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.
Highlights
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)
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]
The view that melatonin may be unfavorable in the case of parkinsonism, was further supported by respective experiments using the melatonin receptor antagonists ML-23 and S-20928, which, again, improved motor functions and, in the case of ML-23, prevented 6-OHDA-induced mortality [309,310]. These findings show that antioxidative protection and even potentially beneficial mitochondrial effects do not suffice for judging the value of a drug under systemic aspects
Summary
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). One might classify the effects of melatonin as (i) antioxidant, including influences on mitochondrial metabolism, (ii) antifibrillogenic and (iii) cytoskeletal, including the suppression of protein hyperphosphorylation Some of these actions were demonstrated at elevated, pharmacological concentrations, but any judgment of the relevance of such findings has to consider the relatively high rates of melatonin secretion into the CSF, uptake into the brain tissue and, presumably the metabolization to other protective compounds, such as the kynuramines AFMK and AMK [40,41], processes which are impaired during aging and in neurodegenerative diseases. Melatonin's undoubtedly existing antiexcitotoxic properties are not clearly apparent in studies focusing on lipid peroxidation
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
