Melatonin in Alzheimer's disease and other neurodegenerative disorders

V Srinivasan¹, SR Pandi-Perumal², DP Cardinali³, B Poeggeler⁴ and R Hardeland^4*

• Corresponding author: R Hardeland rhardel@gwdg.de

Author Affiliations

¹Department of Physiology, School of Medical Sciences, University Sains Malaysia, Kampus Kesihatan, 16150, Kubang kerian, Kelantan, Malaysia

²Comprehensive Center for Sleep Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Mount Sinai School of Medicine, 1176 – 5th Avenue, New York, NY 10029, USA

³Departamento de Fisiología, Facultad de Medicina, Universidad de Buenos Aires, 1121, Buenos Aires, Argentina

⁴Johann Friedrich Blumenbach Institute of Zoology and Anthropology, University of Goettingen, Berliner Str. 28, D-37073 Goettingen, Germany

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Behavioral and Brain Functions 2006, 2:15 doi:10.1186/1744-9081-2-15

The electronic version of this article is the complete one and can be found online at:http://www.behavioralandbrainfunctions.com/content/2/1/15

Received:	21 March 2006
Accepted:	4 May 2006
Published:	4 May 2006

© 2006 Srinivasan et al; licensee BioMed Central Ltd. 

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Increased oxidative stress and mitochondrial dysfunction have been identified as common pathophysiological phenomena associated with neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). As the age-related decline in the production of melatonin may contribute to increased levels of oxidative stress in the elderly, the role of this neuroprotective agent is attracting increasing attention. Melatonin has multiple actions as a regulator of antioxidant and prooxidant enzymes, radical scavenger and antagonist of mitochondrial radical formation. The ability of melatonin and its kynuramine metabolites to interact directly with the electron transport chain by increasing the electron flow and reducing electron leakage are unique features by which melatonin is able to increase the survival of neurons under enhanced oxidative stress. Moreover, antifibrillogenic actions have been demonstrated in vitro, also in the presence of profibrillogenic apoE4 or apoE3, and in vivo, in a transgenic mouse model. Amyloid-β toxicity is antagonized by melatonin and one of its kynuramine metabolites. Cytoskeletal disorganization and protein hyperphosphorylation, as induced in several cell-line models, have been attenuated by melatonin, effects comprising stress kinase downregulation and extending to neurotrophin expression. Various experimental models of AD, PD and HD indicate the usefulness of melatonin in antagonizing disease progression and/or mitigating some of the symptoms. Melatonin secretion has been found to be altered in AD and PD. Attempts to compensate for age- and disease-dependent melatonin deficiency have shown that administration of this compound can improve sleep efficiency in AD and PD and, to some extent, cognitive function in AD patients. Exogenous melatonin has also been reported to alleviate behavioral symptoms such as sundowning. Taken together, these findings suggest that melatonin, its analogues and kynuric metabolites may have potential value in prevention and treatment of AD and other neurodegenerative disorders.

Introduction

Oxidative damage has been suggested to be the primary cause of aging and age-associated neurodegenerative diseases like Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). This concept is based on the free radical hypothesis of aging as proposed by Harman [1]. Many reviews on AD present compelling evidence for a decisive participation of severe oxidative stress in the development of neuropathology seen in this disease[2-9]. Immunohistochemical proof that enhanced oxidative stress and damage to biomolecules are hallmarks of the disease and its progression was first presented by Pappolla et al. [3]. This study confirmed findings demonstrating increased levels of lipid peroxidation in vitro observed in autopsy samples of brains afflicted by AD [10]. Because of its high rate of oxygen consumption and its high content of polyunsaturated fatty acids, the brain exhibits increased vulnerability to oxidative stress. Elevated lipid peroxidation, as found in the brains of AD patients, not only reveals oxidative stress [10-13], but also exerts secondary effects on protein modification, oxidation and conformation [14,15]. Increased protein and DNA oxidation also occurs in AD. Measurements of protein carbonyl, 3,3'-dityrosine and 3-nitrotyrosine in post mortem brain samples from AD patients have shown increased oxidative and nitrosative protein modification in the hippocampal and neocortical regions, but not in the cerebellum [14,16-18]. Free radical attack on DNA results in strand breaks, DNA-protein cross linkage, and base modification. Double- and single-strand breaks were elevated in AD cortex and hippocampus, but this has to be largely attributed to apoptotic fragmentation [19,20]. Enhanced oxidative DNA modification is, however, also demonstrable, mostly as 8-hydroxy-2'-deoxyguanosine (8-OHdG) [21-23], a product primarily formed by attack of hydroxyl radicals [24], but other modified bases such as 8-OH-adenine have also been demonstrated [25]. Augmented free radical damage to lipids, proteins and nucleic acids has been reported for the substantia nigra of parkinsonian patients [26]. Therefore, numerous compounds with antioxidant properties have been suggested for treatment of AD and other neurodegenerative diseases [27-30]. Among these substances, melatonin is unique for several reasons: it is a natural compound synthesized in the pineal gland and other body tissues; it can be released by the pineal gland via the pineal recess into the cerebrospinal fluid (CSF), in much higher concentrations than into the circulation [31,32]; its production decreases with the advancement of age, a fact which has been suggested to be one of the major causes of age-associated neurodegenerative diseases [8,9,33,34]. This review focuses on the role of melatonin in the etiology of AD and other neurodegenerative disorders and on the therapeutic potential of melatonin in these pathologies, including effects on sleep and behavior.

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