney [12–14]. MB is registered in many countries for a number of indications such as visualization of organ structures during surgery, treatment of methaemoglobinaemia, prevention of urogenital infections, treatment of septic shock, prevention of ifosfamid-induced encephalopathy, treatment of priapism, as well as sterilization of blood transfusions [10,11,15–20].
MB is also the oldest synthetic antimalarial drug and has first been used by Paul Ehrlich and colleagues against malaria in a German hospital in the year 1891 [21]. Thereafter it was applied on a large scale in many endemic areas and against all types of malaria – especially against malaria disease which was not responding to quinine treatment – until it was replaced by new synthetic antimalarials without staining properties [22]. The research on the treatment of malaria with MB got reactivated in three biochemical laboratories towards the end of the 1990s and at a time when the development of multi-drug resistance had become a serious threat to global malaria control efforts [2]. Especially the detection of the P. falciparum glutathione reductase as a new drug target paved the way to further research on the role of MB in malaria treatment, with key studies having been conducted at the Heidelberg University Biochemistry Centre and under the leadership of the late Heiner Schirmer [2,10]. In addition to its activity against this enzyme, the effects on the malaria parasites are caused by MB acting as a subversive redox-cycling substrate, by its interaction with the polymerization of haem to hemozoin, and most likely by a number of further and still unknown effects of the pluripotent MB, which makes resistance development rather unlikely [2,10]. Preclinical studies have shown the potency of MB in the inhibition of P. falciparum and P. vivax, including of drug-resistant isolates, it’s very strong effects as to the reduction of P. falciparum gametocytes, and its synergy with artemisinin derivates [23–28]. As a consequence, MB has already been considered a potentially useful partner drug for ACT in the year 2009 [6].
https://www.tandfonline.com/doi/full/10 ... 19.1634545
Dye kills malaria parasites at speed not seen before
Research shows that the dye methylene blue is a safe antimalarial that kills malaria parasites at an unprecedented rate. Within two days, patients are cured of the disease and no longer transmit the parasite if they are bitten again by a mosquito. This discovery was made by Radboud university medical center scientists and international colleagues during a research project conducted in Mali. The results will be published in The Lancet Infectious Diseases on February 6th.
Effect after just 48 hours
The gametocytes can stay in a person's body for several weeks following treatment for malaria. In the new study in Mali, Radboudumc researchers added methylene blue to the artemisinin-based combination therapy. Methylene blue is a blue dye that is used in laboratories to distinguish dead cells from living cells. Adding the dye to the antimalaria medicine ensured that patients no longer infected other mosquitos, within as little as 48 hours. Patients who were not given methylene blue were able to infect other mosquitos for at least a week. Researcher Teun Bousema (Radboudumc) coordinated the study which was conducted together with the University of California (UCSF) and the Malaria Research and Training Center (MRTC). Bousema: "We noted that the male parasites disappeared from the bloodstream more quickly than the female parasites
https://www.sciencedaily.com/releases/2 ... 195624.htm
Methylene Blue has a potent antiviral activity against SARS-CoV-2 in the absence
of UV-activation in vitro
https://www.biorxiv.org/content/10.1101 ... 1.full.pdf
Cellular and Molecular Actions of Methylene Blue in the Nervous System
In summary, MB has a broad range of targets encompassing multiple neurotransmitter systems, ion channels, and enzymes involved in various physiological functions of the nervous system. It appears that many of the biological effects of MB are closely associated with its unique physicochemical properties, including its redox characteristics, ionic charges, and light spectrum characteristics. MB has a high solubility in aqueous media; preclinical and clinical studies demonstrate a low toxicity profile (Küpfer et al., 1994; Riha et al., 2005). In addition, its ability to permeate cellular membranes and to cross the blood-brain barrier (Peter et al., 2000) makes MB attractive as a potential therapeutic agent. Recent clinical investigations on the biological effects of MB range from new trials on malaria treatment (Coulibaly et al., 2009) to the therapy of depression and Alzheimer's disease. However, there are still many open questions regarding the effect of MB in CNS disorders and further studies elucidating the molecular and cellular targets of MB actions are needed.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3005530/
Anti-Aging Potentials of Methylene Blue for Human Skin Longevity
Methylene blue (MB), a traditional mitochondrial-targeting antioxidant, showed a potent ROS scavenging efficacy in cultured human skin fibroblasts derived from healthy donors and from patients with progeria, a genetic premature aging disease. In comparison with other widely used general and mitochondrial-targeting antioxidants, we found that MB was more effective in stimulating skin fibroblast proliferation and delaying cellular senescence. The skin irritation test, performed on an in vitro reconstructed 3D human skin model, indicated that MB was safe for long-term use, and did not cause irritation even at high concentrations. Application of MB to this 3D skin model further demonstrated that MB improved skin viability, promoted wound healing and increased skin hydration and dermis thickness. Gene expression analysis showed that MB treatment altered the expression of a subset of extracellular matrix proteins in the skin, including upregulation of elastin and collagen 2A1, two essential components for healthy skin. Altogether, our study suggests that MB has a great potential for skin care.
https://www.nature.com/articles/s41598-017-02419-3
Methlyene blue
