COVID-19, PNEUMONIA & INFLAMMASOMES – THE MELATONIN CONNECTION
The potential role of melatonin in COVID-19 infection was addressed in an extensive and fully referenced March 14, 2020, article by medical researcher Doris Loh, published in the Italian online magazine Evolutamente.
One question that has not been truly answered is why infants and children under the age of nine do not seem to suffer any severe symptoms upon COVID-19 infection. It is understandable why older patients may be more susceptible to higher risks, but what spares young children? Why are young adults without comorbidities also suffering from pneumonia as a result of COVID-19 infections?
[Source: Grivas TB, Savvidou OD. Melatonin the “light of night” in human biology and adolescent idiopathic scoliosis. Scoliosis. 2007;2:6. Published 2007 Apr 4. doi:10.1186/1748-7161-2-6]
What does this chart measure? An ancient and powerful molecule that everyone is familiar with – melatonin. What does melatonin have to do with SARS-CoV-2?
Melatonin Inhibits NLRP3 Inflammasomes
Melatonin is well known for its chronobiotic effects, regulating biological functions tied to circadian rhythms. Numerous studies have revealed that melatonin exerts effects beyond the control of circadian oscillators. The NLRP3 inflammasome is now recognized as a target for melatonin!
The fact that the pro-inflammatory cytokine storm effects are induced by the activation of NLRP3 inflammasomes, the ability of melatonin to INHIBIT NLRP3 inflammasome elevates this powerful molecule to a truly unique position in the fight against COVID-19. This also means that if a patient, regardless of age, has adequate melatonin, the infectiousness of COVID-19 will be greatly reduced, and the chances of developing ARDS/ALI significantly diminished.
Melatonin is the reason why children under the age of 9 seldom exhibit severe symptoms. In fact, children may exhibit mild or even no symptoms at all, even though they have been infected by SARS-CoV-2. How significant is the difference in melatonin production between children, adults and the elderly?
For most people, peak melatonin production is between the hours of 2 am to 3 am. The maximum melatonin levels measured in healthy adults between the ages of 65 to 70 years appeared to be around 49.3 picograms/ml (pg/ml). Adults more than 75 years of age only have maximum production levels of 27.8 pg/ml.
Young children, on the other hand, have extremely high melatonin levels, compared to adults. The maximum levels recorded for children showed a decline as age increased. Children between the ages of 1 to 5 had peak melatonin at 325 pg/ml, while those between the ages of 5 to 11 already declined to 133 pg/ml.
Compared to healthy adult seniors, a young child can easily have TEN TIMES the amount of peak melatonin levels. But even then, the actual physiological concentration is extremely low. How much is one picogram, exactly?
To give you some perspective, most melatonin supplements are around 3 to 5 mg per capsule or tablet. One milligram equals 1,000,000,000 picograms. That is why the physiological dosage generally recommended for melatonin supplementation is around 0.3 milligram.
The fact that young children have such high melatonin levels explains why they show very mild symptoms after COVID-19 infections.
Melatonin is a potent inhibitor of NLRP3 inflammasomes.
Generally referred to as the “hormone of darkness”, the ability of melatonin to regulate both pro- as well as anti-inflammatory cytokines in different pathophysiological conditions has only been extensively studied in the past several years.
Controlling cytokine storms is one of the major challenges in the treatment of sepsis. The NLRP3 inflammasome has an interesting nickname of “Pandora’s Box for Sepsis”. Yet nature provides all the solutions to difficult health challenges.
NLRP3 inflammasomes is a direct target of melatonin. Animal models of sepsis showed melatonin’s ability to maintain mitochondrial homeostasis, reduce reactive oxygen species and lower production of proinflammatory cytokines. Melatonin was shown to inhibit NLRP3 inflammasomes in mice with myocardial septic conditions, transforming severe myocardial inflammation into milder symptoms, preventing cardiac failure, and significantly enhanced survival rates of septic mice.
An excellent study by Volt et al (2016) showed that chronic low doses of melatonin in aged mice could prevent increase in inflammation, ROS and mitochondria impairments reflective of inflammaging. Volt et al. also showed that acute administration of melatonin could counteract severe inflammatory responses.
It is therefore not surprising to find that melatonin is able to prevent ARDS/ALI through suppression of NLRP3 inflammasomes.
In rodent acute lung injury (ALI) models, melatonin was found to markedly reduce pulmonary injury, lower infiltration of macrophages and neutrophils into lungs. Melatonin protected mice from acute lung injuries by inhibiting the activation of NLRP3 inflammasomes through the suppression of extracellular release of histones and blocking histone-induced NLRP3 inflammasome activation.
In rodent models of acute respiratory distress syndrome (ARDS), combined treatment of melatonin and mitochondria significantly attenuated progression of ARDS.
Melatonin Protects Lung Injury from Mechanical Ventilation Interventions
COVID-19 patients with ARDS/ALI often require intubation with mechanical ventilation. Even though the intervention may help patients, in many instances, patients develop ventilator-induced lung injury as a result of mechanical ventilation. In particular, high ventilation pressures and high tidal volumes required to maintain proper oxygenation and CO2 elimination can cause lung damage and impair gas exchange.
A study released on March 6, 2020 by Geng-Chin Wu et al. demonstrated that by increasing melatonin with the use of a melatonin receptor agonist, damaging effects of ventilator-induced lung injury could be prevented in rodent models.
The full therapeutic potential of melatonin in its ability to modulate the immune system, especially the critical function of suppressing cytokine storms to prevent progression of acute respiratory distress syndrome (ARDS) and respiratory failure in infected patients was clearly demonstrated in a study by Huang et al. (2019). Huang et al. infected rodents with the highly lethal and infectious H1N1 influenza A virus. Co-treatment of these infected rodents with melatonin and an antiviral drug significantly increased their survival rates compared to mice treated only with antivirals alone!
It is no wonder that none of the pregnant mothers infected by COVID-19 admitted to Zhongnan Hospital of Wuhan University, Wuhan, China, developed severe pneumonia or died; nor were their babies infected by COVID-19. Why?
Melatonin secretion in the third trimester of pregnancy is more than doubled compared to the first trimester.
However, if you noticed in the earlier chart showing melatonin levels during various ages, you will notice that infants younger than three months have very little melatonin. Yet studies from China showed that infants under one year of age who were infected by COVID-19 did not exhibit any severe symptoms. Why?
Nitric Oxide and Ascorbic Acid Inhibits NLRP3 Inflammasomes
Nitric oxide produced in nasal passages is possibly part of the defense system against bacterial and viral infections. Newborns have been found to have an extremely high level of nitric oxide in their barely developed paranasal sinuses. The levels of nitric oxide in nasal passages of infants matched those found in adults.
In rodent sepsis models, nitric oxide was demonstrated to inhibit NLRP3 activation [93]. Ascorbic acid, in addition to supporting the production of nitric oxide [97], can act on multiple levels, reducing oxidative stress, regulating hypoxia signaling, mitochondrial membrane potential, furin expression, and modulation of immune defenses to stem the progression of cytokine storms.
Ascorbic acid can dose-dependently inhibit NLRP3 Inflammasomes both in vitro and in vivo, decreasing IL-1β secretion, without inducing any cytotoxic effects nor cell death.
Thus, the combined use of melatonin and ascorbic acid may prove to be most effective in the treatment for COVID-19 patients, especially those with cardiovascular and hypertension comorbidities.
ACE Inhibitors & COVID-19 – The Connection to CVD, Hypertension & Diabetes
Inflammasomes multiprotein complexes formed in macrophages aggravate pulmonary systemic inflammation. Melatonin has recently been shown to reduce IL-1β secretion and attenuate inflammasome-associated vascular disorders by improving endothelial leakage and suppressing NLRP3 inflammasomes [99]. Patients with underlying CVD conditions may greatly benefit from the use of melatonin in the treatment of COVID-19.
Selenium is a strong scavenger of free radicals. Selenium is believed to be effective against viruses such as Ebola, HIV and influenza A virus. However, selenium may also be an effective inhibitor of angiotensin-converting enzyme (ACE). Patients suffering from cardiovascular diseases, hypertension and diabetes are often prescribed drugs that either inhibit ACE or block angiotensin II type-I receptor (ARB). Both types of drugs increase the expression of ACE2.
The use of selenium during COVID-19 infections therefore, can be problematic. ACE inhibitors actually INCREASE expression of ACE2, and SARS-CoV-2 infects host cells through binding with ACE2 receptors [50]. ACE2 receptors are found on lung epithelial cells, intestines, kidneys and blood vessels. Thus using ACE inhibitors either through medication or supplements risk elevating COVID-19 infection and developing severe or even fatal disease complications.
For further understanding on ways to boost your immune system and how it is able to protect you from COVID-19, please read: Ways to Boost your Immune System during this COVID-19 pandemic.
One question that has not been truly answered is why infants and children under the age of nine do not seem to suffer any severe symptoms upon COVID-19 infection. It is understandable why older patients may be more susceptible to higher risks, but what spares young children? Why are young adults without comorbidities also suffering from pneumonia as a result of COVID-19 infections?
What does this chart measure? An ancient and powerful molecule that everyone is familiar with – melatonin. What does melatonin have to do with SARS-CoV-2?
Melatonin Inhibits NLRP3 Inflammasomes
Melatonin is well known for its chronobiotic effects, regulating biological functions tied to circadian rhythms. Numerous studies have revealed that melatonin exerts effects beyond the control of circadian oscillators. The NLRP3 inflammasome is now recognized as a target for melatonin!
The fact that the pro-inflammatory cytokine storm effects are induced by the activation of NLRP3 inflammasomes, the ability of melatonin to INHIBIT NLRP3 inflammasome elevates this powerful molecule to a truly unique position in the fight against COVID-19. This also means that if a patient, regardless of age, has adequate melatonin, the infectiousness of COVID-19 will be greatly reduced, and the chances of developing ARDS/ALI significantly diminished.
Melatonin is the reason why children under the age of 9 seldom exhibit severe symptoms. In fact, children may exhibit mild or even no symptoms at all, even though they have been infected by SARS-CoV-2. How significant is the difference in melatonin production between children, adults and the elderly?
For most people, peak melatonin production is between the hours of 2 am to 3 am. The maximum melatonin levels measured in healthy adults between the ages of 65 to 70 years appeared to be around 49.3 picograms/ml (pg/ml). Adults more than 75 years of age only have maximum production levels of 27.8 pg/ml.
Young children, on the other hand, have extremely high melatonin levels, compared to adults. The maximum levels recorded for children showed a decline as age increased. Children between the ages of 1 to 5 had peak melatonin at 325 pg/ml, while those between the ages of 5 to 11 already declined to 133 pg/ml.
Compared to healthy adult seniors, a young child can easily have TEN TIMES the amount of peak melatonin levels. But even then, the actual physiological concentration is extremely low. How much is one picogram, exactly?
To give you some perspective, most melatonin supplements are around 3 to 5 mg per capsule or tablet. One milligram equals 1,000,000,000 picograms. That is why the physiological dosage generally recommended for melatonin supplementation is around 0.3 milligram.
The fact that young children have such high melatonin levels explains why they show very mild symptoms after COVID-19 infections.
Melatonin is a potent inhibitor of NLRP3 inflammasomes.
Generally referred to as the “hormone of darkness”, the ability of melatonin to regulate both pro- as well as anti-inflammatory cytokines in different pathophysiological conditions has only been extensively studied in the past several years.
Controlling cytokine storms is one of the major challenges in the treatment of sepsis. The NLRP3 inflammasome has an interesting nickname of “Pandora’s Box for Sepsis”. Yet nature provides all the solutions to difficult health challenges.
NLRP3 inflammasomes is a direct target of melatonin. Animal models of sepsis showed melatonin’s ability to maintain mitochondrial homeostasis, reduce reactive oxygen species and lower production of proinflammatory cytokines. Melatonin was shown to inhibit NLRP3 inflammasomes in mice with myocardial septic conditions, transforming severe myocardial inflammation into milder symptoms, preventing cardiac failure, and significantly enhanced survival rates of septic mice.
An excellent study by Volt et al (2016) showed that chronic low doses of melatonin in aged mice could prevent increase in inflammation, ROS and mitochondria impairments reflective of inflammaging. Volt et al. also showed that acute administration of melatonin could counteract severe inflammatory responses.
It is therefore not surprising to find that melatonin is able to prevent ARDS/ALI through suppression of NLRP3 inflammasomes.
In rodent acute lung injury (ALI) models, melatonin was found to markedly reduce pulmonary injury, lower infiltration of macrophages and neutrophils into lungs. Melatonin protected mice from acute lung injuries by inhibiting the activation of NLRP3 inflammasomes through the suppression of extracellular release of histones and blocking histone-induced NLRP3 inflammasome activation.
In rodent models of acute respiratory distress syndrome (ARDS), combined treatment of melatonin and mitochondria significantly attenuated progression of ARDS.
Melatonin Protects Lung Injury from Mechanical Ventilation Interventions
COVID-19 patients with ARDS/ALI often require intubation with mechanical ventilation. Even though the intervention may help patients, in many instances, patients develop ventilator-induced lung injury as a result of mechanical ventilation. In particular, high ventilation pressures and high tidal volumes required to maintain proper oxygenation and CO2 elimination can cause lung damage and impair gas exchange.
A study released on March 6, 2020 by Geng-Chin Wu et al. demonstrated that by increasing melatonin with the use of a melatonin receptor agonist, damaging effects of ventilator-induced lung injury could be prevented in rodent models.
The full therapeutic potential of melatonin in its ability to modulate the immune system, especially the critical function of suppressing cytokine storms to prevent progression of acute respiratory distress syndrome (ARDS) and respiratory failure in infected patients was clearly demonstrated in a study by Huang et al. (2019). Huang et al. infected rodents with the highly lethal and infectious H1N1 influenza A virus. Co-treatment of these infected rodents with melatonin and an antiviral drug significantly increased their survival rates compared to mice treated only with antivirals alone!
It is no wonder that none of the pregnant mothers infected by COVID-19 admitted to Zhongnan Hospital of Wuhan University, Wuhan, China, developed severe pneumonia or died; nor were their babies infected by COVID-19. Why?
Melatonin secretion in the third trimester of pregnancy is more than doubled compared to the first trimester.
However, if you noticed in the earlier chart showing melatonin levels during various ages, you will notice that infants younger than three months have very little melatonin. Yet studies from China showed that infants under one year of age who were infected by COVID-19 did not exhibit any severe symptoms. Why?
Nitric Oxide and Ascorbic Acid Inhibits NLRP3 Inflammasomes
Nitric oxide produced in nasal passages is possibly part of the defense system against bacterial and viral infections. Newborns have been found to have an extremely high level of nitric oxide in their barely developed paranasal sinuses. The levels of nitric oxide in nasal passages of infants matched those found in adults.
In rodent sepsis models, nitric oxide was demonstrated to inhibit NLRP3 activation [93]. Ascorbic acid, in addition to supporting the production of nitric oxide [97], can act on multiple levels, reducing oxidative stress, regulating hypoxia signaling, mitochondrial membrane potential, furin expression, and modulation of immune defenses to stem the progression of cytokine storms.
Ascorbic acid can dose-dependently inhibit NLRP3 Inflammasomes both in vitro and in vivo, decreasing IL-1β secretion, without inducing any cytotoxic effects nor cell death.
Thus, the combined use of melatonin and ascorbic acid may prove to be most effective in the treatment for COVID-19 patients, especially those with cardiovascular and hypertension comorbidities.
ACE Inhibitors & COVID-19 – The Connection to CVD, Hypertension & Diabetes
Inflammasomes multiprotein complexes formed in macrophages aggravate pulmonary systemic inflammation. Melatonin has recently been shown to reduce IL-1β secretion and attenuate inflammasome-associated vascular disorders by improving endothelial leakage and suppressing NLRP3 inflammasomes [99]. Patients with underlying CVD conditions may greatly benefit from the use of melatonin in the treatment of COVID-19.
Selenium is a strong scavenger of free radicals. Selenium is believed to be effective against viruses such as Ebola, HIV and influenza A virus. However, selenium may also be an effective inhibitor of angiotensin-converting enzyme (ACE). Patients suffering from cardiovascular diseases, hypertension and diabetes are often prescribed drugs that either inhibit ACE or block angiotensin II type-I receptor (ARB). Both types of drugs increase the expression of ACE2.
The use of selenium during COVID-19 infections therefore, can be problematic. ACE inhibitors actually INCREASE expression of ACE2, and SARS-CoV-2 infects host cells through binding with ACE2 receptors [50]. ACE2 receptors are found on lung epithelial cells, intestines, kidneys and blood vessels. Thus using ACE inhibitors either through medication or supplements risk elevating COVID-19 infection and developing severe or even fatal disease complications.
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