Stimulation of respiration by methylene blue in rat liver mitochondria

Visarius, Theresa; Stucki, Jörg W.; Lauterburg, Bernhard H.

doi:10.1016/s0014-5793(97)00767-9

Cited by 89 publications

(66 citation statements)

References 27 publications

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“…Cytochrome oxidase is the terminal enzyme of the electron transport chain, and is tightly coupled to neuronal metabolism and ATP production (Wong-Riley 1989). Electrons can be donated from reduced MB to enter the electron transport chain, resulting in enzyme induction of cytochrome oxidase (Scott and Hunter Jr., 1966;Visarius et al 1997). By increasing cytochrome oxidase activity after three days of administration, MB can enhance the amount of ATP available in brain cells in order to improve their overall mnemonic capacity during discrimination learning.…”

Section: Discussionmentioning

confidence: 99%

The brain metabolic enhancer methylene blue improves discrimination learning in rats

Wrubel

Riha

Maldonado

et al. 2007

Pharmacology Biochemistry and Behavior

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Methylene blue (MB) is a metabolic enhancer that has been demonstrated to improve memory retention when given post-training in low doses in a variety of tasks in rats, including inhibitory avoidance, spatial memory (in both normal and metabolically-impaired subjects), object recognition, and habituation to a familiar environment. MB has been also shown to improve memory retention of extinction of fear conditioning in the rat. No experiments have been conducted to determine the effects of MB on more complex learning such as in discrimination tasks that require repeated days of training. This study examined the effects of daily MB on spatial discrimination memory in a baited holeboard maze. Following three days of discrimination training, subjects treated daily with posttraining MB (1 mg/kg) reliably discriminated between rewarded (baited) and non-rewarded (unbaited) trials as indicated by a greater number of correct responses on rewarded trials than nonrewarded trials during the last three days of discrimination training. No such discrimination effects were observed in the saline-treated control group during the same training period. To determine whether the memory-enhancing effects of MB are associated with an increase in metabolic energy capacity in the brain, cytochrome c oxidation was measured in brains from rats treated with 1 mg/ kg MB or saline for three days. The number of daily injections was chosen based on the behavioral data which revealed group differences three days after the beginning of MB treatment. Brain cytochrome oxidase activity in the MB-treated group was approximately 70% higher than in salinetreated rats. The findings suggest that repeated post-training MB may improve memory consolidation between days of learning by an induction in the enzyme cytochrome oxidase, leading to increased metabolic capacity in brain regions requiring more energy during discrimination learning.

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Section: Discussionmentioning

confidence: 99%

The brain metabolic enhancer methylene blue improves discrimination learning in rats

Wrubel

Riha

Maldonado

et al. 2007

Pharmacology Biochemistry and Behavior

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“…The metabolic effect of low-dose MB on memory retention may be due to increased brain oxygen consumption because MB provides an alternate route of electron flow to oxygen (Visarius et al 1997). This increase in brain oxidative metabolism is reflected by the overall increase in brain cytochrome oxidase activity observed in MB-treated animals.…”

Section: Mb Increases Overall Brain Oxidative Metabolismmentioning

confidence: 99%

“…MB is a nonneuroleptic phenothiazine previously used safely in humans as a neuroprotective metabolic agent for treatment of dementia, depression, and drug-induced encephalopathy (Naylor 1986;Wainwright and Crossley 2002). MB serves as a redox compound that at low doses (1-5 mg/kg) improves mitochondrial respiration (Visarius et al 1997) and prevents free radical damage (Salaris et al 1991). Low-dose MB acts on the electron transport chain, and it increases cellular oxygen consumption by a well-known mechanism of action that involves accepting electrons from molecular oxygen (Lindahl and Oberg 1961).…”

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confidence: 99%

Extinction Memory Improvement by the Metabolic Enhancer Methylene Blue

González-Lima¹,

Bruchey²

2004

Learn. Mem.

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We investigated whether postextinction administration of methylene blue (MB) could enhance retention of an extinguished conditioned response. MB is a redox compound that at low doses elevates cytochrome oxidase activity, thereby improving brain energy production. Saline or MB (4 mg/kg intraperitoneally) were administered to rats for 5 d following extinction training of tone-footshock conditioning. Postextinction freezing was lower in rats receiving MB compared with saline, suggesting that MB improved retention of the extinction memory. The MB effect was specific to tone-evoked freezing because there were no differences in pretone freezing. Control subjects similarly injected with MB showed no evidence of nonspecific effects on measures of motor activity and fearfulness. MB-treated rats exhibited both greater retention of extinction and greater overall brain metabolic activity. Rats with higher retention of extinction also showed a relative increase in cytochrome oxidase activity in prefrontal cortical regions, especially anterior infralimbic cortex, dorsal and medial frontal cortex, and lateral orbital cortex. These regional metabolic increases were also correlated to the behavioral freezing index used to assess retention of extinction. It was concluded that MB administered postextinction could enhance retention of extinction memory through an increase in brain cytochrome oxidase activity.

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“…Phenothiazinium redox dyes have diverse applications as biological redox indicators, vital stains and diagnostic dyes [17], modulators of mitochondrial respiration [18], infusional antidotes against cyanide poisoning and methemoglobinemia [19], antiinfective agents [20,21], and photosensitizers [22][23][24], but their therapeutic potential and mechanism of action as anti-cancer redox chemotherapeutics are largely unexplored [23,25]. Compounds containing the 3,7-diaminophenothiazinium redox pharmacophore including thionine (T, 3,7-diamino-phenothiazinium acetate), methylene blue (MB, 3,7-bis (dimethylamino)-phenothiazinium chloride), and toluidine blue O (TB, 2-methyl-3-amino-7-dimethylamino-phenothiazinium chloride) are two-electron redox systems with standard reduction potentials [e.g.…”

Section: Introductionmentioning

confidence: 99%

NQO1-activated phenothiazinium redox cyclers for the targeted bioreductive induction of cancer cell apoptosis

Wondrak

2007

Free Radical Biology and Medicine

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Altered redox signaling and regulation in cancer cells represent a chemical vulnerability that can be targeted by selective chemotherapeutic intervention. Here, we demonstrate that 3,7-diaminophenothiazinium-based redoxcyclers (PRC) induce selective cancer cell apoptosis by NAD (P)H:quinone oxidoreductase (NQO1)-dependent bioreductive generation of cellular oxidative stress. Using PRC lead compounds including toluidine blue against human metastatic G361 melanoma cells, apoptosis occurred with phosphatidylserine-externalization, loss of mitochondrial transmembrane potential, cytochrome C release, caspase-3 activation, and massive ROS production. Consistent with reductive activation and subsequent redoxcycling as the mechanism of PRC cytotoxicity, co-incubation with catalase achieved cell protection, whereas reductive antioxidants enhanced PRC-cytotoxicity. Unexpectedly, human A375 melanoma cells were resistant to PRCinduced apoptosis, and PRC-sensitive G361 cells were protected by preincubation with the NQO1-inhibitor dicoumarol. Indeed, NQO1 specific enzymatic activity was nine fold higher in G361 than in A375 cells. The critical role of NQO1 in PRC-bioactivation and cytotoxicity was confirmed, when NQO1-transfected breast cancer cells (MCF7-DT15) stably overexpressing active NQO1 displayed strongly enhanced PRC-sensitivity as compared to vector-control transfected cells with base line NQO1 activity. Based on the known overexpression of NQO1 in various tumors these findings suggest the feasibility of developing PRC lead compounds into tumor-selective bioreductive chemotherapeutics.

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Stimulation of respiration by methylene blue in rat liver mitochondria

Cited by 89 publications

References 27 publications

The brain metabolic enhancer methylene blue improves discrimination learning in rats

The brain metabolic enhancer methylene blue improves discrimination learning in rats

Extinction Memory Improvement by the Metabolic Enhancer Methylene Blue

NQO1-activated phenothiazinium redox cyclers for the targeted bioreductive induction of cancer cell apoptosis

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