Methylene blue restores spatial memory retention impaired by an inhibitor of cytochrome oxidase in rats

Callaway, Narriman Lee; Riha, Penny D.; Wrubel, Kathryn M.; McCollum, David; González-Lima, Francisco

doi:10.1016/s0304-3940(02)00827-3

Cited by 76 publications

(63 citation statements)

References 18 publications

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“…The results from the biochemical brain study indicated that repeated MB administration enhanced cytochrome oxidase activity very effectively, a finding that supports previous studies indicating that MB appears to work as a brain metabolic enhancer by increasing cytochrome oxidase activity (Callaway et al 2002(Callaway et al ,2004Gonzalez-Lima and Bruchey, 2004). Cytochrome oxidase is the terminal enzyme of the electron transport chain, and is tightly coupled to neuronal metabolism and ATP production (Wong-Riley 1989).…”

Section: Discussionsupporting

confidence: 84%

“…These results suggested that MB could facilitate the memory consolidation occurring in the brain following a learning session. Independent studies in our laboratory have supported this interpretation by showing that post-training MB increases memory retention in appetitive, aversive and spatial learning tasks, such as in object recognition, between-days habituation to a familiar environment, and spatial memory retention and reversal learning in the baited holeboard maze (Callaway et al 2002(Callaway et al ,2004Riha et al 2005). also found that memory retention of extinction of Pavlovian fear conditioning was enhanced with post-extinction administration of MB, and that this effect was related to an increase in brain cytochrome oxidase activity.…”

Section: Introductionmentioning

confidence: 80%

“…Methylene blue (MB) is a brain metabolic enhancer that has been demonstrated to improve memory retention when given post-training in low doses in a variety of simple appetitive and aversive learning tasks in rats (Callaway et al 2002(Callaway et al ,2004Gonzalez-Lima and Bruchey, 2004;Martinez Jr et al 1978;Riha et al 2005). The present results indicate that MB could also facilitate more complex learning such as in discrimination tasks that require repeated days of training.…”

Section: Discussionmentioning

confidence: 99%

“…The goal of the first experiment was to investigate the memory retention effects of daily 1 mg/kg MB on a discrimination learning task in the holeboard maze, using an appetitive spatial memory task that requires repeated days of training. Since previous studies demonstrated an improvement in spatial memory retention in the holeboard maze food search task following MB administration (Callaway et al 2002(Callaway et al ,2004, we were interested in further investigating its effects on the more demanding discrimination learning of rewarded versus non-rewarded trials in the maze.…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionsupporting

confidence: 84%

Section: Introductionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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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“…For example, posttraining MB administration improves memory retention tested 24 h after inhibitory avoidance training (Martinez Jr. et al 1978). Corresponding low doses of MB also increase spatial memory retention in a holeboard food search task (Callaway et al 2002(Callaway et al , 2004. Intrigued by these findings, we have investigated MB as a possible metabolic enhancer that could improve retention of memory for extinction of a conditioned response.…”

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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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Methylene blue does not bypass Complex III antimycin block in mouse brain mitochondria

et al. 2019

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Methylene blue (MB) is a promising prodrug to treat mitochondrial dysfunctions that is currently being used in clinical trials for Alzheimer's disease. MB can penetrate the blood brain barrier, accumulating in brain mitochondria where it acts as a redox mediator in the electron transfer chain (ETC). Mitochondrial flavins are thought to reduce MB, which is then oxidized by cytochrome c, thereby bypassing inhibited Complex I of ETC. We found that in mouse brain mitochondria, MB fails to restore the membrane potential and respiration inhibited by antimycin. Furthermore, antimycin inhibits MB‐induced H2O2 generation. Our data suggest that the acceptor of electrons from MB is a Qo ubiquinol‐binding site of Complex III; thus, MB‐based drugs might not be helpful in mitochondrial dysfunctions involving Complex III inhibition.

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Methylene blue restores spatial memory retention impaired by an inhibitor of cytochrome oxidase in rats

Cited by 76 publications

References 18 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

Methylene blue does not bypass Complex III antimycin block in mouse brain mitochondria

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