Always tired? San Francisco integrative medicine physician, Dr. Payal Bhandari explains her techniques for treating chronic fatigue syndrome.
Last week, I discussed the rationale for using melatonin based on what we know about how COVID-19 infections wreak havoc on the body’s tissues.
This week and next, I want to focus specifically on it’s anti-inflammatory, anti-oxidative, and immunomodulatory role in health and wellbeing. I will also dive into how to put all of this into practice, as well as other supportive adjuvant agents. Because I’m spending almost a month on this topic, it tells you how important I think it is!
How Melatonin Works
Melatonin possesses anti-inflammatory action through various pathways. Let’s start with Sirtuin-1, which is a member of a protein family that functions in the cellular response to inflammatory, metabolic, and oxidative stressors. If your body senses danger, Sirtuin-1 (or SIRT1) is activated and goes in to assess the chemical damage.
SIRT1 is one of the hallmark proteins in the body; it engages with your mitochondria and regulates the expression of genes key for ATP generation and proliferation. SIRT1 also increases mitochondrial biogenesis—the process by which cells increase mitochondrial mass—, thereby contributing to increased healthy life-span and reducing aging-related diseases (Yuan et al., 2016). It’s a protein you want hanging around, especially if you have increased inflammation!
This protein appears to mediate the anti-inflammatory effect of melatonin by inhibiting a protein called HMG-1 (or high-mobility group box 1 protein), which is secreted by immune cells like macrophages, monocytes, and dendritic cells. HMG-1 is a nuclear protein that organizes the DNA and regulates transcription (Klune et al., 2008). Thus, SIRT1, with the help of melatonin, downregulates the polarization of macrophages towards the pro-inflammatory type (Hardeland, 2018).
In sepsis-induced acute lung injury (ALI), the “proper” regulation of SIRT1 reduces lung injury and inflammation, and the application of melatonin adds to the therapeutic effect of SIRT1 (Wang et al., 2019). We know that SIRT1 plays a key role in chronic inflammation, and its expression and protein levels are reduced in several common (and chronic) inflammatory diseases in the U.S., including arterial inflammation, obesity, and Alzheimer’s disease (Hadar et al., 2017)
Nuclear factor kappa-B (NF-κB) is another essential pathway, and if there is anything you take away from this blog (besides the benefit of melatonin), it’s that we want to turn off NF-κB as much as we possibly can.
Granted, the influence that NF-κB has on cell survival is an ever-evolving story; it can be neuroprotective or proinflammatory, depending on cell type, developmental stage, and pathological state (Qin et al., 2007), but this is beyond the scope of this post. For this discussion, NF-κB is generally (and closely) associated with pro-inflammatory and pro-oxidative responses, while at the same time being an inflammatory mediator in ALI. The anti-inflammatory effect of melatonin involves the suppression of NF-κB activation in acute respiratory distress syndrome (ARDS) (Sun et al., 2015; Ling et al., 2018). Melatonin downregulates NF-κB activation in T cells and lung tissue (Shang et al., 2009; da Cunha Pedrosa et al., 2010). This halts the build up of inflammation.
And since NF-κB is involved in cell survival, which works to our advantage in the acute sense, it’s clear why we find it turned on indefinitely in cancer cells. Besides melatonin, though, calorie restriction (or fasting) is one of the most effective ways to shut down NF-κB, thereby shutting down the entire inflammatory system that drives the progression of chronic and acute diseases.
While some inflammation is actually good for us, we too often tip the scale and accumulate an excessive amount of reactive oxygen species (ROS) in our cellular environment. This is considered to give rise to an unfortunately unrecognized state plaguing our society: underlying oxidative stress (Sies, 1997).
Fortunately for us, each cell in our body has its own internal defense mechanism to fight against oxidative stress. Chiefly, this is mediated by the transcription factor NF-E2-related factor 2 (Nrf2). If NF-κB is the master regulator of pro-inflammatory cascades, Nrf2 is the master regulator of anti-inflammatory cascades; it offers a battery of defensive mechanisms and regulates detoxification genes. Indeed, Nrf2 is stabilized and activated when ROS and electrophiles rise (Shelton & Jaiswal, 2013).
Bottom line: Inflammation is associated with an elevated production of cytokines and chemokines, and melatonin is associated with a reduction in those pro-inflammatory cytokines , with a concomitant elevation in the level of the anti-inflammatory cytokine IL-10 (Habtemariam et al., 2017; Hardeland, 2019). While there are a few concerns about the potential pro-inflammatory actions of melatonin when used in very high doses or under suppressed immune conditions (where it may induce an increase production of pro-inflammatory cytokines, IL-1β, IL-2, IL-6, IL-12, TNF-α, and IFN-γ) (Carrascal et al., 2018), it’s important to remember that in ALI-infection models, melatonin consistently demonstrates anti-inflammatory and protective action (Huang et al., 2010).
The Antioxidative Effect of Melatonin
Viral infections (and their replication) constantly produce oxidized products. We know this from SARS-induced acute lung injury (ALI) models, where the production of oxidized low density lipoprotein (LDL) activate the innate immune response by the overproduction of IL-6 lung (alveolar) macrophages via Toll-like receptor 4 (TLR4)/NF-kB signaling, thereby leading to ALI (Imai et al., 2008).
TLR4 is a receptor for the innate immune system, and it is also a therapeutic target for melatonin. In cerebral ischemia (when an insufficient amount of blood flows to the brain), gastritis, and periodontitis disease models, melatonin has documented anti-inflammation actions via TLR4 signaling (Luo et al., 2018; Renn et al., 2018; Zhao et al., 2019).
The anti-oxidative effect of melatonin has also been identified in acute lung injury caused by radiation, sepsis, and ischemia-reperfusion (Chen et al., 2014; Wang et al., 2018; Wu et al., 2019). In ALI/ARDS patients, especially when this condition is advanced and in patients treated in ICUs, severe inflammation, hypoxemia, and mechanical ventilation with high oxygen concentrations increases oxidant generation locally and, inevitably, spills out to the rest of the body systematically (Sarma & Ward, 2011; Tamura et al., 2020). Melatonin could help clean a lot of this inflammatory damage up.
Melatonin’s use is not a novel idea.
Its use as a therapy has been known for well over a decade, thanks, in part, to the extensive studies conducted by Gitto and his colleagues in 2004 and 20055 (during the aftermath of the first SARS pandemic). It was this team that used melatonin to treat newborn infants with respiratory distress that found the antioxidant and anti-inflammatory actions of melatonin in the lung. Thus, the application of melatonin would likely be beneficial in controlling inflammation and oxidation in those infected with coronavirus.
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