Błękit metylenowy

Anti-Aging Potentials of Methylene Blue for Human Skin Longevity

Typ badania: non-rct in vitro

Liczba cytowań: 90

Rok: 2017

Autorzy: Zheng-Mei Xiong, M. O’Donovan, Linlin Sun, Ji-Young Choi, M. Ren, Kan Cao

Czasopismo: Scientific Reports

Ranking czasopisma: Q1

Główne wnioski: Methylene blue is a safe and effective antioxidant for human skin care, promoting skin viability, wound healing, and increasing hydration and dermis thickness without causing irritation.

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

Typ badania:

Liczba cytowań: 119

Rok: 2017

Autorzy: Donovan Tucker, Yujiao Lu, Quanguang Zhang

Czasopismo: Molecular Neurobiology

Ranking czasopisma: Q1

Główne wnioski: Methylene blue shows promise as a neuroprotective agent by promoting mitochondrial activity and mitigating neuroinflammation, potentially benefiting conditions like stroke, global cerebral ischemia, Alzheimer's disease, Parkinson's disease, and traumatic brain injury.

Streszczenie: 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.

Methylene blue upregulates Nrf2/ARE genes and prevents tau-related neurotoxicity.

Typ badania: non-rct experimental

Liczba cytowań: 132

Rok: 2014

Autorzy: Cliona Stack, Shari Jainuddin, Ceyhan Elipenahli, Meri Gerges, N. Starkova, A. Starkov, M. Jové, M. Portero-Otín, Nathalie Launay, A. Pujol, N. Kaidery, B. Thomas, D. Tampellini, M. Beal, M. Dumont, M. Dumont

Czasopismo: Human molecular genetics

Ranking czasopisma: Q1

Główne wnioski: Methylene blue has neuroprotective effects by reducing tau pathology, inflammation, and oxidative damage in tauopathy mice, with Nrf2/ARE genes playing a key role in antioxidant defenses and preventing protein aggregation.

Streszczenie: Methylene blue (MB, methylthioninium chloride) is a phenothiazine that crosses the blood brain barrier and acts as a redox cycler. Among its beneficial properties are its abilities to act as an antioxidant, to reduce tau protein aggregation and to improve energy metabolism. These actions are of particular interest for the treatment of neurodegenerative diseases with tau protein aggregates known as tauopathies. The present study examined the effects of MB in the P301S mouse model of tauopathy. Both 4 mg/kg MB (low dose) and 40 mg/kg MB (high dose) were administered in the diet ad libitum from 1 to 10 months of age. We assessed behavior, tau pathology, oxidative damage, inflammation and numbers of mitochondria. MB improved the behavioral abnormalities and reduced tau pathology, inflammation and oxidative damage in the P301S mice. These beneficial effects were associated with increased expression of genes regulated by NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE), which play an important role in antioxidant defenses, preventing protein aggregation, and reducing inflammation. The activation of Nrf2/ARE genes is neuroprotective in other transgenic mouse models of neurodegenerative diseases and it appears to be an important mediator of the neuroprotective effects of MB in P301S mice. Moreover, we used Nrf2 knock out fibroblasts to show that the upregulation of Nrf2/ARE genes by MB is Nrf2 dependent and not due to secondary effects of the compound. These findings provide further evidence that MB has important neuroprotective effects that may be beneficial in the treatment of human neurodegenerative diseases with tau pathology.

Review on Methylene Blue: Its Properties, Uses, Toxicity and Photodegradation

Typ badania: literature review

Liczba cytowań: 960

Rok: 2022

Autorzy: Idrees Khan, K. Saeed, Ivar Zekker, Baoliang Zhang, Abdulmajeed H. Hendi, Ashfaq Ahmad, Shujaat Ahmad, Noor Zada, H. Ahmad, L. Shah, Tariq Shah, Ibrahim Khan

Czasopismo: Water

Ranking czasopisma: Q1

Główne wnioski: Photodegradation is an environmentally friendly, efficient technology for removing methylene blue from wastewater, converting it into nontoxic, noncarcinogenic species, and reducing processing costs.

Streszczenie: The unavailability of clean drinking water is one of the significant health issues in modern times. Industrial dyes are one of the dominant chemicals that make water unfit for drinking. Among these dyes, methylene blue (MB) is toxic, carcinogenic, and non-biodegradable and can cause a severe threat to human health and environmental safety. It is usually released in natural water sources, which becomes a health threat to human beings and living organisms. Hence, there is a need to develop an environmentally friendly, efficient technology for removing MB from wastewater. Photodegradation is an advanced oxidation process widely used for MB removal. It has the advantages of complete mineralization of dye into simple and nontoxic species with the potential to decrease the processing cost. This review provides a tutorial basis for the readers working in the dye degradation research area. We not only covered the basic principles of the process but also provided a wide range of previously published work on advanced photocatalytic systems (single-component and multi-component photocatalysts). Our study has focused on critical parameters that can affect the photodegradation rate of MB, such as photocatalyst type and loading, irradiation reaction time, pH of reaction media, initial concentration of dye, radical scavengers and oxidising agents. The photodegradation mechanism, reaction pathways, intermediate products, and final products of MB are also summarized. An overview of the future perspectives to utilize MB at an industrial scale is also provided. This paper identifies strategies for the development of effective MB photodegradation systems.

Revisiting the physiological effects of methylene blue as a treatment of cyanide intoxication

Typ badania: non-rct experimental

Liczba cytowań: 25

Rok: 2018

Autorzy: P. Haouzi, M. Guéguinou, T. Sonobe, A. Judenherc-Haouzi, Nicole Tubbs, M. Trebak, J. Cheung, F. Bouillaud

Czasopismo: Clinical Toxicology

Ranking czasopisma: Q1

Główne wnioski: Methylene blue may have potential as a treatment for cyanide intoxication, restoring blood pressure, cardiac contractility, and cellular metabolism, potentially due to its unique properties.

Streszczenie: Abstract Background: Although methylene blue (MB) had long been proposed to counteract the effects of cyanide (CN) intoxication, research on its mechanisms of action and efficacy has been abandoned for decades. Recent studies on the benefits of MB in post-anoxic injuries have prompted us to reexamine the relevance of this historical observation. Methods: Our study was performed in adult male Sprague–Dawley rats and on HEK293T epithelial cells. First, the effects and toxicity of MB (0–80 mg/kg) on circulation and metabolism were established in four urethane-anesthetized rats. Then nine rats received a lethal infusion of a solution of KCN (0.75 mg/kg/min) and were treated by either saline or MB, at 20 mg/kg, a dose that we found to be innocuous in rat and to correspond to a dose of about 4 mg/kg in humans. MB was also administered 5 min after the end of a sub-lethal exposure to CN in a separate group of 10 rats. In addition, ATP/ADP ratio, ROS production, mitochondrial membrane potential (Δψm) and cellular O2 consumption rate (OCR) were determined in HEK293T cells exposed to toxic levels of CN (200 µM for 10 min) before and after applying a solution containing MB (1–100 µM for 10 min). Results: Methylene blue was found to be innocuous up to 50 mg/kg. KCN infusion (0.75 mg/kg/min) killed all animals within 7–8 min. MB (20 mg/kg) administered at the same time restored blood pressure, cardiac contractility and limited O2 deficit, allowing all the animals to survive, without any significant methemoglobinemia. When administered 5 min after a non-lethal CN intoxication, MB sped up the recovery of lactate and O2 deficit. Finally, MB was able to decrease the production of ROS and restore the ATP/ADP ratio, Δψm as well as OCR of epithelial cells intoxicated by CN. Conclusions: The present observations should make us consider the potential interest of MB in the treatment of CN intoxication. The mechanisms of the antidotal properties of MB cannot be accounted for by the creation of a cyanomethemoglobinemia, rather its protective effects appears to be related to the unique properties of this redox dye, which, depending on the dose, could directly oppose some of the consequences of the metabolic depression produced by CN at the cellular level.

Clinical effectiveness and prospects of methylene blue: A systematic review

Typ badania: systematic review

Liczba cytowań: 10

Rok: 2022

Autorzy: Assel Seitkazina, Jin-Kyoung Yang, Sehoon Kim

Czasopismo: Precision and Future Medicine

Ranking czasopisma: brak

Główne wnioski: Methylene blue shows potential as a multi-targeted therapeutic agent for brain diseases, cancer imaging, infectious diseases, and cardiovascular diseases, with potential for use in nanoparticle-based delivery methods.

Streszczenie: Methylene blue (MB) is a well-known pharmaceutical ingredient that is thought to have a multi-targeted therapeutic effect as an anti-malarial and neuroprotective agent and has recently been identified as a treatment for coronavirus disease 2019 (COVID-19). In this review, we present an overview of relevant clinical trials, including ongoing trials, on the therapeutic uses of MB. A search for clinical trials on clinicaltrials.gov was performed using the terms 'methylene blue' and 'methylthionine chloride.' This review focuses on clinical trials of MB-based therapies applied to brain diseases, cancer imaging and diagnosis, infectious diseases such as malaria or COVID-19, and cardiovascular diseases. Nanoparticle-based delivery techniques have also been briefly discussed in addition to common delivery methods.

Effect of methylene blue on outcomes in patients with distributive shock: a meta-analysis of randomised controlled trials

Typ badania: meta-analysis

Liczba cytowań: 7

Rok: 2024

Autorzy: Xinhui Huang, Wenqing Yan, Zhi Chen, Yihong Qian

Czasopismo: BMJ Open

Ranking czasopisma: Q1

Główne wnioski: Methylene blue may not reduce mortality in patients with distributive shock, but may shorten mechanical ventilation duration, ICU stay, and hospital stay.

Streszczenie: Objective This meta-analysis aimed to demonstrate the effect of methylene blue (MB) in patients with distributive shock. Design Meta-analysis. Methods According to the Prospective International Register of Systematic Reviews (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we searched the relevant randomised controlled trials (RCTs) via PubMed, Embase and Cochrane Library from the date of database inception to 19 April 2023. The primary outcome was mortality during follow-up, and secondary outcomes included mean arterial pressure (mm Hg), mechanical ventilation time (hours), intensive care unit (ICU) length of stay (LOS) (days), hospital LOS (days) and heart rate (times/min). Results This study included six RCTs with 265 participants. The study showed no significant difference in mortality between the MB and placebo groups (ORs: 0.59; 95% CI 0.32 to −1.06). However, MB reduced the duration of mechanical ventilation (mean difference (MD): −0.68; 95% CI −1.23 to −0.14), ICU LOS (MD: −1.54; 95% CI −2.61 to −0.48) and hospital LOS (MD: −1.97; 95% CI −3.92 to −0.11). Conclusions The use of MB may not reduce mortality in patients with distributive shock, but may shorten the duration of mechanical ventilation, ICU LOS and hospital LOS. More clinical studies are needed to confirm these findings in the future. Trial registration number CRD42023415938.

Methylene blue: a controversial diagnostic acid and medication?

Typ badania: systematic review

Liczba cytowań: 22

Rok: 2022

Autorzy: M. Bužga, E. Machytka, Eliška Dvořáčková, Z. Švagera, D. Stejskal, J. Máca, J. Kral

Czasopismo: Toxicology research

Ranking czasopisma: Q3

Główne wnioski: Methylene blue (MB) is a controversial diagnostic acid and medication with potential severe adverse effects, making its clinical use controversial due to heterogeneous data and lack of preclinical data.

Streszczenie: A narrative review of the literature was conducted to determine if the administration of methylene blue (MB) in humans has potential risks. Studies were identified from MEDLINE, Web of Science, Scopus, and Cochrane. MB is a diagnostic substance used during some diagnostic procedures and also a part of the treatment of several diseases including methemoglobinemia, vasoplegic syndrome, fosfamide-induced encephalopathy, and cyanide intoxication, and the detection of leaks or position of parathyroid corpuscles during surgery. Although the use of MB is historically justified, and it ought to be safe, because it originated as a diagnostic material, the basic toxicological characteristics of this substance are unknown. Despite reports of severe adverse effects of MB, which could significantly exceed any possible benefits evaluated for the given indication. Therefore, the clinical use of MB currently represents a controversial problem given the heterogeneity of available data and the lack of preclinical data. This is in conflict with standards of safe use of such substances in human medicinal practice. The toxic effects of the application of MB are dose-dependent and include serious symptoms such as hemolysis, methemoglobinemia, nausea and vomitus, chest pain, dyspnoea, and hypertension. Some countries regard MB as harmful because of the resulting skin irritation and triggering of an adverse inflammatory response. MB induced serotoninergic toxicity clinically manifests as neuromuscular hyperactivity. This review aims to summarize the current understanding concerning the indications for MB administration and define the potential adverse effects of MB.

Fundamentals and photocatalysis of methylene blue dye using various nanocatalytic assemblies- a critical review

Typ badania: literature review

Liczba cytowań: 302

Rok: 2021

Autorzy: M. I. Din, R. Khalid, J. Najeeb, Zaib Hussain

Czasopismo: Journal of Cleaner Production

Ranking czasopisma: Q1

Główne wnioski: Nanomaterials-based photocatalytic assemblies effectively degrade methylene blue dye, reducing its harmful impact on humans and marine life.

The Potentials of Methylene Blue as an Anti-Aging Drug

Typ badania: literature review

Liczba cytowań: 22

Rok: 2021

Autorzy: Huijing Xue, Abhirami Thaivalappil, Kan Cao

Czasopismo: Cells

Ranking czasopisma: Q1

Główne wnioski: Methylene blue shows potential as an anti-aging drug due to its anti-oxidative properties and potential in treating age-related conditions like neurodegeneration, memory loss, skin aging, and progeria.

Streszczenie: Methylene blue (MB), as the first fully man-made medicine, has a wide range of clinical applications. Apart from its well-known applications in surgical staining, malaria, and methemoglobinemia, the anti-oxidative properties of MB recently brought new attention to this century-old drug. Mitochondrial dysfunction has been observed in systematic aging that affects many different tissues, including the brain and skin. This leads to increaseding oxidative stress and results in downstream phenotypes under age-related conditions. MB can bypass Complex I/III activity in mitochondria and diminish oxidative stress to some degree. This review summarizes the recent studies on the applications of MB in treating age-related conditions, including neurodegeneration, memory loss, skin aging, and a premature aging disease, progeria.

Methylene Blue in Septic Shock: A Systematic Review and Meta-Analysis

Typ badania: meta-analysis

Liczba cytowań: 7

Rok: 2024

Autorzy: S. Fernando, Alexandre Tran, Karim Soliman, Barbara Flynn, Thomas Oommen, Wenzhe Li, N. Adhikari, S. Kanji, Andrew J. E. Seely, Alison E Fox-Robichaud, Randy Wax, Deborah J. Cook, F. Lamontagne, B. Rochwerg

Czasopismo: Critical Care Explorations

Ranking czasopisma: Q1

Główne wnioski: Methylene blue may reduce short-term mortality, vasopressor duration, and hospital stay in critically ill adults with septic shock, without evidence of increased adverse events.

Streszczenie: OBJECTIVES: Although clinicians may use methylene blue (MB) in refractory septic shock, the effect of MB on patient-important outcomes remains uncertain. We conducted a systematic review and meta-analysis to investigate the benefits and harms of MB administration in patients with septic shock. DATA SOURCES: We searched six databases (including PubMed, Embase, and Medline) from inception to January 10, 2024. STUDY SELECTION: We included randomized clinical trials (RCTs) of critically ill adults comparing MB with placebo or usual care without MB administration. DATA EXTRACTION: Two reviewers performed screening, full-text review, and data extraction. We pooled data using a random-effects model, assessed the risk of bias using the modified Cochrane tool, and used Grading of Recommendations Assessment, Development, and Evaluation to rate certainty of effect estimates. DATA SYNTHESIS: We included six RCTs (302 patients). Compared with placebo or no MB administration, MB may reduce short-term mortality (RR [risk ratio] 0.66 [95% CI, 0.47–0.94], low certainty) and hospital length of stay (mean difference [MD] –2.1 d [95% CI, –1.4 to –2.8], low certainty). MB may also reduce duration of vasopressors (MD –31.1 hr [95% CI, –16.5 to –45.6], low certainty), and increase mean arterial pressure at 6 hours (MD 10.2 mm Hg [95% CI, 6.1–14.2], low certainty) compared with no MB administration. The effect of MB on serum methemoglobin concentration was uncertain (MD 0.9% [95% CI, –0.2% to 2.0%], very low certainty). We did not find any differences in adverse events. CONCLUSIONS: Among critically ill adults with septic shock, based on low-certainty evidence, MB may reduce short-term mortality, duration of vasopressors, and hospital length of stay, with no evidence of increased adverse events. Rigorous randomized trials evaluating the efficacy of MB in septic shock are needed. REGISTRATION: Center for Open Science (https://osf.io/hpy4j).

Methylene blue delays cellular senescence and enhances key mitochondrial biochemical pathways

Typ badania: non-rct in vitro

Liczba cytowań: 275

Rok: 2008

Autorzy: Hani Atamna, Andy Nguyen, Carla S Schultz, Kathleen Boyle, Justin Newberry, Hiroyuki Kato, Bruce N. Ames

Czasopismo: The FASEB Journal

Ranking czasopisma: Q1

Główne wnioski: Methylene blue delays cellular senescence and enhances mitochondrial function, potentially benefiting aging and Alzheimer's disease.

Streszczenie: Methylene blue (MB) has been used clinically for about a century to treat numerous ailments. We show that MB and other diaminophenothia‐zines extend the life span of human IMR90 fibroblasts in tissue culture by >20 population doubling (PDLs). MB delays senescence at nM levels in IMR90 by enhancing mitochondrial function. MB increases mitochon‐drial complex IV by 30%, enhances cellular oxygen consumption by 37–70%, increases heme synthesis, and reverses premature senescence caused by H2O2 or cadmium. MB also induces phase‐2 antioxidant enzymes in hepG2 cells. Flavin‐dependent enzymes are known to use NAD(P)H to reduce MB to leucomethyl‐ene blue (MBH2), whereas cytochrome c reoxidizes MBH2 to MB. Experiments on lysates from rat liver mitochondria suggest the ratio MB/cytochrome c is important for the protective actions of MB. We propose that the cellular senescence delay caused by MB is due to cycling between MB and MBH2 in mitochondria, which may partly explain the increase in specific mito‐chondrial activities. Cycling of MB between oxidized and reduced forms may block oxidant production by mitochondria. Mitochondrial dysfunction and oxidative stress are thought to be key aberrations that lead to cellular senescence and aging. MB may be useful to delay mitochondrial dysfunction with aging and the decrease in complex IV in Alzheimer disease.—At‐amna H., Nguyen, A., Schultz, C., Boyle, K., Newberry, J., Kato, H., Ames B. N. Methylene blue delays cellular senescence and enhances key mitochondrial biochemical pathways. FASEB J. 22, 703–712 (2008)

Toxic Effects of Methylene Blue on the Growth, Reproduction and Physiology of Daphnia magna

Typ badania: non-rct experimental

Liczba cytowań: 35

Rok: 2023

Autorzy: Shuhui Li, Yixin Cui, Min Wen, Gaohua Ji

Czasopismo: Toxics

Ranking czasopisma: Q1

Główne wnioski: Methylene blue has toxic effects on the growth, reproduction, and physiological responses of Daphnia magna zooplankton, affecting their reproductive ability and impacting aquaculture guidelines.

Streszczenie: Methylene blue (MB) is a disinfectant used in aquaculture to prevent and treat fish diseases. However, the release of MB can pose a risk to the receiving water bodies. Zooplankton are the most sensitive organisms among aquatic life. Hence, this study examined the acute and chronic toxic effects of MB on zooplankton using Daphnia magna (D. magna) as a test organism to provide basic data for risk assessment. The results show that 48 h-EC50 and 24 h-LC50 were 61.5 ± 2.3 and 149.0 ± 2.2 μg/L, respectively. Chronic exposure to MB affected the heart rate, beat frequency of the thoracic limbs, and reproductive ability of D. magna at environmental concentrations higher than 4.7 μg/L. The cumulative molts, time to production of the first brood, and total number of living offspring were affected at different MB concentrations, while “abortions” were observed in high-exposure groups. The activity of superoxide dismutase was increased, while glutathione S-transferase activity was stimulated at low concentrations and inhibited at high concentrations. In addition, the malondialdehyde content increased with increasing concentrations of MB. Our findings demonstrate the impact of MB on the reproduction and growth of freshwater species, as well as their physiological responses. These results have implications for establishing guidelines on the use of MB in aquaculture and setting discharge standards.

Efficacy and safety of methylene blue in patients with vasodilatory shock: A systematic review and meta-analysis

Typ badania: meta-analysis

Liczba cytowań: 22

Rok: 2022

Autorzy: Cong-cong Zhao, Yu-jia Zhai, Zhenjie Hu, Y. Huo, Zhi-Qiang Li, Gui-jun Zhu

Czasopismo: Frontiers in Medicine

Ranking czasopisma: Q1

Główne wnioski: Methylene blue combined with vasopressors significantly reduced mortality and improved hemodynamics in patients with vasodilatory shock.

Streszczenie: Background The role of methylene blue (MB) in patients with vasodilatory shock is unclear. The purpose of this systematic review and meta-analysis was to evaluate the efficacy and safety of MB in patients with vasodilatory shock. Methods We searched MEDLINE at PubMed, Embase, Web of Science, Cochrane, CNKI, CBM and Wanfang Medical databases for all observational and intervention studies comparing the effect of MB vs. control in vasodilatory shock patients. This study was performed in accordance with the PRISMA statement. There were no language restrictions for inclusion. Results A total of 15 studies with 832 patients were included. Pooled data demonstrated that administration of MB along with vasopressors significantly reduced mortality [odds ratio (OR) 0.54, 95% confidence interval (CI) 0.34 to 0.85, P = 0.008; I2 = 7%]. This benefit in mortality rate was also seen in a subgroup analysis including randomized controlled trials and quasi-randomized controlled trials. In addition, the vasopressor requirement was reduced in the MB group [mean difference (MD) −0.77, 95%CI −1.26 to −0.28, P = 0.002; I2 = 80%]. Regarding hemodynamics, MB increased the mean arterial pressure, heart rate and peripheral vascular resistance. In respect to organ function, MB was associated with a lower incidence of renal failure, while in regards to oxygen metabolism, it was linked to reduced lactate levels. MB had no effect on the other outcomes and no serious side effects. Conclusions Concomitant administration of MB and vasopressors improved hemodynamics, decreased vasopressor requirements, reduced lactate levels, and improved survival in patients with vasodilatory shock. However, further studies are required to confirm these findings. Systematic review registration Identifier: CRD42021281847.

Acarbose, 17-α-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males

Typ badania: non-rct experimental

Liczba cytowań: 360

Rok: 2013

Autorzy: D. Harrison, R. Strong, D. B. Allison, B. Ames, C. M. Astle, H. Atamna, Elizabeth Fernandez, K. Flurkey, M. Javors, N. Nadon, James F. Nelson, S. Pletcher, J. Simpkins, Daniel L. Smith, J. Wilkinson, Richard A Miller

Czasopismo: Aging Cell

Ranking czasopisma: Q1

Główne wnioski: Acarbose, 17--estradiol, and nordihydroguaiaretic acid increase male mouse lifespan, while methylene blue increases female maximum lifespan, providing new pharmacological models for studying sexual dimorphism in aging and health.

Streszczenie: Four agents — acarbose (ACA), 17‐α‐estradiol (EST), nordihydroguaiaretic acid (NDGA), and methylene blue (MB) — were evaluated for lifespan effects in genetically heterogeneous mice tested at three sites. Acarbose increased male median lifespan by 22% (P < 0.0001), but increased female median lifespan by only 5% (P = 0.01). This sexual dimorphism in ACA lifespan effect could not be explained by differences in effects on weight. Maximum lifespan (90th percentile) increased 11% (P < 0.001) in males and 9% (P = 0.001) in females. EST increased male median lifespan by 12% (P = 0.002), but did not lead to a significant effect on maximum lifespan. The benefits of EST were much stronger at one test site than at the other two and were not explained by effects on body weight. EST did not alter female lifespan. NDGA increased male median lifespan by 8–10% at three different doses, with P‐values ranging from 0.04 to 0.005. Females did not show a lifespan benefit from NDGA, even at a dose that produced blood levels similar to those in males, which did show a strong lifespan benefit. MB did not alter median lifespan of males or females, but did produce a small, statistically significant (6%, P = 0.004) increase in female maximum lifespan. These results provide new pharmacological models for exploring processes that regulate the timing of aging and late‐life diseases, and in particular for testing hypotheses about sexual dimorphism in aging and health.

Methylene blue reduces monoamine oxidase expression and oxidative stress in human cardiovascular adipose tissue

Typ badania: non-rct in vitro

Liczba cytowań: 1

Rok: 2024

Autorzy: Oana M Aburel, Laurentiu Braescu, Darius G. Buriman, Adrian P. Merce, A. Bînă, C. Borza, Cristian Mornoș, A. Sturza, D. Muntean

Czasopismo: Molecular and Cellular Biochemistry

Ranking czasopisma: Q1

Główne wnioski: Methylene blue reduces monoamine oxidase expression and oxidative stress in human cardiovascular adipose tissue, potentially reducing cardiometabolic pathologies.

Streszczenie: Cardiovascular diseases represent the major cause of morbidity mainly due to chronic heart failure. Epicardial (EAT) and perivascular adipose tissues (PVAT) are considered major contributors to the pathogenesis of cardiometabolic pathologies. Monoamine oxidases (MAOs) are mitochondrial enzymes recognized as sources of reactive oxygen species (ROS) in cardiometabolic pathologies. Methylene blue (MB) is one of the oldest protective agents, yet no data are available about its effects on adipose tissue. The present pilot study was aimed at assessing the effects of MB: (i) on MAO expression and (ii) oxidative stress in EAT and PVAT harvested from patients with heart failure subjected to cardiac surgery (n = 25). Adipose tissue samples were incubated with MB (0.1 µM/24 h) and used for the assessment of MAO gene and protein expression (qPCS and immune fluorescence) and ROS production (confocal microscopy and spectrophotometry). The human cardiovascular adipose tissues contain both MAO isoforms, predominantly MAO-A. Incubation with MB reduced MAOs expression and oxidative stress; co-incubation with serotonin, the MAO-A substrate, further augmented ROS generation, an effect partially reversed by MB. In conclusion, MAO-A is the major isoform expressed in EAT and PVAT and contribute to local oxidative stress; both effects can be mitigated by methylene blue.

Methylene Blue for the Treatment of Health Conditions: a Scoping Review

Typ badania: systematic review

Liczba cytowań: 11

Rok: 2021

Autorzy: Jessica Galvan, Mariana Xavier Borsoi, Luciana Julek, D. Bordin, L. Cabral, M. Pomini, F. B. T. Alves

Czasopismo: Brazilian Archives of Biology and Technology

Ranking czasopisma: Q2

Główne wnioski: Methylene blue shows promise in treating acute and postoperative conditions, but more research is needed to fill research gaps.

Streszczenie: : studies evaluating effective drugs for health conditions are of crucial importance for public health. Methylene blue (MB) is an accessible synthetic drug that presents low toxicity and has been used in several health areas due to its effectiveness. Objective: this scoping review aims to provide a comprehensive overview of relevant research regarding the use of MB for the treatment of health conditions. Methods: a five-stage framework Arksey and O’maley scoping review was conducted. The literature was searched in Cochrane Library database using Mesh term “methylene blue”. Data were collected by two independent reviewers and submitted to descriptive synthesis. Results: The search resulted in 429 records, from which 16 were included after exclusion criteria were applied. The therapeutic use of MB was identified for acute conditions (malaria and septic shock), chronic conditions (discogenic back pain, bipolar disorder, refractory neuropathic pain, and post-traumatic stress disorder), and postoperative care (vasoplegic syndrome, and pain after haemorrhoidectomy, lumbar discectomy, and traumatic thoracolumbar fixation). Conclusion: there is much evidence emerging from clinical trials about the therapeutic use of MB for acute, postoperative conditions; however, many gaps were identified, which open further avenues for future research.

Methylene blue in sepsis and septic shock: a systematic review and meta-analysis

Typ badania: meta-analysis

Liczba cytowań: 10

Rok: 2024

Autorzy: R. S. Ballarin, Taline Lazzarin, Leonardo A. M. Zornoff, P. Azevedo, Filipe Welson Leal Pereira, S. E. Tanni, M. F. Minicucci

Czasopismo: Frontiers in Medicine

Ranking czasopisma: Q1

Główne wnioski: Methylene blue administration in patients with sepsis and septic shock leads to reduced time to vasopressor discontinuation, shorter intensive care unit stay, and fewer days on mechanical ventilation.

Streszczenie: Background Methylene blue is an interesting approach in reducing fluid overload and vasoactive drug administration in vasodilatory shock. The inhibition of guanylate cyclase induced by methylene blue infusion reduces nitric oxide production and improves vasoconstriction. This systematic review and meta-analysis aimed to assess the effects of methylene blue administration compared to placebo on the hemodynamic status and clinical outcomes in patients with sepsis and septic shock. Methods The authors specifically included randomized controlled trials that compared the use of methylene blue with placebo in adult patients with sepsis and septic shock. The outcomes were length of intensive care unit stay, hemodynamic parameters [vasopressor use], and days on mechanical ventilation. We also evaluated the abnormal levels of methemoglobinemia. This systematic review and meta-analysis were recorded in PROSPERO with the ID CRD42023423470. Results During the initial search, a total of 1,014 records were identified, out of which 393 were duplicates. Fourteen citations were selected for detailed reading, and three were selected for inclusion. The studies enrolled 141 patients, with 70 of them in the methylene blue group and 71 of them in the control group. Methylene blue treatment was associated with a lower length of intensive care unit stay (MD −1.58; 95%CI −2.97, −0.20; I2 = 25%; p = 0.03), decreased days on mechanical ventilation (MD −0.72; 95%CI −1.26, −0.17; I2 = 0%; p = 0.010), and a shorter time to vasopressor discontinuation (MD −31.49; 95%CI −46.02, −16.96; I2 = 0%; p < 0.0001). No association was found with methemoglobinemia. Conclusion Administering methylene blue to patients with sepsis and septic shock leads to reduced time to vasopressor discontinuation, length of intensive care unit stay, and days on mechanical ventilation. Systematic review registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023423470, CRD42023423470.

Alternative mitochondrial electron transfer for the treatment of neurodegenerative diseases and cancers: Methylene blue connects the dots

Typ badania:

Liczba cytowań: 76

Rok: 2017

Autorzy: Shao-Hua Yang, Wenjun Li, N. Sumien, M. Forster, J. Simpkins, Ran Liu

Czasopismo: Progress in Neurobiology

Ranking czasopisma: Q1

Główne wnioski: Methylene blue, an alternative mitochondrial electron transfer drug, may offer protective action against neurodegenerative diseases and inhibit cancer cell proliferation by enhancing energy metabolism.

CNS toxicity involving methylene blue: the exemplar for understanding and predicting drug interactions that precipitate serotonin toxicity

Typ badania: literature review

Liczba cytowań: 160

Rok: 2011

Autorzy: P. Gillman

Czasopismo: Journal of Psychopharmacology

Ranking czasopisma: Q1

Główne wnioski: Methylene blue can cause severe serotonin toxicity when used with serotonin reuptake inhibitors, so caution is needed before combining these treatments.

Streszczenie: Methylene blue has only recently been noted to cause severe central nervous system toxicity. Methylene blue is used for various conditions, including, intravenously, in methemoglobinemia, vasoplegia and as an aid to parathyroidectomy (at doses of 1–7.5 mg kg−1). This review of the current evidence concludes that 13 of 14 of the reported cases of CNS toxicity were serotonin toxicity that met the Hunter Serotonin Toxicity Criteria. That has important preventative and treatment implications. Serotonin toxicity is precipitated by the monoamine oxidase inhibitor (MAOI) property of methylene blue interacting with serotonin reuptake inhibitors. Serotonin toxicity is reviewed, using the lessons inherent in the methylene blue story and experience, to illustrate how the mechanisms and potency of serotonergic drugs interact to determine severity. Recent human data showed that an intravenous dose of only 0.75 mg kg−1 of methylene blue produced a peak plasma concentration of 500 ng ml−1 (1.6 µM), indicating that the concentration in the central nervous system reaches a level that inhibits monoamine oxidase A. That is consonant with the actual occurrence of severe serotonin toxicity in humans at the dose of only 1 mg kg−1. It seems that all proposed uses of methylene blue entail levels that block monoamine oxidase, so cessation of serotonin reuptake inhibitors should be very carefully considered before using methylene blue.

Methylene blue and its importance in medicine

Typ badania:

Liczba cytowań: 13

Rok: 2020

Autorzy: Yaren Kayabaşı, O. Erbaş

Czasopismo: Demiroglu Science University Florence Nightingale Journal of Medicine

Ranking czasopisma: brak

Główne wnioski: Methylene blue is an effective antimalarial, antioxidant, and antifungal agent for treating malaria, Alzheimer's, and candidiasis.

Streszczenie: Methylene blue (MB), a blue-colored aniline-based dye that was first developed for the dyeing of cotton, is a phenothiazine derivative that is soluble in water and organic solvents. Its reduced form, leucomethylene blue, is colorless and has a regulatory effect on the redox cycle. This feature allows it to be used in malarial therapy by inducing glutathione reductase (GR), an enzyme of glutathione metabolism. Malaria is a disease characterized by repeated growth cycles of Plasmodium group parasites in erythrocytes and changes in glutathione metabolism. Methylene blue was recognized as an antimalarial agent when it was observed that it reduced reactive oxygen species (ROS) by inhibiting Plasmodium falciparum glutathione reductase and by selectively inducing oxidative stress. It has also been observed that MB can reduce factors that cause aging and Alzheimer’s disease, such as the accumulation of tau proteins in plaques, mitochondrial dysfunction, and ROS increase due to disorders in the electron transport chain (ETC). Methylene blue has been used in Alzheimer's treatment, considering its features of tau protein inhibition, anti-ROS antioxidant properties, and ability to regulate ETC. Methylene blue, known for its antimalarial and antioxidant effects, has also been used in the treatment of Candida infections as an antifungal agent. In candidiasis infections, MB is aimed to cause mitochondrial dysfunction in yeast and treat the patient. In this review, the history of MB as an antimalarial, antioxidant and antifungal agent; malaria, Alzheimer's, and its role in the treatment of candidiasis. In this review, the history of MB and its role as an antimalarial, antioxidant, and antifungal agent in the treatment of malaria, Alzheimer's, and candidiasis are discussed.

Antiaging agents: safe interventions to slow aging and healthy life span extension

Typ badania:

Liczba cytowań: 68

Rok: 2022

Autorzy: Jikai Liu

Czasopismo: Natural Products and Bioprospecting

Ranking czasopisma: Q1

Główne wnioski: Antiaging agents, including lifestyle modifications and pharmacological/genetic manipulations, show potential in slowing aging and increasing healthy lifespan in various organisms.

Streszczenie: Human longevity has increased dramatically during the past century. More than 20% of the 9 billion population of the world will exceed the age of 60 in 2050. Since the last three decades, some interventions and many preclinical studies have been found to show slowing aging and increasing the healthy lifespan of organisms from yeast, flies, rodents to nonhuman primates. The interventions are classified into two groups: lifestyle modifications and pharmacological/genetic manipulations. Some genetic pathways have been characterized to have a specific role in controlling aging and lifespan. Thus, all genes in the pathways are potential antiaging targets. Currently, many antiaging compounds target the calorie-restriction mimetic, autophagy induction, and putative enhancement of cell regeneration, epigenetic modulation of gene activity such as inhibition of histone deacetylases and DNA methyltransferases, are under development. It appears evident that the exploration of new targets for these antiaging agents based on biogerontological research provides an incredible opportunity for the healthcare and pharmaceutical industries. The present review focus on the properties of slow aging and healthy life span extension of natural products from various biological resources, endogenous substances, drugs, and synthetic compounds, as well as the mechanisms of targets for antiaging evaluation. These bioactive compounds that could benefit healthy aging and the potential role of life span extension are discussed.

Methylene blue in anticancer photodynamic therapy: systematic review of preclinical studies

Typ badania: systematic review

Liczba cytowań: 15

Rok: 2023

Autorzy: Amir Taldaev, R. Terekhov, I. Nikitin, Elizaveta Melnik, Vera Kuzina, Mikhail Klochko, I. Reshetov, Artem Shiryaev, V. Loschenov, Galina Ramenskaya

Czasopismo: Frontiers in Pharmacology

Ranking czasopisma: Q1

Główne wnioski: Methylene blue in photodynamic therapy shows potential in reducing tumor sizes in various types of cancer, with nanopharmaceutics significantly increasing effectiveness.

Streszczenie: Background: Methylene blue has a long history of clinical application. Thanks to phenothiazine chromophore, it has potential in photodynamic anticancer therapy. In spite of the growing body of literature that has evaluated the action of this dye on different types of cancer, the systematic understanding of this problem is still lacking. Therefore, this systematic review was performed to study the efficacy of methylene blue in photodynamic anticancer therapy. Methods: This systematic review was carried out in accordance with the PRISMA guidelines, and the study protocol was registered in PROSPERO (CRD42022368738). Articles for the systematic review were identified through the PubMed database. SYRCLE’s risk of bias tool was used to assess the studies. The results of systematic analysis are presented as narrative synthesis. Results: Ten studies met the inclusion criteria and these full texts were reviewed. In the selected articles, the dosage of dye infusion ranged from 0.04 to 24.12 mg/kg. The effectiveness of photodynamic therapy with methylene blue against different types of cancer was confirmed by a decrease in tumor sizes in seven articles. Conclusion: The results of the systematic review support the suggestions that photodynamic therapy with methylene blue helps against different types of cancer, including colorectal tumor, carcinoma, and melanoma. In cases of nanopharmaceutics use, a considerable increase of anticancer therapy effectiveness was observed. The further research into methylene blue in photodynamic anticancer therapy is needed. Systematic Review Registration: (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=368738), identifier (CRD42022368738).

Effectiveness and tolerability of methylthioninium chloride (methylene blue) for the treatment of methemoglobinemia: twenty-four years of experience at a single poison center

Typ badania: non-rct observational study

Liczba cytowań: 2

Rok: 2025

Autorzy: Roger Rothenberg, Rana Biary, Robert S Hoffman

Czasopismo: Clinical Toxicology

Ranking czasopisma: Q1

Główne wnioski: Methylthioninium chloride is both effective and well-tolerated for treating methemoglobinemia, with a single dose of 1–2 mg/kg being sufficient for most patients.

Streszczenie: Abstract Introduction Despite the widely accepted use of methylthioninium chloride (methylene blue) to treat methemoglobinemia, data regarding clinical outcomes are sparse. We sought to better elucidate the efficacy and tolerability of methylthioninium chloride. Methods We identified all cases reported to the New York City Poison Center from 2000 to 2024 in which methylthioninium chloride was administered for methemoglobinemia. We extracted clinical data from these cases, which we assessed using primarily descriptive statistics. Results A total of 185 cases were included. The median methemoglobin level was 29% (IQR: 19–42%). Implicated xenobiotics were most frequently volatile nitrites (41%), local anesthetics (15%), and dapsone (11%). The median methylthioninium chloride dose was 1 mg/kg (IQR: 1–2 mg/kg; range: 0.5–4 mg/kg). Multiple doses of methylthioninium chloride were administered in 11% of cases, with a median total dose of 2 mg/kg (IQR: 2–3 mg/kg), the majority of which were associated with volatile nitrites (n = 7) or dapsone (n = 6). Improvement after administration of methylthioninium chloride was reported in 98% of cases (95% CI: 96–100%). Adverse effects attributable to methylthioninium chloride were reported in nine cases (4.9%; 95% CI: 4.6–5.1%), including one instance of hemolysis. Glucose-6-phosphate dehydrogenase activity was found to be deficient in two of seven patients tested, only one of whom did not improve after methylthioninium chloride. Two deaths occurred in this series, both associated with sodium nitrite exposure. Discussion Most patients with methemoglobinemia improved after 1–2 mg/kg of methylthioninium chloride, supporting current treatment recommendations. Despite few instances of glucose-6-phosphate dehydrogenase activity testing, major adverse effects attributable to methylthioninium chloride were extremely rare. A relatively large proportion of cases receiving multiple doses were associated with dapsone exposure. Conclusions In this series, methylthioninium chloride was both efficacious and well tolerated in patients with methemoglobinemia, with a single dose of 1–2 mg/kg being sufficient to treat most patients.

Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria

Typ badania: non-rct in vitro

Liczba cytowań: 109

Rok: 2015

Autorzy: Zheng-Mei Xiong, Ji-Young Choi, Kun Wang, Haoyue Zhang, Zeshan Tariq, Di Wu, Eunae Ko, Christina LaDana, H. Sesaki, Kan Cao

Czasopismo: Aging Cell

Ranking czasopisma: Q1

Główne wnioski: Methylene blue treatment alleviates mitochondrial and nuclear abnormalities in progeria cells, suggesting it as a promising therapeutic approach for premature aging.

Streszczenie: Hutchinson–Gilford progeria syndrome (HGPS), a fatal premature aging disease, is caused by a single‐nucleotide mutation in the LMNA gene. Previous reports have focused on nuclear phenotypes in HGPS cells, yet the potential contribution of the mitochondria, a key player in normal aging, remains unclear. Using high‐resolution microscopy analysis, we demonstrated a significantly increased fraction of swollen and fragmented mitochondria and a marked reduction in mitochondrial mobility in HGPS fibroblast cells. Notably, the expression of PGC‐1α, a central regulator of mitochondrial biogenesis, was inhibited by progerin. To rescue mitochondrial defects, we treated HGPS cells with a mitochondrial‐targeting antioxidant methylene blue (MB). Our analysis indicated that MB treatment not only alleviated the mitochondrial defects but also rescued the hallmark nuclear abnormalities in HGPS cells. Additional analysis suggested that MB treatment released progerin from the nuclear membrane, rescued perinuclear heterochromatin loss and corrected misregulated gene expression in HGPS cells. Together, these results demonstrate a role of mitochondrial dysfunction in developing the premature aging phenotypes in HGPS cells and suggest MB as a promising therapeutic approach for HGPS.

Methylene Blue Protects Against Sevoflurane-Induced Cognitive Dysfunction by Suppressing Drp1 deSUMOylation in Aged Mice

Typ badania: non-rct experimental

Liczba cytowań: 25

Rok: 2020

Autorzy: F. Zheng, Peng Fang, Jing Chang, Min Chen, Q. Zhong, Tingting Chen, Chang Chen, Zongze Zhang

Czasopismo: Neurochemical Research

Ranking czasopisma: Q1

Główne wnioski: Methylene blue protects against sevoflurane-induced cognitive dysfunction in aged mice by suppressing Drp1 deSUMOylation and preserving mitochondrial function.

Streszczenie: Exposure to sevoflurane and other inhalational anesthetics can induce cognitive impairment in elderly patients. Studies have indicated that methylene blue (MB) has beneficial effects on multiple neurodegenerative diseases and the mechanism involves mitochondrial function preservation. However, whether MB can attenuate the cognitive decline induced by sevoflurane in aged mice requires further investigation. Forty-five 18-month-old C57/BL mice were used to establish a model of sevoflurane-induced cognitive impairment in which the mice were exposed to 3% sevoflurane for 2 h. Mice in the MB group were intraperitoneally injected with MB at a dose of 5 mg/kg before sevoflurane inhalation. The Morris water maze test was used to evaluate the learning and memory performances. We also examined changes in mitochondrial morphology as well as the expression and interaction of related proteins in the aged hippocampus. Parkin, BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), mitochondrial dynamin-related protein 1 (Drp1), small ubiquitin-like modifier (SUMO2/3), SUMO-specific proteases 3 (SENP3), and ubiquitin‐like conjugating enzyme 9 expression in the mouse hippocampus was detected by western blotting, and SUMO2/3-Drp1 was examined by coimmunoprecipitation. Exposure to sevoflurane increased SENP3 expression and Drp1 deSUMOylation in the aged hippocampus and resulted in cognitive deficiency. MB attenuated sevoflurane-induced memory loss and mitochondrial fragmentation and decreased Drp1 deSUMOylation in the aged hippocampus. This neuroprotective effect provides a mechanistic explanation for how the SUMOylation status of Drp1 acts as a key switch in the cognitive dysfunction induced by sevoflurane.

Targeting mitochondrial dysfunction using methylene blue or mitoquinone to improve skeletal aging

Typ badania: non-rct experimental

Liczba cytowań: 5

Rok: 2023

Autorzy: S. Poudel, Dorra Frikha‐Benayed, R. Ruff, G. Yildirim, M. Dixit, R. Korstanje, Laura Robinson, Richard A. Miller, D. Harrison, J. Strong, M. Schaffler, S. Yakar

Czasopismo: Aging (Albany NY)

Ranking czasopisma: brak

Główne wnioski: Long-term treatment with methylene blue and mitoquinone alone is insufficient to inhibit age-associated bone loss, suggesting that antioxidant interventions alone may not provide adequate protection against skeletal aging.

Streszczenie: Declines in mitochondrial content and impaired cytochrome c oxidase activity (complex IV) can result in reduced energy metabolism and increased levels of oxidants. Methylene blue (MB) is a well-established antioxidant that has been shown to improve mitochondrial function in both in vitro and in vivo settings. Mitoquinone (MitoQ) is a selective antioxidant that specifically targets mitochondria and effectively reduces the accumulation of reactive oxygen species (ROS) within cells. To investigate the effect of acute and long-term administration of MB on skeletal morphology, we administered MB to aged (18 months old) female C57BL/J6 mice, as well as to adult male and female mice with a genetically diverse background (UM-HET3). Additionally, we used MitoQ as an alternative approach to target mitochondrial oxidative stress during aging in adult female and male UM-HET3 mice. Although we observed some beneficial effects of MB and MitoQ in vitro, the administration of these compounds in vivo did not alter the progression of age-induced bone loss. Specifically, treating 18-month-old female mice with MB for 6 or 12 months did not have an effect on age-related bone loss. Similarly, long-term treatment with MB from 7 to 22 months or with MitoQ from 4 to 22 months of age did not affect the morphology of cortical bone at the mid-diaphysis of the femur, trabecular bone at the distal-metaphysis of the femur, or trabecular bone at the lumbar vertebra-5 (L5) in UM-HET3 mice. Based on our findings, it appears that long-term treatment with MB or MitoQ alone, as a means to reduce skeletal oxidative stress, is insufficient to inhibit age-associated bone loss. This supports the notion that interventions solely with antioxidants may not provide adequate protection against skeletal aging.

Prolonged functional life span of artificial red cells in blood circulation by repeated methylene blue injections

Typ badania: non-rct experimental

Liczba cytowań: 2

Rok: 2019

Autorzy: H. Sakai, Cassandra Leong

Czasopismo: Artificial Cells, Nanomedicine, and Biotechnology

Ranking czasopisma: Q2

Główne wnioski: Repeated methylene blue injections significantly extend the functional life span of artificial red cells in blood circulation, potentially improving their safety and efficacy as a transfusion alternative.

Streszczenie: Abstract Hemoglobin-vesicles (HbVs) are artificial oxygen carriers encapsulating purified and concentrated hemoglobin solution in phospholipid vesicles (liposomes) and their safety and efficacy as a transfusion alternative have been evaluated. Because of the absence of enzymatic methemoglobin reduction system in HbV, the level of ferric methemoglobin (metHb) increases gradually after intravenous administration. Our previous studies clarified that the glycolytic electron energies, charged as NAD(P)H in red blood cells (RBC), are donated to reduce metHb compartmentalized in HbV via a water-soluble electron mediator such as methylene blue [MB; 3,7-bis(dimethylamino)phenothiazinium chloride], which freely shuttle across both RBC biomembrane and HbV lipid membrane. Herein, we tried to test repeated injections of MB after the massive HbV administration (28 mL/kg) to hemorrhagic shocked Wistar rats (n = 3). MB was injected (3.1 mg/kg) at 7, 24 and 48 h after HbV administration. Every MB injection showed rapid reduction of metHb and gradual reversal increase. As a result, the functional life span of HbV was significantly extended over 60 h. It is expected that further optimization of injection scheduling will decrease the total amount of MB and prolong the functional life span of HbV.

Methylene Blue in the Treatment of Neuropsychiatric Disorders

Typ badania:

Liczba cytowań: 18

Rok: 2019

Autorzy: M. Alda

Czasopismo: CNS Drugs

Ranking czasopisma: Q1

Główne wnioski: Methylene blue shows promise as a neuroprotective agent and antidepressant for neuropsychiatric disorders, with promising results in bipolar disorder treatment.

Streszczenie: Methylene blue is a long-established drug with complex pharmacology and multiple clinical indications. Its diverse mechanisms of action are most likely responsible for the large variety of its clinical effects. Of interest to psychiatrists, methylene blue has antidepressant, anxiolytic, and neuroprotective properties documented by both animal and human studies. Its stabilizing effect on mitochondrial function and dose-dependent effect on the generation of reactive oxygen species are of significant heuristic value. For these reasons, methylene blue holds promise as a proof-of-concept treatment of organic/neurodegenerative disorders and as a neuroprotective agent in general. In psychiatry, methylene blue has been used for over a century. It was tried successfully in the treatment of psychotic and mood disorders and as a memory enhancer in fear-extinction training. Particularly promising results have been obtained in both short- and long-term treatment of bipolar disorder. In these studies, methylene blue produced an antidepressant and anxiolytic effect without risk of a switch into mania. Long-term use of methylene blue in bipolar disorder led to a better stabilization and a reduction in residual symptoms of the illness. It is usually well tolerated, but caution is needed in the light of its inhibitory effect on monoamine oxidase A.

Methylene blue inhibits Caspase-6 activity, and reverses Caspase-6-induced cognitive impairment and neuroinflammation in aged mice

Typ badania: non-rct experimental

Liczba cytowań: 29

Rok: 2019

Autorzy: Libin Zhou, Joseph Flores, Anastasia Noël, O. Beauchet, P. J. Sjöström, A. LeBlanc

Czasopismo: Acta Neuropathologica Communications

Ranking czasopisma: Q1

Główne wnioski: Methylene blue treatment reverses Caspase-6-induced cognitive deficits and neuroinflammation in aged mice, suggesting it could benefit Alzheimer's disease patients by reversing cognitive decline.

Streszczenie: Activated Caspase-6 (Casp6) is associated with age-dependent cognitive impairment and Alzheimer disease (AD). Mice expressing human Caspase-6 in hippocampal CA1 neurons develop age-dependent cognitive deficits, neurodegeneration and neuroinflammation. This study assessed if methylene blue (MB), a phenothiazine that inhibits caspases, alters Caspase-6-induced neurodegeneration and cognitive impairment in mice. Aged cognitively impaired Casp6-overexpressing mice were treated with methylene blue in drinking water for 1 month. Methylene blue treatment did not alter Caspase-6 levels, assessed by RT-PCR, western blot and immunohistochemistry, but inhibited fluorescently-labelled Caspase-6 activity in acute brain slice intact neurons. Methylene blue treatment rescued Caspase-6-induced episodic and spatial memory deficits measured by novel object recognition and Barnes maze, respectively. Methylene blue improved synaptic function of hippocampal CA1 neurons since theta-burst long-term potentiation (LTP), measured by field excitatory postsynaptic potentials (fEPSPs) in acute brain slices, was successfully induced in the Schaffer collateral-CA1 pathway in methylene blue-treated, but not in vehicle-treated, Caspase-6 mice. Increased neuroinflammation, measured by ionized calcium binding adaptor molecule 1 (Iba1)-positive microglia numbers and subtypes, and glial fibrillary acidic protein (GFAP)-positive astrocytes, were decreased by methylene blue treatment. Therefore, methylene blue reverses Caspase-6-induced cognitive deficits by inhibiting Caspase-6, and Caspase-6-mediated neurodegeneration and neuroinflammation. Our results indicate that Caspase-6-mediated damage is reversible months after the onset of cognitive deficits and suggest that methylene blue could benefit Alzheimer disease patients by reversing Caspase-6-mediated cognitive decline.

Methylene blue inhibits NLRP3, NLRC4, AIM2, and non-canonical inflammasome activation

Typ badania: non-rct experimental

Liczba cytowań: 53

Rok: 2017

Autorzy: Huijeong Ahn, S. Kang, Sung-il Yoon, Hyun-Jeong Ko, P. Kim, E. Hong, B. An, Eunsong Lee, Geun-Shik Lee

Czasopismo: Scientific Reports

Ranking czasopisma: Q1

Główne wnioski: Methylene blue is a broad-spectrum anti-inflammasome candidate molecule, inhibiting canonical and non-canonical inflammasome activation in macrophages.

Fabrication of methylene blue-loaded ovalbumin/polypyrrole nanoparticles for enhanced phototherapy-triggered antitumour immune activation

Typ badania: non-rct in vitro

Liczba cytowań: 21

Rok: 2021

Autorzy: Xiao Xu, Huafen Mao, Yunchao Wu, Suwan Liu, Jingjing Liu, Qianzhe Li, Mengdan Yang, Jinqian Zhu, Shengqiang Zou, F. Du

Czasopismo: Journal of Nanobiotechnology

Ranking czasopisma: Q1

Główne wnioski: Methylene blue-loaded ovalbumin/polypyrrole nanoparticles (MB@OVA/PPY NPs) effectively eliminate solid tumors and trigger a powerful antitumor immune response when combined with phototherapy.

Streszczenie: Background Phototherapy-triggered immunogenic cell death (ICD) rarely elicits a robust antitumour immune response, partially due to low antigen exposure and inefficient antigen presentation. To address these issues, we developed novel methylene blue-loaded ovalbumin/polypyrrole nanoparticles (MB@OVA/PPY NPs) via oxidative polymerization and π–π stacking interactions. Results The as-prepared MB@OVA/PPY NPs with outstanding photothermal conversion efficiency (38%) and photodynamic properties were readily internalized into the cytoplasm and accumulated in the lysosomes and mitochondria. Upon 808 nm and 660 nm laser irradiation, the MB@OVA/PPY NPs not only ablated tumour cells by inducing local hyperthermia but also damaged residual tumour cells by generating a large amount of reactive oxygen species (ROS), finally triggering the release of many damage-associated molecular patterns (DAMPs). Moreover, the MB@OVA/PPY NPs synergized with DAMPs to promote the maturation and improve the antigen presentation ability of DCs in vitro and in vivo. Conclusions This work reported a PPY NPs-based nanoplatform to encapsulate the therepeutic proteins and absorb the functional molecules for combination therapy of tumours. The results demonstrated that the prepared MB@OVA/PPY NPs could be used as effective nanotherapeutic agents to eliminate solid tumours and trigger a powerful antitumour immune response.

New methylene blue derivatives suggest novel anti-orthopoxviral strategies

Typ badania: non-rct in vitro

Liczba cytowań: 22

Rok: 2021

Autorzy: Lalita Priyamvada, Jillybeth Burgado, M. Baker-Wagner, Anatoliy Kitaygorodskyy, V. Olson, V. Lingappa, P. Satheshkumar

Czasopismo: Antiviral Research

Ranking czasopisma: Q1

Główne wnioski: PAV-866 and other methylene blue derivatives show potential as novel anti-orthopoxviral strategies by inhibiting viral binding, fusion, and entry, potentially offering a new approach to combat emerging infections.

Comparative Study Regarding the Properties of Methylene Blue and Proflavine and Their Optimal Concentrations for In Vitro and In Vivo Applications

Typ badania: literature review

Liczba cytowań: 41

Rok: 2020

Autorzy: Maria-Eliza Nedu, M. Tertiș, C. Cristea, A. Georgescu

Czasopismo: Diagnostics

Ranking czasopisma: Q2

Główne wnioski: Methylene blue and proflavine are effective dyes for diagnosing and treating various diseases, with methylene blue being more effective as a tissue tracer and proflavine being more effective as a disinfectant.

Streszczenie: Methylene blue and proflavine are fluorescent dyes used to stain nucleic acid from the molecular level to the tissue level. Already clinically used for sentinel node mapping, detection of neuroendocrine tumors, methemoglobinemia, septic shock, ifosfamide-induced encephalopathy, and photodynamic inactivation of RNA viruses, the antimicrobial, anti-inflammatory, and antioxidant effect of methylene blue has been demonstrated in different in vitro and in vivo studies. Proflavine was used as a disinfectant and bacteriostatic agent against many gram-positive bacteria, as well as a urinary antiseptic involved in highlighting cell nuclei. At the tissue level, the anti-inflammatory effects of methylene blue protect against pulmonary, renal, cardiac, pancreatic, ischemic-reperfusion lesions, and fevers. First used for their antiseptic and antiviral activity, respectively, methylene blue and proflavine turned out to be excellent dyes for diagnostic and treatment purposes. In vitro and in vivo studies demonstrated that both dyes are efficient as perfusion and tissue tracers and permitted to evaluate the minimal efficient concentration in different species, as well as their pharmacokinetics and toxicity. This review aims to identify the optimal concentrations of methylene blue and proflavine that can be used for in vivo experiments to highlight the vascularization of the skin in the case of a perforasome (both as a tissue tracer and in vascular mapping), as well as their effects on tissues. This review is intended to be a comparative and critical presentation of the possible applications of methylene blue (MB) and proflavine (PRO) in the surgical field, and the relevant biomedical findings from specialized literature to date are discussed as well.

Methylene Blue has a potent antiviral activity against SARS-CoV-2 and H1N1 influenza virus in the absence of UV-activation in vitro

Typ badania: non-rct in vitro

Liczba cytowań: 34

Rok: 2021

Autorzy: V. Cagno, Chiara Medaglia, A. Cerny, T. Cerny, Arnaud Charles-Antoine Zwygart, E. Cerny, C. Tapparel

Czasopismo: Scientific Reports

Ranking czasopisma: Q1

Główne wnioski: Methylene blue shows potent antiviral activity against SARS-CoV-2 and H1N1 influenza virus in vitro, even without UV-activation, suggesting potential for preventive and therapeutic use against these infections.

Photodynamic Action of Curcumin and Methylene Blue against Bacteria and SARS-CoV-2—A Review

Typ badania: systematic review

Liczba cytowań: 11

Rok: 2023

Autorzy: Siu Kan Law, Albert Wingnang Leung, Chuanshan Xu

Czasopismo: Pharmaceuticals

Ranking czasopisma: Q1

Główne wnioski: Curcumin and methylene blue show potential as non-toxic photosensitizers in photodynamic therapy (PDT) against bacteria and SARS-CoV-2 infection, offering an antibacterial effect, anti-viral properties, and disinfection functions.

Streszczenie: Coronavirus disease 19 (COVID-19) has occurred for more than four years, and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19 is a strain of coronavirus, which presents high rates of morbidity around the world. Up to the present date, there are no therapeutics that can avert this form of illness, and photodynamic therapy (PDT) may be an alternative approach against SARS-CoV-2. Curcumin and methylene blue have been approved and used in clinical practices as a photosensitizer in PDT for a long time with their anti-viral properties and for disinfection through photo-inactivated SARS-CoV-2. Previously, curcumin and methylene blue with antibacterial properties have been used against Gram-positive bacteria, Staphylococcus aureus (S. aureus), and Gram-negative bacteria, Escherichia coli (E. coli), Enterococcus faecalis (E. faecalis), and Pseudomonas aeruginosa (P. aeruginosa). Methods: To conduct a literature review, nine electronic databases were researched, such as WanFang Data, PubMed, Science Direct, Scopus, Web of Science, Springer Link, SciFinder, and China National Knowledge Infrastructure (CNKI), without any regard to language constraints. In vitro and in vivo studies were included that evaluated the effect of PDT mediated via curcumin or methylene blue to combat bacteria and SARS-CoV-2. All eligible studies were analyzed and summarized in this review. Results: Curcumin and methylene blue inhibited the replication of SARS-CoV-2. The reactive oxygen species (ROS) are generated during the treatment of PDT with curcumin and methylene blue to prevent the attachment of SARS-CoV-2 on the ACE2 receptor and damage to the nucleic acids either DNA or RNA. It also modulates pro-inflammatory cytokines and attenuates the clotting effects of the host response. Conclusion: The photodynamic action of curcumin and methylene blue provides a possible approach against bacteria and SARS-CoV-2 infection because they act as non-toxic photosensitizers in PDT with an antibacterial effect, anti-viral properties, and disinfection functions.

Methylene Blue Inhibits the SARS-CoV-2 Spike–ACE2 Protein-Protein Interaction–a Mechanism that can Contribute to its Antiviral Activity Against COVID-19

Typ badania: non-rct in vitro

Liczba cytowań: 81

Rok: 2021

Autorzy: Damir Bojadzic, O. Alcázar, P. Buchwald

Czasopismo: Frontiers in Pharmacology

Ranking czasopisma: Q1

Główne wnioski: Methylene blue inhibits the SARS-CoV-2 spike protein-ACE2 protein interaction, potentially contributing to its antiviral activity against COVID-19 by blocking its attachment to ACE2-expressing cells.

Streszczenie: Due to our interest in the chemical space of organic dyes to identify potential small-molecule inhibitors (SMIs) for protein-protein interactions (PPIs), we initiated a screen of such compounds to assess their inhibitory activity against the interaction between SARS-CoV-2 spike protein and its cognate receptor ACE2, which is the first critical step initiating the viral attachment and entry of this coronavirus responsible for the ongoing COVID-19 pandemic. As part of this, we found that methylene blue, a tricyclic phenothiazine compound approved by the FDA for the treatment of methemoglobinemia and used for other medical applications (including the inactivation of viruses in blood products prior to transfusion when activated by light), inhibits this interaction. We confirmed that it does so in a concentration-dependent manner with a low micromolar half-maximal inhibitory concentration (IC50 = 3 μM) in our protein-based ELISA-type setup, while chloroquine, siramesine, and suramin showed no inhibitory activity in this assay. Erythrosine B, which we have shown before to be a promiscuous SMI of PPIs, also inhibited this interaction. Methylene blue inhibited the entry of a SARS-CoV-2 spike bearing pseudovirus into ACE2-expressing cells with similar IC50 (3.5 μM). Hence, this PPI inhibitory activity could contribute to its antiviral activity against SARS-CoV-2 even in the absence of light by blocking its attachment to ACE2-expressing cells and making this inexpensive and widely available drug potentially useful in the prevention and treatment of COVID-19 as an oral or inhaled medication.

Cellular and molecular actions of Methylene Blue in the nervous system

Typ badania:

Liczba cytowań: 382

Rok: 2011

Autorzy: M. Oz, D. Lorke, M. Hasan, G. Petroianu

Czasopismo: Medicinal Research Reviews

Ranking czasopisma: Q1

Główne wnioski: Methylene Blue (MB) has multiple cellular and molecular targets in the nervous system, with its unique physicochemical properties influencing its biological effects and clinical applications.

Streszczenie: Methylene Blue (MB), following its introduction to biology in the 19th century by Ehrlich, has found uses in various areas of medicine and biology. At present, MB is the first line of treatment in methemoglobinemias, is used frequently in the treatment of ifosfamide‐induced encephalopathy, and is routinely employed as a diagnostic tool in surgical procedures. Furthermore, recent studies suggest that MB has beneficial effects in Alzheimer's disease and memory improvement. Although the modulation of the cGMP pathway is considered the most significant effect of MB, mediating its pharmacological actions, recent studies indicate that it has multiple cellular and molecular targets. In the majority of cases, biological effects and clinical applications of MB are dictated by its unique physicochemical properties including its planar structure, redox chemistry, ionic charges, and light spectrum characteristics. In this review article, these physicochemical features and the actions of MB on multiple cellular and molecular targets are discussed with regard to their relevance to the nervous system. © 2009 Wiley Periodicals, Inc. Med Res Rev, 31, No. 1, 93–117, 2010

Methylene blue inhibits replication of SARS-CoV-2 in vitro

Typ badania: non-rct in vitro

Liczba cytowań: 63

Rok: 2020

Autorzy: Mathieu Gendrot, J. Andreani, Isabelle Duflot, M. Boxberger, M. Le Bideau, J. Mosnier, Priscilla Jardot, Isabelle Fonta, Clara Rolland, H. Bogreau, S. Hutter, B. La Scola, B. Pradines

Czasopismo: International Journal of Antimicrobial Agents

Ranking czasopisma: Q1

Główne wnioski: Methylene blue shows promising in vitro antiviral activity against SARS-CoV-2, suggesting it could be a potential treatment for COVID-19.

Methylene blue reduces the serum levels of interleukin-6 and inhibits STAT3 activation in the brain and the skin of lipopolysaccharide-administered mice

Typ badania: non-rct experimental

Liczba cytowań: 3

Rok: 2023

Autorzy: Yujia Li, W. Ying

Czasopismo: Frontiers in Immunology

Ranking czasopisma: Q1

Główne wnioski: Methylene blue administration can decrease IL-6 levels and STAT3 activation, suggesting potential therapeutic potential for multiple inflammation-associated diseases.

Streszczenie: It is valuable to search for novel and economical agents for inhibiting STAT3 activation and blocking increases in IL-6 levels, due to the important roles of STAT3 and IL-6 in inflammation. Since Methylene Blue (MB) has shown therapeutical potential for multiple diseases, it has become increasingly important to investigate the mechanisms underlying the effects of MB on inflammation. Using a mouse model of lipopolysaccharide (LPS)-induced inflammation, we investigated the mechanisms underlying the effects of MB on inflammation, obtaining the following findings: First, MB administration attenuated the LPS-induced increases in the serum levels of IL-6; second, MB administration attenuated LPS-induced STAT3 activation of the brain; and third, MB administration attenuated LPS-induced STAT3 activation of the skin. Collectively, our study has suggested that MB administration can decrease the levels of IL-6 and STAT3 activation - two important factors in inflammation. Since MB is a clinically used and relatively economical drug, our findings have suggested therapeutic potential of MB for multiple inflammation-associated diseases due to its effects on STAT3 activation and IL-6 levels.

Methylene Blue—Current Knowledge, Fluorescent Properties, and Its Future Use

Typ badania: literature review

Liczba cytowań: 109

Rok: 2020

Autorzy: Tomasz Cwalinski, W. Połom, L. Marano, G. Roviello, A. D’Angelo, N. Cwalina, M. Matuszewski, F. Roviello, J. Jaśkiewicz, K. Polom

Czasopismo: Journal of Clinical Medicine

Ranking czasopisma: Q1

Główne wnioski: Methylene blue shows promising potential as a fluorophore in various medical fields, but more research is needed to fully understand its potentials and limitations.

Streszczenie: Methylene blue is a fluorescent dye discovered in 1876 and has since been used in different scientific fields. Only recently has methylene blue been used for intraoperative fluorescent imaging. Here, the authors review the emerging role of methylene blue, not only as a dye used in clinical practice, but also as a fluorophore in a surgical setting. We discuss the promising potential of methylene blue together with the challenges and limitations among specific surgical techniques. A literature review of PubMed and Medline was conducted based on the historical, current and future usage of methylene blue within the field of medicine. We reviewed not only the current usage of methylene blue, but we also tried to grasp its’ function as a fluorophore in five main domains. These domains include the near-infrared imaging visualization of ureters, parathyroid gland identification, pancreatic tumors imaging, detection of breast cancer tumor margins, as well as breast cancer sentinel node biopsy. Methylene blue is used in countless clinical procedures with a relatively low risk for patients. Usage of its fluorescent properties is still at an early stage and more pre-clinical, as well as clinical research, must be performed to fully understand its potentials and limitations.

Methylene blue modulates adhesion molecule expression on microvascular endothelial cells

Typ badania: non-rct in vitro

Liczba cytowań: 2

Rok: 2014

Autorzy: I. Werner, F. Guo, U. Stock, M. Lupinski, P. Meybohm, A. Moritz, A. Beiras-Fernandez

Czasopismo: Inflammation Research

Ranking czasopisma: Q1

Główne wnioski: Methylene blue has an immunomodulatory effect on endothelial cells, increasing the expression of E-selectin and VCAM-1 depending on the dosage and time of exposure.

Streszczenie: Objective and designAs methylene blue (MB) has been recently proposed to preserve blood pressure in case of vasoplegic syndrome and shock, an entity directly related to systemic inflammation, we aimed to elucidate the effect of MB on the expression of adhesion-molecules in endothelial-cells.Materials and treatmentHuman microvascular endothelial-cells (HuMEC-1) were treated with 10, 30 or 60 µM MB for 30 min and 2 h each. Additionally, the treated HuMEC-1 were co-cultured with either human peripheral blood mononuclear cells (PBMCs) or Jurkat cells (human T-lymphocytes) for 2 h.MethodsHuMEC-1 were analyzed after MB treatment and after co-culture experiments for expression of different adhesion-molecules (ICAM-1, VCAM-1, L-selectin, E-selectin) via FACS measurement and western blot analysis. The supernatants of the experiments were analyzed with regard to the soluble forms of the adhesion molecules.ResultsWe found that MB is able to modulate the expression of adhesion-molecules on EC. Administration of MB increases the expression of E-selectin and VCAM-1 depending on the dosage and time of exposure. ICAM-1 measurements provide evidence that different circulating blood cells can differently alter the adhesion-molecule expression on EC after MB exposure.ConclusionOur results provide evidence regarding the immunomodulatory effect of MB upon endothelial-cells after inflammation.

Functional inactivation of lymphocytes by methylene blue with visible light

Typ badania: non-rct in vitro

Liczba cytowań: 4

Rok: 2015

Autorzy: Bo Zhang, Zhenzhen Cheng, Qin Mo, Li Wang, Xun Wang, Xiaofei Wu, Yao Jia, Yuwen Huang

Czasopismo: Photochemical & Photobiological Sciences

Ranking czasopisma: Q2

Główne wnioski: Methylene blue with visible light effectively and irreversibly inactivates lymphocytes, potentially preventing adverse immune responses caused by transfused white blood cells.

Streszczenie: Transfusion of allogeneic white blood cells (WBCs) may cause adverse reactions in immunocompromised recipients, including transfusion-associated graft- versus -host disease (TA-GVHD), which is often fatal and incurable. In this study, the in vitro effect of methylene blue with visible light (MB + L) treatment on lymphocyte proliferation and cytokine production was measured to investigate whether MB + L can be used to prevent immune reactions that result from transfused lymphocytes. WBCs and 3 μM of MB were mixed and transferred into medical PVC bags, which were then exposed to visible light. Gamma irradiation was conducted as a parallel positive control. The cells without treatment were used as untreated group. All the groups were tested for the ability of cell proliferation and cytokine production upon stimulation. After incubation with mitogen phytohemagglutinin (PHA) or plate-bound anti-CD3 plus anti-CD28, the proliferation of MB + L/gamma-irradiation treated lymphocytes was significantly inhibited ( P < 0.01) as compared to the untreated ones; the proliferation inhibitive rate of the MB + L group was even higher than that of gamma-irradiated cells (73.77% ± 28.75% vs. 44.72% ± 38.20%). MB + L treated cells incubated up to 7 days with PHA also showed no significant proliferation. The levels of TNF-α, IFN-γ, IL-6, IL-8, IL-10 and IL-1β present in the supernatant of MB + L treated lymphocytes upon stimulation were significantly lower than those of untreated lymphocytes. These results demonstrated that MB + L treatment functionally and irreversibly inactivated lymphocytes by inhibiting lymphocyte proliferation and the production of cytokines. MB + L treatment might be a promising method for the prevention of adverse immune responses caused by WBCs.

Inhibiting the NLRP3 Inflammasome With Methylene Blue as Treatment Adjunct in Myelodysplasia

Typ badania:

Liczba cytowań: 10

Rok: 2018

Autorzy: R. Kast

Czasopismo: Frontiers in Oncology

Ranking czasopisma: Q2

Główne wnioski: Methylene blue may inhibit NLRP3 inflammasome function, potentially offering a low-risk treatment option for myelodysplasia patients with marrow inflammation and apoptosis.

Streszczenie: Myelodysplasia refers to a group of clonal hematopoietic neoplasms characterized by genetic heterogeneity, different clinical behaviors and prognoses. Some of this group of bone marrow failure conditions have known external causes, some are of unknown origin. Within marrow, intracellular, and extracellular elements of the innate immune system are activated and contribute to creation of multiple cytogenetic abnormalities and are central to the mode of hematopoietic cell failure. Basiorka et al. showed that NLRP3 inflammasome activity is essential to the innate immune system's destruction of marrow hematopoietic cells commonly in myelodysplasia. In April 2018 Hao et al. reported that methylene blue inhibits rat NLRP3 inflammasome function. Methylene blue has been in continuous use in humans for over a century. It is associated with an eminently benign side effect profile in human use. If as in rodents, methylene blue also inhibits NLRP3 inflammasome function in human myelodysplasia a trial of adjunctive methylene blue treatment in transfusion dependent, low risk myelodysplasia where marrow inflammation and apoptosis predominates, would be worth trying. HIGHLIGHTS - Cytogenetic abnormalities and innate immune activation are seen in myelodysplasia - The NLRP3 inflammasome is a core element generating marrow failure of myelodysplasia - In April 2018 methylene blue was reported to potently inhibit NLRP3 inflammasome function - Methylene blue has benign side effects and has been in human use for a century - Study of methylene blue treatment of myelodysplasia would be a low-risk intervention

Cardiotoxic and Cardioprotective Effects of Methylene Blue in the Animal Model of Cardiac Ischemia and Reperfusion

Typ badania:

Liczba cytowań: 1

Rok: 2024

Autorzy: H. J. Fernandes Júnior, Erisvaldo Amarante de Araújo, José Antônio Machado Junior, Fabio Marinho Lutz Motta, Gabriela Ferrazzano Guarize, Lucas Chen Cheng, J. Tantray, Jand Venes Rolim Medeiros, L. D. Nicolau, Adriano Henrique Pereira Barbosa, Adriano Caixeta, I. Rocco, S. Guizilini, Marcelo Pires-Oliveira, M. Taha, Afonso Caricati-Neto, Walter José Gomes, F. Tallo, F. S. Menezes-Rodrigues

Czasopismo: Biomedicines

Ranking czasopisma: Q1

Główne wnioski: Methylene blue has both cardiotoxic effects before cardiac ischemia and cardioprotective effects after ischemia but before cardiac reperfusion in an animal model of cardiac ischemia and reperfusion.

Streszczenie: Background/Objectives: Treatment of patients with myocardial ischemic diseases crucially involves cardiac reperfusion (CR). However, oxidative stress and tissue lesions caused by CR may also lead to lethal complications, such as arrythmias and vasoplegic syndrome (VS). Although methylene blue (MB) has long been used to treat VS due to cardiac ischemia and reperfusion (CIR) and/or surgery because of its vascular effects, MB’s effects on the heart are unclear. Therefore, we investigated the potential cardioprotective or arrhythmogenic effects of MB in an animal model of CIR. To this end, 12–16-week-old male Wistar rats were divided into four experimental groups: (a) rats subjected to SHAM surgery with no ischemia; (b) rats subjected to CIR and treated with a vehicle (SS + CIR); and (c) rats subjected to CIR and treated with 2 mg/kg i.v. MB before ischemia (MB + ISQ) or (d) after ischemia but before reperfusion (ISQ + MB). An ECG analysis was used to evaluate the incidence of ventricular arrhythmias (VAs), atrioventricular blocks (AVBs), and lethality (LET) resulting from CIR. After CIR, rat hearts were removed for histopathological analysis and lipid hydroperoxide (LH) measurements. Results: The incidence of VA, AVB, and LET was significantly increased in the MB + ISQ group (VA = 100%; AVB = 100%; LET = 100%) but significantly reduced in the ISQ + MB group (VA = 42.8%; AVB = 28.5%; LET = 21.4%) compared with the SS + CIR group (VA = 85.7%; AVB = 71.4%; LET = 64.2%). LH concentration was significantly reduced in both MB-treated groups, but myocardial injuries were increased only in the MB + ISQ group when compared with the SS + CIR group. Conclusions: These results indicate that MB produces a biphasic effect on CIR, with cardiotoxic effects when administered before cardiac ischemia and cardioprotective effects when administered after ischemia but before cardiac reperfusion.

Efficacy of methylene blue in a murine model of amlodipine overdose.

Typ badania: rct

Liczba cytowań: 5

Rok: 2020

Autorzy: L. E. de Castro Brás, C. Baccanale, L. Eccleston, T. Sloan, Jason C St Antoine, Steven Matthew-Lewis Verzwyvelt, Peggy Pittman, D. O’Rourke, W. Meggs

Czasopismo: The American journal of emergency medicine

Ranking czasopisma: Q1

Główne wnioski: Methylene blue effectively decreased cardiac toxicity in a mouse model of amlodipine overdose, preserving cardiac function and reducing death rates.

Methylene blue counteracts cyanide cardiotoxicity: cellular mechanisms.

Typ badania: non-rct in vitro

Liczba cytowań: 22

Rok: 2018

Autorzy: J. Cheung, Jufang Wang, Xueqian Zhang, Jianliang Song, D. Tomar, M. Madesh, A. Judenherc-Haouzi, P. Haouzi

Czasopismo: Journal of applied physiology

Ranking czasopisma: Q1

Główne wnioski: Methylene blue effectively reverses cyanide-induced cardiotoxicity by preserving intracellular calcium homeostasis, minimizing arrhythmia risks, and reducing superoxide levels.

Streszczenie: In adult left ventricular mouse myocytes, exposure to sodium cyanide (NaCN) in the presence of glucose dose-dependently reduced contraction amplitude, with ~80% of maximal inhibitory effect attained at 100 µM. NaCN (100 µM) exposure for 10 min significantly decreased contraction and intracellular Ca2+ concentration ([Ca2+]i) transient amplitudes, systolic but not diastolic [Ca2+]i, and maximal L-type Ca2+ current ( ICa) amplitude, indicating acute alteration of [Ca2+]i homeostasis largely accounted for the observed excitation-contraction abnormalities. In addition, NaCN depolarized resting membrane potential ( Em), reduced action potential (AP) amplitude, prolonged AP duration at 50% (APD50) and 90% repolarization (APD90), and suppressed depolarization-activated K+ currents but had no effect on Na+-Ca2+ exchange current ( INaCa). NaCN did not affect cellular adenosine triphosphate levels but depolarized mitochondrial membrane potential (ΔΨm) and increased superoxide (O2·-) levels. Methylene blue (MB; 20 µg/ml) added 3 min after NaCN restored contraction and [Ca2+]i transient amplitudes, systolic [Ca2+]i, Em, AP amplitude, APD50, APD90, ICa, depolarization-activated K+ currents, ΔΨm, and O2·- levels toward normal. We conclude that MB reversed NaCN-induced cardiotoxicity by preserving intracellular Ca2+ homeostasis and excitation-contraction coupling ( ICa), minimizing risks of arrhythmias ( Em, AP configuration, and depolarization-activated K+ currents), and reducing O2·- levels. NEW & NOTEWORTHY Cyanide poisoning due to industrial exposure, smoke inhalation, and bioterrorism manifests as cardiogenic shock and requires rapidly effective antidote. In the early stage of cyanide exposure, adenosine triphosphate levels are normal but myocyte contractility is reduced, largely due to alterations in Ca2+ homeostasis because of changes in oxidation-reduction environment of ion channels. Methylene blue, a drug approved by the U.S. Food and Drug Administration, ameliorates cyanide toxicity by normalizing oxidation-reduction state and Ca2+ channel function.

Methylene Blue: Revisited

Typ badania:

Liczba cytowań: 300

Rok: 2010

Autorzy: Prashant R Ginimuge, SD Jyothi

Czasopismo: Journal of Anaesthesiology, Clinical Pharmacology

Ranking czasopisma: Q2

Główne wnioski: Methylene blue improves blood pressure and cardiac function in various clinical states, including hypotension, cirrhosis, and septic shock.

Streszczenie: Methylene blue, an inhibitor of nitric oxide synthase and guanylate cyclase has many uses in medicine. It has been found to improve the hypotension associated with various clinical states. It also improves hypoxia and hyper dynamic circulation in cirrhosis of liver and severe hepatopulmonary syndrome. It also results in transient and reproducible improvement in blood pressure and cardiac function in septic shock.

Methylene Blue Reduces Mortality in Critically Ill and Perioperative Patients: A Meta-Analysis of Randomized Trials.

Typ badania: meta-analysis

Liczba cytowań: 20

Rok: 2023

Autorzy: Alessandro Pruna, A. Bonaccorso, A. Belletti, S. Turi, Ambra Licia di Prima, Filippo D'Amico, A. Zangrillo, Y. Kotani, Giovanni Landoni

Czasopismo: Journal of cardiothoracic and vascular anesthesia

Ranking czasopisma: Q1

Główne wnioski: Methylene blue reduces mortality and length of stay in critically ill and perioperative patients by reversing vasodilation and potentially improving survival.

Streszczenie: Vasodilatory hypotension is common in critically ill and perioperative patients, and is associated with adverse outcomes. As a nitric oxide production inhibitor, methylene blue (MB) exerts its vasoconstrictor property and is an adjuvant for catecholamine-refractory vasodilatory shock. However, the effects of MB on clinically relevant outcomes remain unclear. Therefore, the authors performed a meta-analysis of randomized trials on MB in critically ill and perioperative patients. The authors searched through databases for randomized trials on MB in critically ill and perioperative patients, which yielded 11 studies consisting of 556 patients. The primary outcome was mortality at the longest follow-up. Secondary outcomes included hemodynamic parameters and organ dysfunction (PROSPERO: CRD42023409243). Nine out of the 11 included randomized trials reported mortality, which was significantly lower in the MB group (risk ratio, 0.60 [95% CI 0.43-0.84] p = 0.003), with findings confirmed in septic shock and cardiac surgery subgroups. The authors found reduced lengths of stay in the intensive care unit (mean difference [MD], -0.9 days [95% CI -1.06 to -0.77] p < 0.001) and in the hospital (MD, -2.2 days [95% CI, -2.68 to -1.70] p < 0.001) in the MB group. MB was associated with increased mean arterial pressure (MD, 8.4 mmHg [95% CI 5.01-11.75] p < 0.001) and systemic vascular resistance (MD, 94.5 dyn/s/cm5 [95% CI 17.73-171.15] p = 0.02), with no difference in cardiac output (standardized MD, 0.16 [95% CI, -0.25 to 0.57] p = 0.45). This meta-analysis showed that MB reverses vasodilation in critically ill and perioperative patients and might improve survival. Further adequately powered randomized trials are needed to confirm these findings.

Cardioprotection by methylene Blue Against Epinephrine-Induced Cardiac Arrhythmias and Myocardial Injury

Typ badania:

Liczba cytowań: 3

Rok: 2023

Autorzy: O. Abdel-Salam, Marawan Abd El Baset Mohamed Sayed, E. Omara, A. Sleem

Czasopismo: WSEAS TRANSACTIONS ON BIOLOGY AND BIOMEDICINE

Ranking czasopisma: Q4

Główne wnioski: Methylene blue dose-dependently prevents epinephrine-induced cardiac arrhythmias and myocardial muscle injury in rats.

Streszczenie: Methylene blue is used in the treatment of vasoplegic syndrome after cardiac surgery, anaphylaxis, and septic shock refractory to epinephrine and fluid resuscitation. In this study, we investigated the potential protective effect of methylene blue on the development of cardiac arrhythmias after injection of epinephrine in rats. Methylene blue was given intraperitoneally at doses of 50 or 100 mg/kg. Cardiac arrhythmia was then induced with 10 μg/kg of epinephrine intravenously. In untreated, control rats, epinephrine caused bradycardia (96.48 ± 1.06 vs. 365.03 ± 0.68 beats/min), increased PR interval (0.54 ± 0.04 vs. 0.039 ± 0.004), RR interval (0.64 ± 0.003 vs. 0.16 ± 0.004 sec), shortened QTc interval (0.067 ± 0.05 vs. 0.1 ± 0.004 sec), increased QRS duration (0.048 ± 0.005 vs. 0.028 ± 0.002 sec), decreased R wave amplitude (0.3 ± 0.03 vs. 0.49 ± 0.04 mv), decreased the height of the ST segment (-0.0696 ± 0.004 vs. -0.0054 ± 0.003 mv), and caused ventricular extrasystoles (7.92 ± 0.56 vs. 0.5 ± 0.5). Methylene blue given at 50 or 100 mg/kg increased the heart rate, decreased RR interval, QRS duration and the drop in the ST height, increased duration of QTc interval and R wave amplitude and decreased the number of extrasystoles. The histological study showed that methylene blue protected against myocardial structural disorganization, cellular damage, necrosis, and haemorrhage between muscle fibres induced by epinephrine injection. We conclude that methylene blue dose-dependently prevented epinephrine-induced arrhythmias and cardiac muscle injury.

Methylene blue increases myocardial function in septic shock.

Typ badania: non-rct experimental

Liczba cytowań: 133

Rok: 1995

Autorzy: Catharina R G Daemen-Gubbels, P. Groeneveld, A. Groeneveld, G. V. van Kamp, W. Bronsveld, L. Thijs

Czasopismo: Critical care medicine

Ranking czasopisma: Q1

Główne wnioski: Methylene blue infusion increases myocardial function and oxygen delivery in septic shock patients, suggesting nitric oxide may be a mediator of circulatory changes.

Streszczenie: OBJECTIVE To study whether the circulatory changes of human septic shock are mediated in part by nitric oxide. DESIGN Open-label, nonrandomized clinical trial on the effects of methylene blue, an inhibitor of nitric oxide action. SETTING Intensive care unit of a teaching hospital. PATIENTS Nine consecutive patients with documented septic shock and a pulmonary artery catheter in place, after initial resuscitation with fluids, sympathomimetics, and mechanical ventilation. INTERVENTIONS Hemodynamic and metabolic variables were measured before and then 15, 30, 60, and 120 mins after the start of a 20-min infusion of 2 mg/kg of methylene blue. MEASUREMENTS AND MAIN RESULTS Patients had a hyperdynamic circulation, and methylene blue increased (p < .01) mean arterial pressure from 84 +/- 18 to 109 +/- 31 mm Hg and cardiac index from 4.7 +/- 0.9 to 5.6 +/- 1.2 L/min/m2, before and 30 mins after starting the methylene blue infusion, respectively. Cardiac filling pressures did not change. In the same time interval, the subnormal systemic vascular resistance index increased (p = .09) and arterial compliance decreased (p < .05). Oxygen delivery and oxygen uptake increased (p < .05) from 714 +/- 188 to 865 +/- 250 mL/min/m2 and from 160 +/- 39 to 186 +/- 44 mL/min/m2, respectively. Except for heart rate, which increased by 11 +/- 8 beats/min (p < .01), variables returned to baseline values at time = 120 mins. CONCLUSIONS After initial resuscitation from human septic shock, a single dose of methylene blue transiently increases mean arterial pressure and oxygen uptake, associated with a decrease in arterial compliance and increases in myocardial function and oxygen delivery. Hence, nitric oxide may be a mediator of the circulatory changes of human septic shock.

Methylene blue as a vasopressor: a meta-analysis of randomised trials.

Typ badania: meta-analysis

Liczba cytowań: 45

Rok: 2013

Autorzy: L. Pasin, Michele Umbrello, T. Greco, Massimo Zambon, F. Pappalardo, M. Crivellari, G. Borghi, A. Morelli, A. Zangrillo, G. Landoni

Czasopismo: Critical care and resuscitation : journal of the Australasian Academy of Critical Care Medicine

Ranking czasopisma: Q1

Główne wnioski: Methylene blue effectively increases arterial blood pressure and systemic vascular resistances in vasoplegic patients without a detrimental effect on survival.

Effects of methylene blue on microcirculatory alterations following cardiac surgery

Typ badania: non-rct experimental

Liczba cytowań: 5

Rok: 2021

Autorzy: C. Maurin, P. Portran, R. Schweizer, B. Allaouchiche, S. Junot, M. Jacquet-Lagrèze, J. Fellahi

Czasopismo: European Journal of Anaesthesiology

Ranking czasopisma: Q1

Główne wnioski: Methylene blue administration can improve microcirculatory alterations in patients with refractory vasoplegic syndrome after cardiac surgery, despite normalized cardiac index and mean arterial pressure.

Streszczenie: BACKGROUND Methylene blue is used as rescue therapy to treat catecholamine-refractory vasoplegic syndrome after cardiac surgery. However, its microcirculatory effects remain poorly documented. OBJECTIVE We aimed to study microcirculatory abnormalities in refractory vasoplegic syndrome following cardiac surgery with cardiopulmonary bypass and assess the effects of methylene blue. DESIGN A prospective open-label cohort study. SETTING 20-Bed ICU of a tertiary care hospital. PATIENTS 25 Adult patients receiving 1.5 mg kg−1 of methylene blue intravenously for refractory vasoplegic syndrome (defined as norepinephrine requirement more than 0.5 μg kg−1 min−1) to maintain mean arterial pressure (MAP) more than 65 mmHg and cardiac index (CI) more than 2.0 l min−1 m−2. MAIN OUTCOME MEASURES Complete haemodynamic set of measurements at baseline and 1 h after the administration of methylene blue. Sublingual microcirculation was investigated by sidestream dark field imaging to obtain microvascular flow index (MFI), total vessel density, perfused vessel density and heterogeneity index. Microvascular reactivity was assessed by peripheral near-infrared (IR) spectroscopy combined with a vascular occlusion test. We also performed a standardised measurement of capillary refill time. RESULTS Despite normalised CI (2.6 [2.0 to 3.8] l min−1 m−2) and MAP (66 [55 to 76] mmHg), patients with refractory vasoplegic syndrome showed severe microcirculatory alterations (MFI < 2.6). After methylene blue infusion, MFI significantly increased from 2.0 [0.1 to 2.5] to 2.2 [0.2 to 2.8] (P = 0.008), as did total vessel density from 13.5 [8.3 to 18.5] to 14.9 [10.1 to 14.7] mm mm−2 (P = 0.02) and perfused vessel density density from 7.4 [0.1 to 11.5] to 9.1 [0 to 20.1] mm mm−2 (P = 0.02), but with wide individual variation. Microvascular reactivity assessed by tissue oxygen resaturation speed also increased from 0.5 [0.1 to 1.8] to 0.7 [0.1 to 2.7]% s−1 (P = 0.002). Capillary refill time remained unchanged throughout the study. CONCLUSION In refractory vasoplegic syndrome following cardiac surgery, we found microcirculatory alterations despite normalised CI and MAP. The administration of methylene blue could improve microvascular perfusion and reactivity, and partially restore the loss of haemodynamic coherence. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT04250389.

The effects of methylene blue during and after cardiac arrest in a porcine model; a randomized, blinded, placebo-controlled study.

Typ badania: rct

Liczba cytowań: 1

Rok: 2023

Autorzy: C. M. Johannsen, Casper Nørholt, C. Baltsen, Mark Eggertsen, Andreas Magnussen, Lasse Vormfenne, S. Ø. Mortensen, Esben Søvsø Szocska Hansen, Lauge Vammen, L. Andersen, A. Granfeldt

Czasopismo: The American journal of emergency medicine

Ranking czasopisma: Q1

Główne wnioski: A bolus of methylene blue during cardiac arrest and after resuscitation did not significantly improve hemodynamic function or yield neuroprotective effects in a porcine model.

A dose-finding study of methylene blue to inhibit nitric oxide actions in the hemodynamics of human septic shock.

Typ badania: rct

Liczba cytowań: 91

Rok: 2010

Autorzy: N. Juffermans, M. Vervloet, Catharina R G Daemen-Gubbels, J. Binnekade, M. de Jong, A. Groeneveld

Czasopismo: Nitric oxide : biology and chemistry

Ranking czasopisma: Q2

Główne wnioski: Methylene blue increases blood pressure and myocardial function in septic shock patients, with dose-dependency, but high doses may compromise splanchnic perfusion and should be avoided in future studies.

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

Typ badania: rct

Liczba cytowań: 91

Rok: 1995

Autorzy: Haibo Zhang, P. Rogiers, J. Preiser, H. Spapen, P. Manikis, G. Metz, J. Vincent

Czasopismo: Critical care medicine

Ranking czasopisma: Q1

Główne wnioski: Methylene blue infusion can increase arterial blood pressure and improve peripheral blood flow during endotoxic shock, but does not affect cardiac index.

Streszczenie: OBJECTIVE We hypothesized that methylene blue, by inhibiting the activation of soluble guanylate cyclase mediated by nitric oxide, may reverse systemic hypotension, enhance myocardial function, and improve peripheral distribution of blood flow during endotoxic shock. DESIGN Randomized, controlled, acute intervention study. SETTING University intensive care laboratory. SUBJECTS Twenty-one healthy, anesthetized, mongrel dogs, weighing 26 +/- 4 kg. INTERVENTIONS Groups 1 (n = 7) and 2 (n = 7) received endotoxin (2 mg/kg iv) alone combined with increasing doses of 2.5, 5, 10, and 20 mg/kg iv of methylene blue. Each dose was administrated for 30 mins with a free interval of 30 mins. Group 3 (n = 7) served as a control group, receiving the same doses of methylene blue in the absence of endotoxin. All animals were given normal saline to keep cardiac filling pressures constant. Blood flow probes were placed around the superior mesenteric, renal, and femoral arteries to measure regional blood flow by ultrasonic technique. Data were collected every 30 mins during the study. MEASUREMENTS AND MAIN RESULTS After endotoxemia, methylene blue increased systemic and pulmonary arterial pressure and vascular resistances in a dose-dependent manner up to 10 mg/kg, but had no effect on cardiac index. At the highest dose, methylene blue decreased arterial pressure and systemic vascular resistance. At doses of methylene blue of < or = 10 mg/kg, mesenteric and femoral blood artery flow increased. At the highest dose of 20 mg/kg, femoral artery blood flow further increased, but mesenteric blood flow decreased. Renal artery blood flow was unaffected by methylene blue. In the absence of endotoxin, methylene blue at doses of 2.5 or 5 mg/kg did not alter mean arterial pressure, but reduced cardiac index, indicating an increase in systemic vascular resistance. In contrast, the higher doses of 10 or 20 mg/kg of methylene blue decreased mean arterial pressure and systemic vascular resistance. However, pulmonary arterial pressure and pulmonary vascular resistance increased in a dose-dependent manner. Mesenteric and renal artery blood flow decreased but femoral blood flow increased. As in the presence of endotoxin, methylene blue induced dose-related increases in oxygen uptake and oxygen extraction ratio, but did not alter oxygen delivery. Methylene blue largely attenuated the endotoxin-induced increase in plasma nitrite concentrations. CONCLUSIONS Low and moderate doses of methylene blue can significantly increase arterial blood pressure but not cardiac index during endotoxic shock. Methylene blue infusion may selectively increase mesenteric blood flow. High doses of methylene blue can worsen systemic hypotension, myocardial depression, and pulmonary hypertension after endotoxemia.

Methylene blue improves mitochondrial respiration and decreases oxidative stress in a substrate-dependent manner in diabetic rat hearts.

Typ badania: non-rct experimental

Liczba cytowań: 24

Rok: 2017

Autorzy: O. Duicu, Andreea I Privistirescu, A. Wolf, A. Petruș, Maria D Dănilă, Corina Ratiu, D. Muntean, A. Sturza

Czasopismo: Canadian journal of physiology and pharmacology

Ranking czasopisma: Q3

Główne wnioski: Methylene blue improves mitochondrial respiration and decreases oxidative stress in diabetic rat hearts, with a substrate-dependent effect on reactive oxygen species production.

Streszczenie: Diabetic cardiomyopathy has been systematically associated with compromised mitochondrial energetics and increased generation of reactive oxygen species (ROS) that underlie its progression to heart failure. Methylene blue is a redox drug with reported protective effects mainly on brain mitochondria. 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.

Neuro‐ and Cardioprotective Effects of Blockade of Nitric Oxide Action by Administration of Methylene Blue

Typ badania:

Liczba cytowań: 69

Rok: 2007

Autorzy: L. Wiklund, S. Basu, A. Miclescu, P. Wiklund, G. Ronquist, H. Sharma

Czasopismo: Annals of the New York Academy of Sciences

Ranking czasopisma: Q1

Główne wnioski: Methylene blue has neuroprotective and cardioprotective effects in ischemia-reperfusion situations, due to its blocking effect on nitric oxide synthase and guanylyl cyclase.

Streszczenie: Methylene blue (MB), generic name methylthioninium (C16H18ClN3 S · 3H2O), is a blue dye synthesized in 1876 by Heinrich Caro for use as a textile dye and used in the laboratory and clinically since the 1890s, with well‐known toxicity and pharmacokinetics. It has experimentally proven neuroprotective and cardioprotective effects in a porcine model of global ischemia–reperfusion in experimental cardiac arrest. This effect has been attributed to MB's blocking effect on nitric oxide synthase and guanylyl cyclase, the latter blocking the synthesis of the second messenger of nitric oxide. The physiological effects during reperfusion include stabilization of the systemic circulation without significantly increased total peripheral resistance, moderately increased cerebral cortical blood flow, a decrease of lipid peroxidation and inflammation, and less anoxic tissue injury in the brain and the heart. The last two effects are recorded as less increase in plasma concentrations of astroglial protein S‐100β, as well as troponin I and creatine kinase isoenzyme MB, respectively.

Catastrophic cardiovascular adverse reactions to protamine are nitric oxide/cyclic guanosine monophosphate dependent and endothelium mediated: should methylene blue be the treatment of choice?

Typ badania:

Liczba cytowań: 79

Rok: 2002

Autorzy: Fernanda Viaro, M. Dalio, P. Evora

Czasopismo: Chest

Ranking czasopisma: Q1

Główne wnioski: Methylene blue may be a novel approach to prevent and treat hemodynamic complications caused by protamine after cardiopulmonary bypass, potentially improving treatment of distributive shock.

Streszczenie: Clinical and experimental observations prove that heparin-neutralizing doses of protamine increase pulmonary artery pressures and decrease systemic BP. Protamine also increases myocardial oxygen consumption, cardiac output, and heart rate, and decreases systemic vascular resistance. These cardiovascular effects have clinical consequences that have justified studies in this area. Protamine adverse reactions usually have three different categories: systemic hypotension, anaphylactoid reactions, and catastrophic pulmonary vasoconstriction. The precise mechanism that explains protamine-mediated systemic hypotension is unknown. Four experimental protocols performed at Mayo Clinic, Rochester, MN, studied the intrinsic mechanism of protamine vasodilation. The first study reported in vitro systemic and coronary vasodilation after protamine infusion. The second in vitro study suggested that the pulmonary circulation is extensively involved in the protamine-mediated effects on endothelial function. The third study, carried out in anesthetized dogs, reported the methylene blue and nitric oxide synthase blockers neutralization of the protamine vasodilatatory effects. The fourth study suggested that protamine also causes endothelium-dependent vasodilation in heart microvessels and conductance arteries by different mechanisms including hyperpolarization. Reviewing these experimental results and our clinical experience, we suggest methylene blue as a novel approach to prevent and treat hemodynamic complications caused by the use of protamine after cardiopulmonary bypass. In the absence of prospective clinical trials, a growing body of cumulative clinical evidence suggests that methylene blue may be strongly considered as a therapeutic approach in the treatment of distributive shock.

Hydroxocobalamin Versus Methylene Blue for Treatment of Vasoplegic Shock Following Cardiopulmonary Bypass: A Systematic Review and Meta-analysis.

Typ badania: meta-analysis

Liczba cytowań: 3

Rok: 2024

Autorzy: Matthew Cadd, Ultan Watson, Thomas Kilpatrick, Ben Hardy, Laura Gallop, Alexander Gerard, Cyrille Cabaret

Czasopismo: Journal of cardiothoracic and vascular anesthesia

Ranking czasopisma: Q1

Główne wnioski: Hydroxocobalamin has a beneficial effect on hemodynamics and vasopressor requirements in vasoplegic cardiac surgery patients compared to methylene blue, but more well-powered randomized controlled trials are needed.

Streszczenie: OBJECTIVES To summarize the evidence of the hemodynamic effects and vasopressor requirements of adult cardiac surgery patients with vasoplegic shock treated with hydroxocobalamin or methylene blue. DESIGN Systematic review and meta-analysis. SETTING Multi-institutional. PARTICIPANTS Adult cardiac surgery patients with vasoplegic shock. INTERVENTIONS Administration of hydroxocobalamin or methylene blue. MEASUREMENTS AND MAIN RESULTS A total of 263 patients in four retrospective observational studies were included in a pooled analysis. There was no significant difference in the primary outcome, vasopressor requirement at 1 hour (mean difference [MD]: 0.00 mcg/kg/min norepinephrine equivalent [NEE], 95% confidence interval [CI]: -0.09 to 0.08). Hydroxocobalamin was associated with a significant improvement in mean arterial pressure at 1 hour (MD: 5.30 mmHg, 95% CI: 2.98 to 7.62), total vasopressor dose at 1 hour (MD: -0.13 mcg/kg/min NEE, 95% CI: -0.25 to -0.01), total vasopressor at 6 hours (MD: -0.15 mcg/kg/min NEE, 95% CI: -0.21 to -0.08). No differences were observed in systemic vascular resistance or mortality between groups. Three studies were deemed at moderate risk of bias and one at serious risk. CONCLUSIONS Hydroxocobalamin has been shown to have a beneficial effect on hemodynamics and vasopressor requirements in vasoplegic cardiac surgery patients compared with methylene blue, although evidence is limited, and further well-powered randomized controlled trials are required.

Methylene Blue for Vasoplegic Syndrome After Cardiac Operation: Early Administration Improves Survival.

Typ badania: non-rct observational study

Liczba cytowań: 88

Rok: 2017

Autorzy: J. Mehaffey, L. Johnston, R. Hawkins, E. Charles, Leora T. Yarboro, J. Kern, G. Ailawadi, I. Kron, R. Ghanta

Czasopismo: The Annals of thoracic surgery

Ranking czasopisma: Q1

Główne wnioski: Early administration of methylene blue improves survival and reduces the risk-adjusted rate of major adverse events in patients with vasoplegia after cardiopulmonary bypass.

Methylene Blue Pretreatment Protects Against Repeated Neonatal Isoflurane Exposure-Induced Brain Injury and Memory Loss.

Typ badania: non-rct experimental

Liczba cytowań: 6

Rok: 2024

Autorzy: Chongyun Wu, Qianting Deng, Ling Zhu, Timon Cheng-yi Liu, Rui Duan, Luodan Yang

Czasopismo: Molecular neurobiology

Ranking czasopisma: Q1

Główne wnioski: Methylene blue pretreatment effectively reduces neonatal isoflurane exposure-induced brain injury and memory loss, offering a promising approach to protect the brain against postoperative cognitive dysfunction.

Streszczenie: Perioperative neurocognitive impairment (PND) is a common medical complication in the postoperative period. General anesthesia through volatile anesthetics poses a high risk of POCD. Moreover, the developing brain is especially vulnerable to anesthesia-induced neurotoxicity. Therefore, finding a practical approach to prevent or alleviate neonatal isoflurane (ISO) exposure-induced brain injury and cognitive decline is essential for reducing medical complications following major surgery during the early postnatal period. Using a repeated neonatal ISO exposure-induced PND rat model, we investigated the effects of methylene blue (MB) pretreatment on repeated neonatal isoflurane exposure-induced brain injury and memory loss. Intraperitoneal injection of low-dose MB (1 mg/kg) was conducted three times 24 h before each ISO exposure. The Barnes maze and novel objection test were conducted to assess learning and memory. Immunofluorescence staining, F-Jade C staining, TUNEL staining, and Western blot analysis were performed to determine mitochondrial fragmentation, neuronal injury, degeneration, and apoptosis. Evans blue extravasation assay, total antioxidant capacity assay, MDA assay kit, and related inflammatory assay kits were used to test blood-brain barrier (BBB) disruption, antioxidant capacity, and neuroinflammation. Behavioral tests revealed that MB pretreatment significantly ameliorated ISO exposure-induced cognitive deficits. In addition, MB pretreatment alleviates neuronal injury, apoptosis, and degeneration. Furthermore, the BBB integrity was preserved by MB pretreatment. Additional studies revealed that ISO-induced excessive mitochondrial fragmentation, oxidative stress, and neuroinflammation were significantly attenuated by MB pretreatment in the PND rat model. Our findings suggest that MB pretreatment alleviates ISO exposure-induced brain injury and memory loss for the first time, supporting MB pretreatment as a promising approach to protect the brain against neonatal ISO exposure-induced postoperative cognitive dysfunction.

Neurometabolic mechanisms for memory enhancement and neuroprotection of methylene blue

Typ badania: literature review

Liczba cytowań: 162

Rok: 2012

Autorzy: J. Rojas, A. K. Bruchey, F. Gonzalez-Lima

Czasopismo: Progress in Neurobiology

Ranking czasopisma: Q1

Główne wnioski: Low doses of methylene blue show promise for improving memory and treating memory impairment and neurodegeneration associated with mitochondrial dysfunction.

Neuroprotective effects of methylene blue in streptozotocin-induced model of Alzheimer’s disease

Typ badania: non-rct experimental

Liczba cytowań: 6

Rok: 2023

Autorzy: E. Stelmashook, D. N. Voronkov, A. Stavrovskaya, S. Novikova, N. G. Yamshikova, A. S. Olshanskij, Anastasiya S. Guschina, M. Shedenkova, E. Genrikhs, N. Isaev

Czasopismo: Brain Research

Ranking czasopisma: Q2

Główne wnioski: Methylene blue has neuroprotective, anti-inflammatory effects, and can prevent autophagy in Alzheimer's disease models, potentially playing a role in treating neurodegenerative processes.

Customized Intranasal Hydrogel Delivering Methylene Blue Ameliorates Cognitive Dysfunction against Alzheimer's Disease

Typ badania: non-rct experimental

Liczba cytowań: 45

Rok: 2024

Autorzy: Yujing Liu, Yun Tan, Guopan Cheng, Yaqiong Ni, Aihua Xie, Xiaozhen Zhu, Chao Yin, Yi Zhang, Tongkai Chen

Czasopismo: Advanced Materials

Ranking czasopisma: Q1

Główne wnioski: A customized intranasal hydrogel delivering methylene blue effectively improves cognitive dysfunction in Alzheimer's disease mouse models by suppressing tau neuropathology, restoring mitochondrial function, and alleviating neuroinflammation.

Streszczenie: The accumulation of hyperphosphorylated tau protein aggregates is a key pathogenic event in Alzheimer's disease (AD) and induces mitochondrial dysfunction and reactive oxygen species overproduction. However, the treatment of AD remains challenging owning to the hindrance caused by the blood–brain barrier (BBB) and the complex pathology of AD. Nasal delivery represents an effective means of circumventing the BBB and delivering drugs to the brain. In this study, black phosphorus (BP) is used as a drug carrier, as well as an antioxidant, and loaded with a tau aggregation inhibitor, methylene blue (MB), to obtain BP‐MB. For intranasal (IN) delivery, a thermosensitive hydrogel is fabricated by cross‐linking carboxymethyl chitosan and aldehyde Pluronic F127 (F127‐CHO) micelles. The BP‐MB nanocomposite is incorporated into the hydrogel to obtain BP‐MB@Gel. BP‐MB@Gel could be injected intranasally, providing high nasal mucosal retention and controlled drug release. After IN administration, BP‐MB is continuously released and delivered to the brain, exerting synergistic therapeutic effects by suppressing tau neuropathology, restoring mitochondrial function, and alleviating neuroinflammation, thus inducing cognitive improvements in mouse models of AD. These findings highlight a potential strategy for brain‐targeted drug delivery in the management of the complex pathologies of AD.

Methylene Blue Improves Brain Mitochondrial ABAD Functions and Decreases Aβ in a Neuroinflammatory Alzheimer’s Disease Mouse Model

Typ badania: non-rct experimental

Liczba cytowań: 45

Rok: 2015

Autorzy: Aya Zakaria, N. Hamdi, R. Abdel-Kader

Czasopismo: Molecular Neurobiology

Ranking czasopisma: Q1

Główne wnioski: Methylene blue improves brain mitochondrial ABAD functions and reduces amyloid beta levels in Alzheimer's disease mouse models, potentially benefiting cognitive functions in Alzheimer's patients.

Streszczenie: Methylene blue (MB) phase II clinical trials reported improvements in cognitive functions of Alzheimer’s disease (AD) patients. Regarding MB mechanism of action, its antioxidant and mitochondrial protective effects have been previously described. In relation to AD, it has been recently reported that MB reduced amyloid beta (Aβ) levels in AD models. The mitochondrial enzyme amyloid-binding alcohol dehydrogenase (ABAD) has been shown to bind Aβ inducing mitochondrial dysfunction, providing a direct relation between Aβ toxicity and mitochondrial dysfunction occurring in AD. Since it has been reported that inhibiting ABAD protects mitochondrial functions and prevents Aβ-induced toxicity, the aim of the current study was to investigate if the protective effects of MB could be associated with an effect on ABAD levels and functions. The current study shows that MB is able to enhance cell viability, reduce both reactive oxygen species levels and importantly Aβ oligomers in a lipopolysaccharide (LPS) mouse model. Interestingly, ABAD levels were increased in the brains of the LPS mouse model and MB treatment was able to reduce its levels. Given that regulation of the estradiol level is a well-established function of ABAD, brain estradiol level was compared in LPS mouse model and in MB-treated mice. The results of the current study show that MB treatment is able to improve significantly the LPS-induced decrease of estradiol levels in mice brains, indicating its ability to modulate both levels and function of ABAD. These results give a new insight to possible mechanisms of MB in AD.

Methylene Blue Preserves Cytochrome Oxidase Activity and Prevents Neurodegeneration and Memory Impairment in Rats With Chronic Cerebral Hypoperfusion

Typ badania: non-rct experimental

Liczba cytowań: 11

Rok: 2020

Autorzy: A. Auchter, Douglas W. Barrett, M. Monfils, F. Gonzalez-Lima

Czasopismo: Frontiers in Cellular Neuroscience

Ranking czasopisma: Q2

Główne wnioski: Methylene blue prevents neurodegeneration and memory impairment in rats with chronic cerebral hypoperfusion by preserving cytochrome oxidase activity and strengthening interregional correlations.

Streszczenie: Chronic cerebral hypoperfusion in neurocognitive disorders diminishes cytochrome oxidase activity leading to neurodegenerative effects and impairment of learning and memory. Methylene blue at low doses stimulates cytochrome oxidase activity and may thus counteract the adverse effects of cerebral hypoperfusion. However, the effects of methylene blue on cytochrome oxidase activity during chronic cerebral hypoperfusion have not been described before. To test this hypothesis, rats underwent bilateral carotid artery occlusion or sham surgery, received daily 4 mg/kg methylene blue or saline injections, and learned a visual water task. Brain mapping of cytochrome oxidase activity was done by quantitative enzyme histochemistry. Permanent carotid occlusion for 1 month resulted in decreased cytochrome oxidase activity in visual cortex, prefrontal cortex, perirhinal cortex, hippocampus and amygdala, and weaker interregional correlation of cytochrome oxidase activity between these regions. Methylene blue preserved cytochrome oxidase activity in regions affected by carotid occlusion and strengthened their interregional correlations of cytochrome oxidase activity, which prevented neurodegenerative effects and facilitated task-specific learning and memory. Brain-behavior correlations revealed positive correlations between performance and brain regions in which cytochrome oxidase activity was preserved by methylene blue. These results are the first to demonstrate that methylene blue prevents neurodegeneration and memory impairment by preserving cytochrome oxidase activity and interregional correlation of cytochrome oxidase activity in brain regions susceptible to chronic hypoperfusion. This demonstration provides further support for the hypothesis that lower cerebral blood flow results in an Alzheimer’s-like syndrome and that stimulating cytochrome oxidase activity with low-dose methylene blue is neuroprotective.

Methylene Blue Reduces Aβ Levels and Rescues Early Cognitive Deficit by Increasing Proteasome Activity

Typ badania: non-rct experimental

Liczba cytowań: 209

Rok: 2011

Autorzy: David X. Medina, A. Caccamo, S. Oddo

Czasopismo: Brain Pathology

Ranking czasopisma: Q1

Główne wnioski: Methylene blue treatment reduces A levels and improves cognitive deficits in Alzheimer's disease mice by increasing proteasome activity.

Streszczenie: Promising results have emerged from a phase II clinical trial testing methylene blue (MB) as a potential therapeutic for Alzheimer disease (AD), where improvements in cognitive functions of AD patients after 6 months of MB administration have been reported. Despite these reports, no preclinical testing of MB in mammals has been published, and thus its mechanism of action in relation to AD pathology remains unknown. In order to elucidate the effects of MB on AD pathology and to determine its mechanism of action, we used a mouse model (3xTg‐AD) that develops age‐dependent accumulation of Aβ and tau and cognitive decline. Here, we report that chronic dietary MB treatment reduces Aβ levels and improves learning and memory deficits in the 3xTg‐AD mice. The mechanisms underlying the effects of MB on Aβ pathology appears to be mediated by an increase in Aβ clearance as we show that MB increases the chymotrypsin‐ and trypsin‐like activities of the proteasome in the brain. To our knowledge, this is the first report showing that MB increases proteasome function and ameliorates AD‐like pathology in vivo. Overall, the data presented here support the use of MB for the treatment of AD and offer a possible mechanism of action.

Methylene blue exerts a neuroprotective effect against traumatic brain injury by promoting autophagy and inhibiting microglial activation

Typ badania: rct

Liczba cytowań: 49

Rok: 2015

Autorzy: Mingfei Zhao, Feng Liang, Hangdi Xu, Wei Yan, Jianmin Zhang

Czasopismo: Molecular Medicine Reports

Ranking czasopisma: Q2

Główne wnioski: Methylene blue protects against traumatic brain injury by increasing autophagy, decreasing brain edema, and inhibiting microglial activation.

Streszczenie: Traumatic brain injury (TBI) leads to permanent neurological impairment, and methylene blue (MB) exerts central nervous system neuroprotective effects. However, only one previous study has investigated the effectiveness of MB in a controlled cortical impact injury model of TBI. In addition, the specific mechanisms underlying the effect of MB against TBI remain to be elucidated. Therefore, the present study investigated the neuroprotective effect of MB on TBI and the possible mechanisms involved. In a mouse model of TBI, the animals were randomly divided into sham, vehicle (normal saline) or MB groups. The treatment time-points were 24 and 72 h (acute phase of TBI), and 14 days (chronic phase of TBI) post-TBI. The brain water content (BWC), and levels of neuronal death, and autophagy were determined during the acute phase, and neurological deficit, injury volume and microglial activation were assessed at all time-points. The injured hemisphere BWC was significantly increased 24 h post-TBI, and this was attenuated following treatment with MB. There was a significantly higher number of surviving neurons in the MB group, compared with the Vehicle group at 24 and 72 h post-TBI. In the acute phase, the MB-treated animals exhibited significantly upregulated expression of Beclin 1 and increased LC3-II to LC3-I ratios, compared with the vehicle group, indicating an increased rate of autophagy. Neurological functional deficits, measured using the modified neurological severity score, were significantly lower in the acute phase in the MB-treated animals and cerebral lesion volumes in the MB-treated animals were significantly lower, compared with the other groups at all time-points. Microglia were activated 24 h after TBI, peaked at 72 h and persisted until 14 days after TBI. Although the number of Iba-1-positive cells in the vehicle and MB groups 24 h post-TBI were not significantly different, marked microglial inhibition was observed in the MB group 72 h and 14 days after-TBI. These results indicated that MB exerts a neuroprotective effect by increasing autophagy, decreasing brain edema and inhibiting microglial activation.

Mitochondria as a target for neuroprotection: role of methylene blue and photobiomodulation

Typ badania: literature review

Liczba cytowań: 97

Rok: 2020

Autorzy: Luodan Yang, Hannah A Youngblood, Chongyun Wu, Quanguang Zhang

Czasopismo: Translational Neurodegeneration

Ranking czasopisma: Q1

Główne wnioski: Methylene blue and photobiomodulation show potential in improving brain mitochondrial function and reducing inflammation and oxidative stress in brain diseases.

Streszczenie: 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.

Neuroprotective Effects of Methylene Blue In Vivo and In Vitro

Typ badania: non-rct experimental

Liczba cytowań: 18

Rok: 2019

Autorzy: E. Stelmashook, E. E. Genrikhs, E. Mukhaleva, M. R. Kapkaeva, R. Kondratenko, V. Skrebitsky, N. Isaev

Czasopismo: Bulletin of Experimental Biology and Medicine

Ranking czasopisma: Q3

Główne wnioski: Methylene blue injections can effectively reduce functional disorders in affected extremities after traumatic brain injury and reduce neuron death caused by paraquat or zinc ions.

Streszczenie: Focal unilateral traumatic brain injury in the sensorimotor cortical region disturbed the functions of contralateral limbs controlled by the damaged hemisphere. A single intravenous injection of methylene blue (1 mg/kg) immediately before or 30 min after the injury significantly weakened functional disorders in the affected extremities. In vitro experiments showed that methylene blue effectively reduced death of cultured neurons provoked by paraquat or zinc ions producing the toxic effects on mitochondrias.

Effect of Methylene Blue on White Matter Injury after Ischemic Stroke

Typ badania: non-rct experimental

Liczba cytowań: 7

Rok: 2021

Autorzy: Quancheng Cheng, Xuhao Chen, Jiayi Ma, Xingyuan Jiang, Jiahui Chen, Mengqin Zhang, Yejun Wu, Weiguang Zhang, Chunhua Chen

Czasopismo: Oxidative Medicine and Cellular Longevity

Ranking czasopisma: Q1

Główne wnioski: Methylene blue administration after ischemic stroke surgery reduces infarct volume, improves neurological deficits, and reduces white matter injury through myelin basic protein (BMP) protection.

Streszczenie: Methylene blue, the FDA-grandfathered drug was proved to be neuroprotective in ischemic stroke in rat. However, the mechanism of the protective effect was unknown. In this study, we used different animal models to investigate the effect of MB administration given within and beyond the therapeutic time window on behavioral deficits and infarct volume and related mechanism about the white matter protection. Middle cerebral artery occlusion and reperfusion (MCAO) and photothrombotic middle cerebral artery occlusion (PT-MCAO) models were used. Behavioral deficits and infarct volume were measured by foot fault test, Garcia neurological score, and TTC staining. Black gold staining and western blot were used to evaluate the brain white matter injury. We found that intraperitoneal administration of MB immediately or 24 h after the MCAO or PT-MCAO surgery reduced infarct volume, improved the neurological deficits, and reduced the white matter injury via myelin basic protein (BMP) protection. These findings suggested that MB relieved the white matter injury besides neuronal protection and has potential therapeutic effects on ischemic stroke.

Methylene blue modulates functional connectivity in the human brain

Typ badania: rct

Liczba cytowań: 11

Rok: 2017

Autorzy: P. Rodriguez, A. P. Singh, Kristen E. Malloy, W. Zhou, Douglas W. Barrett, C. Franklin, W. Altmeyer, J. Gutiérrez, Jinqi Li, B. Heyl, J. Lancaster, F. Gonzalez-Lima, T. Duong

Czasopismo: Brain Imaging and Behavior

Ranking czasopisma: Q1

Główne wnioski: Low-dose methylene blue can modulate task-related and resting-state neural networks in the human brain, supporting further investigations in healthy and disease populations.

Streszczenie: Methylene blue USP (MB) is a FDA-grandfathered drug used in clinics to treat methemoglobinemia, carbon monoxide poisoning and cyanide poisoning that has been shown to increase fMRI evoked blood oxygenation level dependent (BOLD) response in rodents. Low dose MB also has memory enhancing effect in rodents and humans. However, the neural correlates of the effects of MB in the human brain are unknown. We tested the hypothesis that a single low oral dose of MB modulates the functional connectivity of neural networks in healthy adults. Task-based and task-free fMRI were performed before and one hour after MB or placebo administration utilizing a randomized, double-blinded, placebo-controlled design. MB administration was associated with a reduction in cerebral blood flow in a task-related network during a visuomotor task, and with stronger resting-state functional connectivity in multiple regions linking perception and memory functions. These findings demonstrate for the first time that low-dose MB can modulate task-related and resting-state neural networks in the human brain. These neuroimaging findings support further investigations in healthy and disease populations.

The Delayed Neuroprotective Effect of Methylene Blue in Experimental Rat Brain Trauma

Typ badania: non-rct experimental

Liczba cytowań: 6

Rok: 2020

Autorzy: E. Genrikhs, E. Stelmashook, D. N. Voronkov, S. Novikova, O. P. Alexandrova, M. Gulyaev, N. Isaev

Czasopismo: Antioxidants

Ranking czasopisma: Q1

Główne wnioski: Methylene blue injections after traumatic brain injury can preserve limb function and promote autophagy, with a therapeutic effect lasting up to 180 days.

Streszczenie: After traumatic brain injury (TBI), an increase in dysfunction of the limbs contralateral to injury focus was observed. Using different behavioral tests, we found that a single intravenous injection of methylene blue (MB, 1 mg/kg) 30 min after the injury reduced the impairment of the motor functions of the limbs from 7 to 120 days after TBI. Administration of methylene blue 30 min after the injury and then monthly (six injections in total) was the most effective both in terms of preservation of limb function and duration of therapeutic action. This therapeutic effect was clearly manifested from the seventh day and continued until the end of the experiment—by the 180th day after TBI. MB is known to possess antioxidant properties; it has a protective effect against TBI by promoting autophagy and minimizing lesion volume in the first two weeks after TBI. Studies of the brains on the 180th day after TBI demonstrated that the monthly treatment of animals with MB statistically significantly prevented an increase in the density of microglial cells in the ipsilateral hemisphere and a decrease in the thickness of the corpus callosum in the contralateral hemisphere in comparison with untreated animals. However, on the 180th day after TBI, the magnetic resonance imaging scan of the animal brains did not show a significant reduction in the volume of the lesion in MB-treated animals. These findings are important for understanding the development of the long-term effects of TBI and expand the required therapeutic window for targeted neuroprotective interventions.

Neuroprotective and Functional Improvement Effects of Methylene Blue in Global Cerebral Ischemia

Typ badania: non-rct experimental

Liczba cytowań: 54

Rok: 2016

Autorzy: Qing Lu, Donovan Tucker, Yan Dong, Ningjun Zhao, Quanguang Zhang

Czasopismo: Molecular Neurobiology

Ranking czasopisma: Q1

Główne wnioski: Methylene blue treatment significantly improves neuronal survival and cognitive deficits in transient global cerebral ischemia, suggesting potential therapeutic applications.

Streszczenie: Transient global cerebral ischemia (GCI) causes delayed neuronal cell death in the vulnerable hippocampus CA1 subfield, as well as behavioral deficits. Ischemia reperfusion (I/R) produces excessive reactive oxygen species and plays a key role in brain injury. The mitochondrial electron respiratory chain is the main cellular source of free radical generation, and dysfunction of mitochondria has a significant impact on the neuronal cell death in ischemic brain. The aim of the present study is to investigate the potential beneficial effects of methylene blue (MB) in a four-vessel occlusion (4VO) GCI model on adult male rats. MB was delivered at a dose of 0.5 mg/kg/day for 7 days, through a mini-pump implanted subcutaneously after GCI. We first found that MB significantly improved ischemic neuronal survival in the hippocampal CA1 region as measured by cresyl violet staining as well as NeuN staining. We also found that MB has the ability to rescue ischemia-induced decreases of cytochrome c oxidase activity and ATP generation in the CA1 region following I/R. Further analysis with labeling of MitoTracker® Red revealed that the depolarization of mitochondrial membrane potential (MMP) was markedly attenuated following MB treatment. In addition, the induction of caspase-3, caspase-8, and caspase-9 activities and the increased numbers of TUNEL-positive cells of the CA1 region were significantly reduced by MB application. Correspondingly, Barnes maze tests showed that the deterioration of spatial learning and memory performance following GCI was significantly improved in the MB-treatment group compared to the ischemic control group. In summary, our study suggests that MB may be a promising therapeutic agent targeting neuronal cell death and cognitive deficits following transient global cerebral ischemia.

Methylene blue is neuroprotective against mild traumatic brain injury.

Typ badania: rct

Liczba cytowań: 72

Rok: 2014

Autorzy: Lora Talley Watts, Justin A. Long, Jonathan Chemello, Samantha Van Koughnet, Angelica Fernandez, Shiliang Huang, Q. Shen, T. Duong

Czasopismo: Journal of neurotrauma

Ranking czasopisma: Q1

Główne wnioski: Methylene blue treatment minimizes lesion volume, behavioral deficits, and neuronal degeneration after mild traumatic brain injury in rats.

Streszczenie: Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Methylene blue (MB) has known energy-enhancing and antioxidant properties. This study tested the hypothesis that MB treatment reduces lesion volume and behavioral deficits in a rat model of mild TBI. In a randomized double-blinded design, animals received either MB (n=5) or vehicle (n=6) after TBI. Studies were performed on 0, 1, 2, 7, and 14 days following an impact to the primary forelimb somatosensory cortex. MRI lesion was not apparent 1 h after TBI, became apparent 3 h after TBI, and peaked at 2 days for both groups. The MB-treated animals showed significantly smaller MRI lesion volume than the vehicle-treated animals at all time points studied. The MB-treated animals exhibited significantly improved scores on forelimb placement asymmetry and foot fault tests than did the vehicle-treated animals at all time points studied. Smaller numbers of dark-stained Nissl cells and Fluoro-Jade(®) positive cells were observed in the MB-treated group than in vehicle-treated animals 14 days post-TBI. In conclusion, MB treatment minimized lesion volume, behavioral deficits, and neuronal degeneration following mild TBI. MB is already approved by the United States Food and Drug Administration (FDA) to treat a number of indications, likely expediting future clinical trials in TBI.

Multimodal Randomized Functional MR Imaging of the Effects of Methylene Blue in the Human Brain.

Typ badania: rct

Liczba cytowań: 30

Rok: 2016

Autorzy: P. Rodriguez, W. Zhou, Douglas W. Barrett, W. Altmeyer, J. Gutiérrez, Jinqi Li, J. Lancaster, F. Gonzalez-Lima, T. Duong

Czasopismo: Radiology

Ranking czasopisma: Q1

Główne wnioski: Low-dose methylene blue can enhance sustained attention, short-term memory tasks, and memory retrieval in the healthy human brain.

Streszczenie: Purpose To investigate the sustained-attention and memory-enhancing neural correlates of the oral administration of methylene blue in the healthy human brain. Materials and Methods The institutional review board approved this prospective, HIPAA-compliant, randomized, double-blinded, placebo-controlled clinical trial, and all patients provided informed consent. Twenty-six subjects (age range, 22-62 years) were enrolled. Functional magnetic resonance (MR) imaging was performed with a psychomotor vigilance task (sustained attention) and delayed match-to-sample tasks (short-term memory) before and 1 hour after administration of low-dose methylene blue or a placebo. Cerebrovascular reactivity effects were also measured with the carbon dioxide challenge, in which a 2 × 2 repeated-measures analysis of variance was performed with a drug (methylene blue vs placebo) and time (before vs after administration of the drug) as factors to assess drug × time between group interactions. Multiple comparison correction was applied, with cluster-corrected P < .05 indicating a significant difference. Results Administration of methylene blue increased response in the bilateral insular cortex during a psychomotor vigilance task (Z = 2.9-3.4, P = .01-.008) and functional MR imaging response during a short-term memory task involving the prefrontal, parietal, and occipital cortex (Z = 2.9-4.2, P = .03-.0003). Methylene blue was also associated with a 7% increase in correct responses during memory retrieval (P = .01). Conclusion Low-dose methylene blue can increase functional MR imaging activity during sustained attention and short-term memory tasks and enhance memory retrieval. © RSNA, 2016 Online supplemental material is available for this article.