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


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.


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



Triple-Tg mouse model of Alzheimer’s disease




Arylalkylamine N-acetyltransferase


Alzheimer’s disease


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


N 1-acetyl-5-methoxykynuramine


Amyotrophic lateral sclerosis


Apolipoprotein E4


Amyloid protein precursor


Acetylserotonin O-methyltransferase


Arginine vasopressin

Amyloid beta


Blood brain barrier


B cell lymphoma proto-oncogene protein


Cyclic 3-hydroxymelatonin




Cerebrospinal fluid




Electron transport chain


γ-Aminobutyric acid


Growth hormone


Glutathione peroxidase


Glutathione reductase




Glycogen synthase kinase 3


Huntington’s disease


Hydroxyindole-O-methyl transferase




Interleukin-1 receptor 1


Inducible nitric oxide synthase


Kainic acid


Monoamine oxidase


Microtubule-associated protein


Mild cognitive impairment


Mutated huntingtin gene


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


Melatonin receptor 1


Melatonin receptor 2


Mitochondrial nitric oxide synthase


Mitochondrial permeability transition pore




Neuronal nitric oxide synthase


Nitric oxide synthase


Parkinson’s disease


Protein phosphatase


Presenilin 1


Quinone reductase


Rapid eye movement-associated sleep behavior disorder


Reactive nitrogen species


Reactive oxygen species


Suprachiasmatic nuclei


Superoxide dismutase




Tumor necrosis factor receptor 1


Tumor necrosis factor-α


Vascular endothelial growth factor


Vasoactive intestinal polypeptide



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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