Memory facilitation by methylene blue: Dose-dependent effect on behavior and brain oxygen consumption

Riha, Penny D.; Bruchey, Aleksandra K.; Echevarria, David J.; González-Lima, Francisco

doi:10.1016/j.ejphar.2005.02.001

Cited by 85 publications

(97 citation statements)

References 31 publications

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“…Studies show that the memory retention effects of low dose MB cannot be attributed to alterations in locomotor activity, motivation, reward value, feeding, or fearfulness Riha et al 2005). Despite these reports, and in order to control for any state-dependent learning or side-effects that may occur by administering MB pre-training, administration occurred following training in these behavioral studies.…”

Section: Discussionmentioning

confidence: 99%

“…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: 84%

“…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%

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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: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 84%

Section: Discussionmentioning

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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“…AD patients show disrupted correlations in metabolism between cortical regions (Horwitz et al, 1987) and increased brain lipid peroxidation (Mielke and Lyketsos, 2006). Therefore, sodium azidetreated PCC may be a useful animal model for characterizing behavior and brain changes associated with amnestic mild cognitive impairment, and for testing neuroprotective and metabolic enhancing strategies to improve memory (Messier, 2004;Riha et al, 2005;Gold, 2006;Wrubel et al, 2007). This novel animal model presenting a specific PCC metabolic lesion, similar to that in patients with MCI who later convert to early-stage AD, may provide opportunities to characterize neurobehavioral alterations and to test therapeutics to reverse memory impairment.…”

Section: Discussionmentioning

confidence: 99%

Animal model of posterior cingulate cortex hypometabolism implicated in amnestic MCI and AD

Riha

Rojas

Colorado³

et al. 2008

Neurobiology of Learning and Memory

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The posterior cingulate cortex (PCC) is the brain region displaying the earliest sign of energy hypometabolism in patients with amnestic mild cognitive impairment (MCI) who develop Alzheimer's disease (AD). In particular, the activity of the mitochondrial respiratory enzyme cytochrome oxidase (C.O.) is selectively inhibited within the PCC in AD. The present study is the first experimental analysis designed to model in animals the localized cortical C.O. inhibition found as the earliest metabolic sign of early-stage AD in human neuroimaging studies. Rats were used to model local inhibition of C.O. by direct injection of the C.O. inhibitor sodium azide into the PCC. Learning and memory were examined in a spatial holeboard task and brains were analyzed using quantitative histochemical, morphological and biochemical techniques. Behavioral results showed that sodium azide-treated rats were impaired in their memory of the baited pattern in probe trials as compared to their training scores before treatment, without non-specific behavioral differences. Brain analyses showed that C.O. inhibition was specific to the PCC, and sodium azide increased lipid peroxidation, gliosis and neuron loss, and lead to a network functional disconnection between the PCC and interconnected hippocampal regions. It was concluded that impaired memory by local C.O. inhibition in the PCC may serve to model in animals a metabolic lesion similar to that found in patients with amnestic MCI and early-stage AD. This model may be useful as an in vivo testing platform to investigate neuroprotective strategies to prevent or reduce the amnestic effects produced by posterior cingulate energy hypometabolism.

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“…Methylene blue (MB) has been demonstrated to perform diverse biological functions and has been used for various medical applications (1). MB readily crosses the blood-brain barrier and accumulates in the mitochondrial matrix (2,3); therefore, its biological functions primarily involve improving mitochondrial functions, such as enhancing cytochrome c oxidase activity (4), oxygen consumption (5,6) and ATP production (7) and reducing reactive oxygen species (ROS) generation (8). Clinically, MB has been approved by the FDA for methemoglobinemia and as an antidote to cyanide poisoning (9,10).…”

Section: Introductionmentioning

confidence: 99%

Methylene Blue Reduces Acute Cerebral Ischemic Injury via the Induction of Mitophagy

Yao

Zhao

et al. 2015

Mol Med

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Memory facilitation by methylene blue: Dose-dependent effect on behavior and brain oxygen consumption

Cited by 85 publications

References 31 publications

The brain metabolic enhancer methylene blue improves discrimination learning in rats

The brain metabolic enhancer methylene blue improves discrimination learning in rats

Animal model of posterior cingulate cortex hypometabolism implicated in amnestic MCI and AD

Methylene Blue Reduces Acute Cerebral Ischemic Injury via the Induction of Mitophagy

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