Ana Coto-Montes

Melatonin: an ancient molecule that makes oxygen metabolically tolerable

Melatonin is remarkably functionally diverse with actions as a free radical scavenger and antioxidant, circadian rhythm regulator, anti‐inflammatory and immunoregulating molecule, and as an oncostatic agent. We hypothesize that the initial and primary function of melatonin in photosynthetic cyanobacteria, which appeared on Earth 3.5–3.2 billion years ago, was as an antioxidant. The evolution of melatonin as an antioxidant by this organism was necessary as photosynthesis is associated with the generation of toxic‐free radicals. The other secondary functions of melatonin came about much later in evolution. We also surmise that mitochondria and chloroplasts may be primary sites of melatonin synthesis in all eukaryotic cells that possess these organelles. This prediction is made on the basis that mitochondria and chloroplasts of eukaryotes developed from purple nonsulfur bacteria (which also produce melatonin) and cyanobacteria when they were engulfed by early eukaryotes. Thus, we speculate that the melatonin‐synthesizing actions of the engulfed bacteria were retained when these organelles became mitochondria and chloroplasts, respectively. That mitochondria are likely sites of melatonin formation is supported by the observation that this organelle contains high levels of melatonin that are not impacted by blood melatonin concentrations. Melatonin has a remarkable array of means by which it thwarts oxidative damage. It, as well as its metabolites, is differentially effective in scavenging a variety of reactive oxygen and reactive nitrogen species. Moreover, melatonin and its metabolites modulate a large number of antioxidative and pro‐oxidative enzymes, leading to a reduction in oxidative damage. The actions of melatonin on radical metabolizing/producing enzymes may be mediated by the Keap1‐Nrf2‐ARE pathway. Beyond its direct free radical scavenging and indirect antioxidant effects, melatonin has a variety of physiological and metabolic advantages that may enhance its ability to limit oxidative stress.

Melatonin is protective against MPTP-induced striatal and hippocampal lesions

The in vivo effect of melatonin on MPTP-induced neurotoxicity in mouse brain was studied. Melatonin (10 mg/kg) or saline was administered intraperitoneally (i.p.) to mice 30 min prior to a s.c. injection of MPTP (20 mg/kg). After MPTP treatment, the animals received melatonin or saline injections every hour for three hours. Mice were killed 4 hours after the MPTP injection. Regionally-specific increases in lipid peroxidation were observed in corpus striatum and hippocampus (71% and 58%, respectively), but not in cerebral cortex, cerebellum or midbrain. Treatment with melatonin completely reversed the rises in lipid peroxidation products. MPTP-treated mice showed a significant decrease in the striatal tyrosine hydroxylase immunoreactive nerve terminals, an effect that was also prevented by melatonin. These data show that melatonin is neuroprotective in this MPTP model of Parkinsons disease and suggest that melatonin, an endogenous antioxidant and nontoxic compound, may have potential beneficial effects for this neurodegenerative disorder.

Alzheimer’s disease: pathological mechanisms and the beneficial role of melatonin

Abstract:  Alzheimer’s disease (AD) is a highly complex neurodegenerative disorder of the aged that has multiple factors which contribute to its etiology in terms of initiation and progression. This review summarizes these diverse aspects of this form of dementia. Several hypotheses, often with overlapping features, have been formulated to explain this debilitating condition. Perhaps the best‐known hypothesis to explain AD is that which involves the role of the accumulation of amyloid‐β peptide in the brain. Other theories that have been invoked to explain AD and summarized in this review include the cholinergic hypothesis, the role of neuroinflammation, the calcium hypothesis, the insulin resistance hypothesis, and the association of AD with peroxidation of brain lipids. In addition to summarizing each of the theories that have been used to explain the structural neural changes and the pathophysiology of AD, the potential role of melatonin in influencing each of the theoretical processes involved is discussed. Melatonin is an endogenously produced and multifunctioning molecule that could theoretically intervene at any of a number of sites to abate the changes associated with the development of AD. Production of this indoleamine diminishes with increasing age, coincident with the onset of AD. In addition to its potent antioxidant and anti‐inflammatory activities, melatonin has a multitude of other functions that could assist in explaining each of the hypotheses summarized above. The intent of this review is to stimulate interest in melatonin as a potentially useful agent in attenuating and/or delaying AD.

Role of melatonin in the regulation of autophagy and mitophagy: A review

Oxidative stress plays an essential role in triggering many cellular processes including programmed cell death. Proving a relationship between apoptosis and reactive oxygen species has been the goal of numerous studies. Accumulating data point to an essential role for oxidative stress in the activation of autophagy. The term autophagy encompasses several processes including not only survival or death mechanisms, but also pexophagy, mitophagy, ER-phagy or ribophagy, depending of which organelles are targeted for specific autophagic degradation. However, whether the outcome of autophagy is survival or death and whether the initiating conditions are starvation, pathogens or death receptors, reactive oxygen species are invariably involved. The role of antioxidants in the regulation of these processes, however, has been sparingly investigated. Among the known antioxidants, melatonin has high efficacy and, in both experimental and clinical situations, its protective actions against oxidative stress are well documented. Beneficial effects against mitochondrial dysfunction have also been described for melatonin; thus, this indoleamine seems to be linked to mitophagy. The present review focuses on data and the most recent advances related to the role of melatonin in health and disease, on autophagy activation in general, and on mitophagy in particular.

Emergence of naturally occurring melatonin isomers and their proposed nomenclature

Abstract:  Melatonin was considered to be the sole member of this natural family. The emergence of naturally occurring melatonin isomers (MIs) has opened an exciting new research area. Currently, several MIs have been identified in wine, and these molecules are believed to be synthesized by either yeasts or bacteria. A tentative nomenclature for the MIs is proposed in this article. It will be important to explore whether all organisms have the capacity to synthesize MIs, especially under the conditions of environmental stress. These isomers probably share many of the biological functions of melatonin, but their activities seem to exceed those of melatonin. On basis of the limited available information, it seems that MIs differ in their biosynthetic pathways from melatonin. Especially in those compounds in which the aliphatic side chain is not attached to ring atom 3, the starting material may not be tryptophan. Also, the metabolic pathways of MIs remain unknown. This, therefore, is another promising area of research to explore. It is our hypothesis that MIs would increase the performance of yeasts and probiotic bacteria during the processes of fermentation. Therefore, yeasts producing elevated levels of these isomers might have a superior alcohol tolerance and be able to produce higher levels of alcohol. This can be tested by comparing existing yeast strains differing in alcohol tolerance. Selection for MIs may become a strategy for isolating more resistant yeast and Lactobacillus strains, which can be of interest for industrial alcohol production and quality improvements in bacterially fermented foods such as kimchi.

Beneficial actions of melatonin in the management of viral infections: a new use for this "molecular handyman"?

Melatonin (N‐acetyl‐5‐methoxytryptamine) is a multifunctional signaling molecule that has a variety of important functions. Numerous clinical trials have examined the therapeutic usefulness of melatonin in different fields of medicine. Clinical trials have shown that melatonin is efficient in preventing cell damage under acute (sepsis, asphyxia in newborns) and chronic states (metabolic and neurodegenerative diseases, cancer, inflammation, aging). The beneficial effects of melatonin can be explained by its properties as a potent antioxidant and antioxidant enzyme inducer, a regulator of apoptosis and a stimulator of immune functions. These effects support the use of melatonin in viral infections, which are often associated with inflammatory injury and increases in oxidative stress. In fact, melatonin has been used recently to treat several viral infections, which are summarized in this review. The role of melatonin in infections is also discussed herein. Copyright

Melatonin as a potential agent in the treatment of sarcopenia

Considering the increased speed at which the world population is aging, sarcopenia could become an epidemic in this century. This condition currently has no means of prevention or treatment. Melatonin is a highly effective and ubiquitously acting antioxidant and free radical scavenger that is normally produced in all organisms. This molecule has been implicated in a huge number of biological processes, from anticonvulsant properties in children to protective effects on the lung in chronic obstructive pulmonary disease. In this review, we summarize the data which suggest that melatonin may be beneficial in attenuating, reducing or preventing each of the symptoms that characterize sarcopenia. The findings are not limited to sarcopenia, but also apply to osteoporosis-related sarcopenia and to age-related neuromuscular junction dysfunction. Since melatonin has a high safety profile and is drastically reduced in advanced age, its potential utility in the treatment of sarcopenic patients and related dysfunctions should be considered.

Virus and Autophagy: Enemies or Allies

Viral infection is one of the several stimuli which trigger autophagy, a self-degradative process that is important for balancing sources of energy at critical times in development and in response to nutrient stress. This process also plays a housekeeping role in removing misfolded or aggregated proteins and clearing damaged organelles. Virus-induced autophagy has a dual role since it may be beneficial to the host by eliminating intracellular pathogens or it may benefit some viruses, which have developed strategies to directly or indirectly subvert autophagy in order to promote different stages of the viral life cycle. The upregulation of both oxidative and endoplasmic reticulum stresses has been reported as a means by which virus-induced pathways trigger autophagy. In this chapter the relationships between autophagy and viral infection are considered.