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Methylene blue and its analogues as antidepressant compounds

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Abstract

Methylene Blue (MB) is considered to have diverse medical applications and is a well-described treatment for methemoglobinemias and ifosfamide-induced encephalopathy. In recent years the focus has shifted to MB as an antimalarial agent and as a potential treatment for neurodegenerative disorders such as Alzheimer’s disease. Of interest are reports that MB possesses antidepressant and anxiolytic activity in pre-clinical models and has shown promise in clinical trials for schizophrenia and bipolar disorder. MB is a noteworthy inhibitor of monoamine oxidase A (MAO-A), which is a well-established target for antidepressant action. MB is also recognized as a non-selective inhibitor of nitric oxide synthase (NOS) and guanylate cyclase. Dysfunction of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) cascade is strongly linked to the neurobiology of mood, anxiety and psychosis, while the inhibition of NOS and/or guanylate cyclase has been associated with an antidepressant response. This action of MB may contribute significantly to its psychotropic activity. However, these disorders are also characterised by mitochondrial dysfunction and redox imbalance. By acting as an alternative electron acceptor/donor MB restores mitochondrial function, improves neuronal energy production and inhibits the formation of superoxide, effects that also may contribute to its therapeutic activity. Using MB in depression co-morbid with neurodegenerative disorders, like Alzheimer’s and Parkinson’s disease, also represents a particularly relevant strategy. By considering their physicochemical and pharmacokinetic properties, analogues of MB may provide therapeutic potential as novel multi-target strategies in the treatment of depression. In addition, low MAO-A active analogues may provide equal or improved response with a lower risk of adverse effects.

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Abbreviations

5HIAA:

5-Hydroxyindoleacetic acid

5-HT:

5-Hydroxytryptamine/ serotonin

AChE:

Acetylcholinesterase

ADP:

Adenosine diphosphate

APP:

Amyloid precursor protein

ATP:

Adenosine triphosphate

Aβ:

Amyloid beta

BuChE:

Butyrylcholinesterase

cAMP:

Cyclic adenosine monophosphate

cGMP:

Cyclic guanosine monophosphate

Cmax :

Maximal concentration in plasma

CNS:

Central nervous system

DLC:

Delocalized lipophilic cation

DPAG:

Dorsal periaqueductal grey matter

ETC:

Ethylthioninium chloride

FAD:

Flavin adenine dinucleotide

FADH2 :

Reduced flavin adenine dinucleotide

FSL:

Flinders sensitive line

FST:

Forced swim test

GABA:

γ-Aminobutyric acid

GC:

Guanylate cyclase

i.p.:

Intraperitoneal

i.v.:

Intravenous

LeucoMB:

Reduced methylene blue

MAO:

Monoamine oxidase

MB:

Methylene blue

MG:

Methylene green

MPP+ :

1-Methyl-4-phenylpyridinium

NAD+ :

Nicotinamide adenine dinucleotide

NADH:

Reduced nicotinamide adenine dinucleotide

NADPH:

Reduced nicotinamide adenine dinucleotide phosphate

NMDA:

N-Methyl-D-aspartate

NO:

Nitric oxide

NOS:

Nitric oxide synthase

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

SRI:

Serotonin reuptake inhibitor

ST:

Serotonin toxicity

λmax :

Wavelength of maximal absorption

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Acknowledgements

We gratefully acknowledge financial support by the Medical Research Council of South Africa and the National Research Foundation (BHH grant number: 77323). The grant-holder acknowledges that opinions, findings and conclusions or recommendations expressed in any publication generated by NRF supported research are those of the authors, and that the NRF accepts no liability whatsoever in this regard.

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  1. Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom, 2520, South Africa

    Anzelle Delport, Brian H. Harvey, Anél Petzer & Jacobus P. Petzer

  2. Division of Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom, 2520, South Africa

    Anzelle Delport, Anél Petzer & Jacobus P. Petzer

  3. Division of Pharmacology, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom, 2520, South Africa

    Brian H. Harvey

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The authors declare that they have no direct conflicts of interest. BHH declares that over the past three years, he has participated in advisory boards and received honoraria from Servier®, and has received research funding from Servier® and Lundbeck®. BHH declares that, except for income from the primary employer and research funding from the above-mentioned organisations and agencies, no financial support or compensation has been received from any individual or corporate entity over the past three years for research or professional services, and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.

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Delport, A., Harvey, B.H., Petzer, A. et al. Methylene blue and its analogues as antidepressant compounds. Metab Brain Dis 32, 1357–1382 (2017). https://doi.org/10.1007/s11011-017-0081-6

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