Methylene blue competes with paraquat for reduction by flavo-enzymes resulting in decreased superoxide production in the presence of heme proteins

Kelner, Michael J.; Bagnell, Richard; Hale, Braden; Alexander, Natalie

doi:10.1016/0003-9861(88)90393-1

Cited by 72 publications

(52 citation statements)

References 26 publications

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“…Several NAD(P)H-dependent dehydrogenases also reduce MB to form the colorless leucomethylene blue (MBH 2 ). MBH 2 can be reoxidized to MB by O 2 in the absence of suitable electron acceptors such as cytochrome c [129] or other hemeproteins [130]. MB is soluble in both water and organic solvents; the lipid solubility of MBH 2 is higher than that of MB.…”

Section: Properties Of Methylene Bluementioning

confidence: 99%

“…MB has been proposed to act by inhibiting the NO-activating soluble guanylate cyclase (sGC) [150] (though the basal activity of sGC is not affected); inhibiting nitric oxide synthase (NOS) [126]; inhibiting MAO [149]; and acting as an antioxidant precursor [130,151]. The effects of MB were measured at concentrations greater than 10 µM.…”

Section: Proposed Mechanisms Of Actions Of Methylene Blue In Current mentioning

confidence: 99%

“…Although numerous NAD(P)H-dependent enzymes can reduce MB to MBH 2 , cytochrome c in the mitochondria and methemoglobin (in the red blood cells) are the only heme proteins reported to reoxidize MBH 2 to MB [129,130]. Cytochrome c is an electron carrier from complex III (the natural enzyme that reduces cytochrome c) to complex IV (the natural enzyme that oxidizes cytochrome c).…”

Section: Proposed Mechanisms Of Actions Of Methylene Blue In Current mentioning

confidence: 99%

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Protective Role of Methylene Blue in Alzheimer's Disease via Mitochondria and Cytochrome c Oxidase

Atamna

Kumar

2010

JAD

120

100

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Abstract. The key cytopathologies in the brains of Alzheimer's disease (AD) patients include mitochondrial dysfunction and energy hypometabolism, which are likely caused by the accumulation of toxic species of amyloid-β (Aβ) peptides. This review discusses two potential approaches to delay the onset of AD. The first approach is use of diaminophenothiazines (e.g., methylene blue; MB) to prevent mitochondrial dysfunction and to attenuate energy hypometabolism. We have shown that MB increases heme synthesis, cytochrome c oxidase (complex IV), and mitochondrial respiration, which are impaired in AD brains. Consistently, MB is one of the most effective agents to delay senescence in normal human cells. A key action of MB appears to be enhancing mitochondrial function, which is achieved at nM concentrations. We propose that the cycling of MB between the reduced leucomethylene blue (MBH2) and the oxidized (MB) forms may explain, in part, the mitochondria-protecting activities of MB. The second approach is use of naturally occurring osmolytes to prevent the formation of toxic forms of Aβ. Osmolytes (e.g., taurine, carnosine) are brain metabolites typically accumulated in tissues at relatively high concentrations following stress conditions. Osmolytes enhance thermodynamic stability of proteins by stabilizing natively-folded protein conformation, thus preventing aggregation, without perturbing other cellular processes. Experimental evidence suggests that the level of carnosine is significantly lower in AD patients. Osmolytes may inhibit the formation of Aβ species in vivo, thus preventing the formation of soluble oligomers. Osmolytes are efficient antioxidants that may also increase neural resistance to Aβ. The potential significance of combining MB and osmolytes to treat AD are discussed.

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Section: Properties Of Methylene Bluementioning

confidence: 99%

Section: Proposed Mechanisms Of Actions Of Methylene Blue In Current mentioning

confidence: 99%

Section: Proposed Mechanisms Of Actions Of Methylene Blue In Current mentioning

confidence: 99%

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Protective Role of Methylene Blue in Alzheimer's Disease via Mitochondria and Cytochrome c Oxidase

Atamna

Kumar

2010

JAD

120

100

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“…For example, MB inhibits sGC, attenuating the NO-mediated increase in cGMP levels (11,12,15). It can also inhibit other iron-containing enzymes such as NOS, acting as a direct NOS inhibitor (16), or directly antagonize NO through the generation of superoxide anions derived from its oxidative metabolism (17).…”

mentioning

confidence: 99%

Anxiolytic effect of methylene blue microinjected into the dorsal periaqueductal gray matter

de-Oliveira

Guimarães

1999

Braz J Med Biol Res

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The dorsal periaqueductal gray (DPAG) has been implicated in the behavioral and autonomic expression of defensive reactions. Several results suggest that, along with GABA, glutamate and serotonin, nitric oxide (NO) may play a role in defense reactions mediated by this region. To further investigate this possibility we microinjected methylene blue (MB; 10, 30 or 100 nmol/0.5 µl) into the DPAG of rats submitted to the elevated plus-maze test, an animal model of anxiety. MB has been used as an inhibitor of soluble guanylate cyclase (sGC) to demonstrate cGMP-mediated processes, and there is evidence that NO may exert its biological effects by binding to the heme part of guanylate cyclase, causing an increase in cGMP levels. The results showed that MB (30 nmol) significantly increased the percent of time spent in the open arms (saline = 11.57 ± 1.54, MB = 18.5 ± 2.45, P<0.05) and tended to do the same with the percentage of open arm entries (saline = 25.8 ± 1.97, MB = 33.77 ± 3.07, P<0.10), but did not change the number of enclosed arm entries. The dose-response curve, however, had an inverted U shape. These results indicate that MB, within a limited dose range, has anxiolytic properties when microinjected into the DPAG.

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“…Lung injury is accompanied by biochemical and ultrastructural changes of the pulmonary capillary endothelium and damage to the alveolar epithelium (Roth et al 1979;Dearden et al 1982;Bus & Gibson 1984). Paraquat is reduced to the paraquat radical by flavoenzymes, such as NADPH-cytochrome P450 reductase (Bus et al 1974;Frank et al 1987;Hara et al 1991), xanthine oxidase (Winterbourn 1981;Kelner et al 1988), and mitochondrial NADH-quinone oxidoreductase (Shimada et al 1998), to generate superoxide. Redox cycling of paraquat results in producing other reactive oxygen species that are highly reactive to cellular macromolecules and/ or oxidation of reducing equivalents, leading to oxidative stress (Bus & Gibson 1984).…”

mentioning

confidence: 99%

Paraquat‐Induced Membrane Dysfunction in Pulmonary Microvascular Endothelial Cells

Tsukamoto

Tampo

Sawada

et al. 2000

Pharmacology & Toxicology

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Membrane dysfunction monitored by lactate dehydrogenase release from cultured pulmonary microvascular endothelial cells of pigs, which were exposed to paraquat at different concentrations (0.1-2 mM), was examined. Paraquat caused a time-dependent increase in lactate dehydrogenase release. Lactate dehydrogenase releases after 72 hr, 32, 58, and 84% by 0.1, 0.5, and 2 mM paraquat, respectively, were well correlated with cell viability measured by cell adherence. In contrast, reductions of two tetrazolium compounds were depleted profoundly by 72 hr after exposure to 0.5 mM paraquat, suggesting depletion of intracellular reductive substances. Extracellular hydrogen peroxide began to significantly increase 56 hr or 32 hr after exposure to 0.5 mM or 1.5 mM paraquat, respectively, preceding the initial increase of lactate dehydrogenase release (64 hr by 0.5 mM or 48 hr by 1.5 mM). Lactate dehydrogenase release 72 hr after exposure to 0.5 mM paraquat was prevented strongly by catalase (1000 units/ml), but weakly by superoxide dismutase (1000 units/ml). These enzymes failed to restore the reduced acid phosphatase activity. Also, 0.1 mM desferal or a,aø-dipyridyl protected lactate dehydrogenase release. Similarly, 1 mM thiourea or dimethylthiourea, and 0.5 mM a-tocopherol or trolox, were effective, but diethylenetriaminepentaacetic acid (0.1 mM) and probucol (5 or 10 mM) were ineffective. Exposure of 0.5 or 1.5 mM paraquat suppressed levels of lipid peroxidation. These results indicate that membrane dysfunction by paraquat is ascribed to an iron-catalyzed reaction of extracellularly increased hydrogen peroxide. A deleterious species for the membrane dysfunction is discussed.

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Methylene blue competes with paraquat for reduction by flavo-enzymes resulting in decreased superoxide production in the presence of heme proteins

Cited by 72 publications

References 26 publications

Protective Role of Methylene Blue in Alzheimer's Disease via Mitochondria and Cytochrome c Oxidase

Protective Role of Methylene Blue in Alzheimer's Disease via Mitochondria and Cytochrome c Oxidase

Anxiolytic effect of methylene blue microinjected into the dorsal periaqueductal gray matter

Paraquat‐Induced Membrane Dysfunction in Pulmonary Microvascular Endothelial Cells

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