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Melatonin Antioxidative Defense: Therapeutical Implications for Aging and Neurodegenerative Processes

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Abstract

The pineal product melatonin has remarkable antioxidant properties. It is secreted during darkness and plays a key role in various physiological responses including regulation of circadian rhythms, sleep homeostasis, retinal neuromodulation, and vasomotor responses. It scavenges hydroxyl, carbonate, and various organic radicals as well as a number of reactive nitrogen species. Melatonin also enhances the antioxidant potential of the cell by stimulating the synthesis of antioxidant enzymes including superoxide dismutase, glutathione peroxidase, and glutathione reductase, and by augmenting glutathione levels. Melatonin preserves mitochondrial homeostasis, reduces free radical generation and protects mitochondrial ATP synthesis by stimulating Complexes I and IV activities. The decline in melatonin production in aged individuals has been suggested as one of the primary contributing factors for the development of age-associated neurodegenerative diseases. The efficacy of melatonin in preventing oxidative damage in either cultured neuronal cells or in the brains of animals treated with various neurotoxic agents, suggests that melatonin has a potential therapeutic value as a neuroprotective drug in treatment of Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), stroke, and brain trauma. Therapeutic trials with melatonin indicate that it has a potential therapeutic value as a neuroprotective drug in treatment of AD, ALS, and HD. In the case of other neurological conditions, like PD, the evidence is less compelling. Melatonin’s efficacy in combating free radical damage in the brain suggests that it can be a valuable therapeutic agent in the treatment of cerebral edema following traumatic brain injury or stroke. Clinical trials employing melatonin doses in the range of 50–100 mg/day are warranted before its relative merits as a neuroprotective agent is definitively established.

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Abbreviations

3xTg-AD:

Triple-Tg mouse model of Alzheimer’s disease

6-OHDA:

6-Hydroxydopamine

AANAT:

Arylalkylamine N-acetyltransferase

AD:

Alzheimer’s disease

AFMK:

N 1-acetyl-N 2-formyl-5-methoxykynuramine

AMK:

N 1-acetyl-5-methoxykynuramine

ALS:

Amyotrophic lateral sclerosis

apoE4:

Apolipoprotein E4

APP:

Amyloid protein precursor

ASMT:

Acetylserotonin O-methyltransferase

AVP:

Arginine vasopressin

Aβ:

Amyloid beta

BBB:

Blood brain barrier

Bcl-2:

B cell lymphoma proto-oncogene protein

c3OHM:

Cyclic 3-hydroxymelatonin

CaM:

Calmodulin

CSF:

Cerebrospinal fluid

DA:

Dopamine

ETC:

Electron transport chain

GABA:

γ-Aminobutyric acid

GH:

Growth hormone

GPx:

Glutathione peroxidase

GR:

Glutathione reductase

GSH:

Glutathione

GSK-3:

Glycogen synthase kinase 3

HD:

Huntington’s disease

HIOMT:

Hydroxyindole-O-methyl transferase

IL-1β:

Interleukin-1β

IL-R1 :

Interleukin-1 receptor 1

iNOS:

Inducible nitric oxide synthase

KA:

Kainic acid

MAO:

Monoamine oxidase

MAP:

Microtubule-associated protein

MCI:

Mild cognitive impairment

mHtt:

Mutated huntingtin gene

MPTP:

1-Methyl-4-phenyl-1,2,3,6 tetrahydropyridine

MT1 :

Melatonin receptor 1

MT2 :

Melatonin receptor 2

mtNOS:

Mitochondrial nitric oxide synthase

mtPTP:

Mitochondrial permeability transition pore

NMDA:

N-methyl-d-aspartate

nNOS:

Neuronal nitric oxide synthase

NOS:

Nitric oxide synthase

PD:

Parkinson’s disease

PP:

Protein phosphatase

PS1:

Presenilin 1

QR2:

Quinone reductase

RBD:

Rapid eye movement-associated sleep behavior disorder

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

SCN:

Suprachiasmatic nuclei

SOD:

Superoxide dismutase

Tg:

Transgenic

TNF-R1 :

Tumor necrosis factor receptor 1

TNF-α:

Tumor necrosis factor-α

VEGF:

Vascular endothelial growth factor

VIP:

Vasoactive intestinal polypeptide

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Disclosures

S.R. Pandi-Perumal is a stockholder and the President and Chief Executive Officer of Somnogen Canada Inc., a Canadian Corporation. He declares that he has no competing interests that might be perceived to influence the content of this article. All remaining authors declare that they have no proprietary, financial, professional, nor any other personal interest of any nature or kind in any product or services and/or company that could be construed or considered to be a potential conflict of interest that might have influenced the views expressed in this manuscript.

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Authors and Affiliations

  1. Somnogen Canada Inc, College Street, Toronto, ON, M6H 1C5, Canada

    Seithikurippu R. Pandi-Perumal

  2. Sleep Disorders Center, College of Medicine, King Saud University, Box 225503, Riyadh, 11324, Saudi Arabia

    Seithikurippu R. Pandi-Perumal & Ahmed S. BaHammam

  3. Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    Gregory M. Brown

  4. Centre for Addiction and Mental Health, 250 College St., Toronto, ON, M5T 1R8, Canada

    Gregory M. Brown

  5. 323 Brock Ave, Toronto, ON, Canada

    D. Warren Spence

  6. Nutrition and Toxicology Laboratory, Defence Institute of High Altitude Research (DIHAR), Defence Research and Development Organization (DRDO), Ministry of Defence, C/o- 56 APO, Leh, 194101, India

    Vijay K. Bharti

  7. Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore

    Charanjit Kaur

  8. Institut fur Zoologie und Anthropologie, Universitat Gottingen, 37073, Gottingen, Germany

    Rüdiger Hardeland

  9. Departmento de Docencia e Investigación, Facultad de Ciencias Médicas, Pontificia Universidad Católica Argentina, 1107, Buenos Aires, Argentina

    Daniel P. Cardinali

Authors
  1. Seithikurippu R. Pandi-Perumal
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  2. Ahmed S. BaHammam
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  3. Gregory M. Brown
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  4. D. Warren Spence
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  5. Vijay K. Bharti
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  6. Charanjit Kaur
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  7. Rüdiger Hardeland
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  8. Daniel P. Cardinali
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Corresponding author

Correspondence to Daniel P. Cardinali.

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Pandi-Perumal, S.R., BaHammam, A.S., Brown, G.M. et al. Melatonin Antioxidative Defense: Therapeutical Implications for Aging and Neurodegenerative Processes. Neurotox Res 23, 267–300 (2013). https://doi.org/10.1007/s12640-012-9337-4

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  • DOI: https://doi.org/10.1007/s12640-012-9337-4

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