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Neurotoxicity Research

, Volume 23, Issue 3, pp 267–300 | Cite as

Melatonin Antioxidative Defense: Therapeutical Implications for Aging and Neurodegenerative Processes

  • Seithikurippu R. Pandi-Perumal
  • Ahmed S. BaHammam
  • Gregory M. Brown
  • D. Warren Spence
  • Vijay K. Bharti
  • Charanjit Kaur
  • Rüdiger Hardeland
  • Daniel P. CardinaliEmail author
Review

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.

Keywords

Melatonin Mitochondria Free radicals Oxidative stress Aging Parkinson’s disease Alzheimer’s disease Huntington’s disease Amyotrophic lateral sclerosis Stroke 

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

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

Notes

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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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Seithikurippu R. Pandi-Perumal
    • 1
    • 2
  • Ahmed S. BaHammam
    • 2
  • Gregory M. Brown
    • 3
    • 4
  • D. Warren Spence
    • 5
  • Vijay K. Bharti
    • 6
  • Charanjit Kaur
    • 7
  • Rüdiger Hardeland
    • 8
  • Daniel P. Cardinali
    • 9
    Email author
  1. 1.Somnogen Canada IncTorontoCanada
  2. 2.Sleep Disorders Center, College of MedicineKing Saud UniversityRiyadhSaudi Arabia
  3. 3.Department of PsychiatryUniversity of TorontoTorontoCanada
  4. 4.Centre for Addiction and Mental HealthTorontoCanada
  5. 5.TorontoCanada
  6. 6.Nutrition and Toxicology Laboratory, Defence Institute of High Altitude Research (DIHAR), Defence Research and Development Organization (DRDO)Ministry of DefenceLehIndia
  7. 7.Department of Anatomy, Yong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
  8. 8.Institut fur Zoologie und AnthropologieUniversitat GottingenGottingenGermany
  9. 9.Departmento de Docencia e Investigación, Facultad de Ciencias MédicasPontificia Universidad Católica ArgentinaBuenos AiresArgentina

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