[Melatonin: A short clarification for the over-enthusiasts]. / Mélatonine - Petit précis à l'usage des trop enthousiastes.

Melatonin is a naturally occurring molecule derived from tryptophan. Melatonin is a key player in relaying the circadian rhythm between our environment and our body. It has also a key role in rhythming the seasons (more production during long nights and less during short ones) as well as in the reproduction cycles of the mammals. Melatonin is often and surprisingly presented as a molecule with multiple therapeutic properties that can fix (or help to fix) many health issues, such as diseases (cancer, ageing, virus-induced affections including COVID-19, etc…) or toxicological situations (metals, venoms, chemical such as adriamycin [doxorubicin], methotrexate or paclitaxel). The mechanistics behind those wonders is still missing and this is puzzling. In the present commentary, the main well-established biological properties are presented and briefly discussed with the aim of delineating the borders between facts and wishful thinking.

TITLE: Mélatonine - Petit précis à l'usage des trop enthousiastes. ABSTRACT: La mélatonine est une molécule naturelle dérivée du tryptophane. Son rôle est de servir de relai entre la rythmicité jour/nuit et notre corps. Elle sert donc de marqueur circadien : concentration haute pendant la nuit et basse pendant la journée. Elle sert aussi de marque saisonnière : plus les nuits sont longues et plus longuement elle est produite (et vice-versa), ce qui a un rôle primordial dans les cycles reproductifs des animaux. Mais elle est aussi affublée de multiples propriétés thérapeutiques concernant la plupart des maladies humaines, du cancer à la COVID-19 en passant par l'infection par le virus Ebola, ainsi que de capacités thérapeutiques vis-à-vis de multiples toxicités (métaux, venins, produits chimiques comme l'adriamycine [doxorubicine], le méthotrexate ou le paclitaxel). Alors que l'enthousiasme à propos de cette molécule est troublant, l'assise scientifique de ces descriptions est dans le meilleur des cas faible et dans la plupart des cas, inexistante. Dans ce commentaire, les données scientifiques bien établies liées à la mélatonine sont résumées et brièvement discutées, en tâchant de redessiner les limites entre ce qui est connu et bien établi et ce qui reste du domaine du fantasme.

Melatonin and healthy aging.

Preservation of a robust circadian rhythmicity (particulsarly of the sleep/wake cycle), a proper nutrition and adequate physical exercise are key elements for healthy aging. Aging comes along with circadian alteration, e.g. a disrupted sleep and inflammation, that leads to metabolic disorders. In turn, sleep cycle disturbances cause numerous pathophysiological changes that accelerates the aging process. In the central nervous system, sleep disruption impairs several functions, among them, the clearance of waste molecules. The decrease of plasma melatonin, a molecule of unusual phylogenetic conservation present in all known aerobic organisms, plays a particular role as far as the endocrine sequels of aging. Every day, the late afternoon/nocturnal increase of melatonin synchronizes both the central circadian pacemaker located in the hypothalamic suprachiasmatic nuclei as well as myriads of peripheral cellular circadian clocks. This is called the "chronobiotic effect" of melatonin, the methoxyindole being the prototype of the endogenous family of chronobiotic agents. In addition, melatonin exerts a significant cytoprotective action by buffering free radicals and reversing inflammation via down regulation of proinflammatory cytokines, suppression of low degree inflammation and prevention of insulin resistance. Because of these properties melatonin has been advocated to be a potential therapeutic tool in COVID 19 pandemic. Melatonin administration to aged animals counteracts a significant number of senescence-related changes. In humans, melatonin is effective both as a chronobiotic and a cytoprotective agent to maintain a healthy aging. Circulating melatonin levels are consistently reduced in the metabolic syndrome, ischemic and non-ischemic cardiovascular diseases and neurodegenerative disorders like the Alzheimer's and Parkinson's diseases. The potential therapeutic value of melatonin has been suggested by a limited number of clinical trials generally employing melatonin in the 2-10mg/day range. However, from animal studies the cytoprotective effects of melatonin need higher doses to become apparent (i.e. in the 100mg/day range). Hence, controlled studies employing melatonin doses in this range are urgently needed.

Cellular Mechanisms of Melatonin: Insight from Neurodegenerative Diseases.

Neurodegenerative diseases are the second most common cause of death and characterized by progressive impairments in movement or mental functioning in the central or peripheral nervous system. The prevention of neurodegenerative disorders has become an emerging public health challenge for our society. Melatonin, a pineal hormone, has various physiological functions in the brain, including regulating circadian rhythms, clearing free radicals, inhibiting biomolecular oxidation, and suppressing neuroinflammation. Cumulative evidence indicates that melatonin has a wide range of neuroprotective roles by regulating pathophysiological mechanisms and signaling pathways. Moreover, melatonin levels are decreased in patients with neurodegenerative diseases. In this review, we summarize current knowledge on the regulation, molecular mechanisms and biological functions of melatonin in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, vascular dementia and multiple sclerosis. We also discuss the clinical application of melatonin in neurodegenerative disorders. This information will lead to a better understanding of the regulation of melatonin in the brain and provide therapeutic options for the treatment of various neurodegenerative diseases.

Possible effect of epinephrine in minimizing COVID-19 severity: a review.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) shows a wide range of severity, ranging from an asymptomatic presentation to a severe illness requiring intensive care unit admission. Identification of a strategy to manage the severity of this disease will not only help to reduce its case fatality but also help to remove some of the burden from the already overwhelmed health care systems. While successful management of symptoms in general is important, identifying measures to modify the severity of the illness is a key factor in the fight against this pandemic. METHODS: This paper presents a short literature review to suggest a new treatment modality for COVID-19. RESULTS: COVID-19 is less severe and rarely fatal in children than in adults, which could be caused by greater fluctuations of plasma epinephrine in children. Our literature survey endorses this hypothesis according to both the epidemiological and immunological findings. CONCLUSION: Application of epinephrine pulses with a specific amplitude may be considered an intervention to minimize the severity of COVID-19.

Can melatonin reduce the severity of COVID-19 pandemic?

The current COVID-19 pandemic is one of the most devastating events in recent history. The virus causes relatively minor damage to young, healthy populations, imposing life-threatening danger to the elderly and people with diseases of chronic inflammation. Therefore, if we could reduce the risk for vulnerable populations, it would make the COVID-19 pandemic more similar to other typical outbreaks. Children don't suffer from COVID-19 as much as their grandparents and have a much higher melatonin level. Bats are nocturnal animals possessing high levels of melatonin, which may contribute to their high anti-viral resistance. Viruses induce an explosion of inflammatory cytokines and reactive oxygen species, and melatonin is the best natural antioxidant that is lost with age. The programmed cell death coronaviruses cause, which can result in significant lung damage, is also inhibited by melatonin. Coronavirus causes inflammation in the lungs which requires inflammasome activity. Melatonin blocks these inflammasomes. General immunity is impaired by anxiety and sleep deprivation. Melatonin improves sleep habits, reduces anxiety and stimulates immunity. Fibrosis may be the most dangerous complication after COVID-19. Melatonin is known to prevent fibrosis. Mechanical ventilation may be necessary but yet imposes risks due to oxidative stress, which can be reduced by melatonin. Thus, by using the safe over-the-counter drug melatonin, we may be immediately able to prevent the development of severe disease symptoms in coronavirus patients, reduce the severity of their symptoms, and/or reduce the immuno-pathology of coronavirus infection on patients' health after the active phase of the infection is over.