Melatonin’s antiviral activities via the suppression of inflammatory pathways is of special interest given the known pathophysiological lung characteristics of severe COVID-19 patients. This is motivated by its spectrum of established antiviral activities consequent to its suppression of multiple inflammatory pathways and its strong immuno-stimulatory activity through production of multiple interleukins (IL-1/2/6/12), and of interferon γ (IFN-γ), cytotoxic T cells, and B- and T-cell precursors among others, especially relevant against a disease COVID-19 whose pathophysiological hallmarks include excessive inflammation, oxidation, and an hyper-exaggerated immune response that can culminate in a “cytokine storm” and can progress to and trigger acute lung injury (ALI) / acute respiratory distress syndrome (ARDS) and multiple organ failures, such progression not infrequently proving fatal. Given the epidemiologic observation of high levels of melatonin in children and the significant decline with advanced age that may in part contribute to the vulnerability and high lethality of SARS-2-CoV (COVID-19) infections in the elderly in conjunction with modest impact in exposed children who exhibit appreciable relative resistance, and from the observation of its potential in recent previous Ebolavirus Disease (EVD) outbreaks starting in 2013 to limit or counter oxidative stress and immuno-inflammatory injury, there has been a strong burst of interest and research in the deployment of melatonin for the prevention and treatment of COVID-19 disease. The ubiquitous pineal indolamine molecule melatonin is a chronobiotic, playing a critical role in the regulation of the human circadian rhythm, and exhibiting pleiotropic activity via its well-established anti‐inflammatory, antioxidant and free radical scavenger, antiapoptotic, and immunomodulatory properties, with potential cytoprotective, neuroprotective, nephroprotective, cardioprotective, anti-hypertensive, anti-nociceptive, and antiviral effects consequent to immunomodulation, with emerging evidence of benefit in neurocognitive disorders, these latter two capabilities we discuss more fully below. Melatonin in SARS-2-CoV (COVID-19) disease In the process we review clinical evidence of benefit in these domains, suggesting the strong promise that melatonin appears to provide, with a highly favorable benefit/harm ratio of excellent tolerability, affordability and safety, and sufficiently compelling evidence of efficacy as to be actionable, in the here and now. In this commentary, we explore the frontier edge of the emerging potential role of the chronobiotic agent melatonin, in both the prevention and treatment, and in the amelioration of some of the newly identified pathological neurocognitive sequelae, of SARS-2-CoV infection (COVID-19 disease).
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