Study Shows That Melatonin Based Drugs Inhibit SARS-Cov-2 Entry Into The Brain And Prevent Damage Of Cerebral Vessels. Might Be Good For Long-COVID

COVID-19-Supplements: A new study by researchers from Université de Paris-Grance, University Lille-France, University of Lübeck-Germany and DZHK (German Research Centre for Cardiovascular Research) has found that melatonin-based drugs such as agomelatine and ramelteon or even slow-release melatonin supplements can inhibit SARS-Cov-2 entry into the brain and prevent damage of cerebral vessels. The study findings also show that melatonin might be useful in treatment Long COVID as it alleviates some of the neurological symptoms or conditions manifested in Long COVID or PASC (Post-acute Sequelae of COVID-19).

 
The SARS-CoV-2 coronavirus causes the COVID-19 disease, which is a complex disease with short- and long-term respiratory, inflammatory and neurological symptoms.

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SARS-Cov-2 invasion of the brain has been observed in humans and is postulated to be involved in Long COVID or PASC conditions.
 
Brain infection is particularly pronounced in the K18-hACE2 mouse model of COVID-19.
 
The study findings showed that treatment of K18-hACE2 mice with melatonin and two melatonin-derived marketed drugs, agomelatine and ramelteon, prevent SARS-CoV-2 entry in the brain thereby reducing virus-induced damage of small cerebral vessels, immune cell infiltration and brain inflammation.
 
The findings showed that brain entry of SARS-CoV-2 through endothelial cells is prevented by melatonin through allosteric binding to human angiotensin-converting enzyme 2 (ACE2), which interferes with the cell entry receptor function of ACE2 for SARS-CoV-2.
 
The study findings open new perspectives for the repurposing of melatonergic drugs in the prevention of brain infection by SARS-CoV-2 and COVID-19-related long-term neurological symptoms.
 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2021.12.30.474561v1
 
To date the SARS-CoV-2 coronavirus has infected more than 292.6 million people globally and caused more than 5.45 million COVID-19 deaths.
 
It is now believed  that at least up to 35 percent of all those that have been infected with the SARS-CoV-2 coronavirus, whether they were asymptomatic or even exhibited mild, moderate or severe conditions during infection, would still suffer from a variety of long term medical and health issues or conditions collectively known as Long COVID.
 
Among the most common manifestations of Long COVID are neurological issues such as headache, nausea, anosmia, myalgia, cognitive issues, brain fogginess, dementia, hemorrhage, syncope, seizure and stroke.

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Studies have now confirmed that the SARS-CoV-2 coronavirus is able to infect the human brain and cause a wide range of issues. https://www.thailandmedical.news/news/saudi-arabia-mri-study-provide-further-evidence-that-sars-cov-2-affects-the-brain-with-57-9-percent-of-severe-covid-19-patients-having-brain-lesions
 
https://www.thailandmedical.news/news/breaking-german-scientists-discover-that-sars-cov-2-main-protease-mpro-causes-microvascular-brain-pathology
 
https://www.thailandmedical.news/news/breaking-u-s-nih-study-shockingly-reveals-sars-cov-2-viral-persistence-throughout-human-body-and-in-the-brain-even-in-those-who-were-asymptomatic
 
Melatonin is basically a natural hormone produced by the pineal gland during the night with a wide range of effects on the central nervous system (CNS) including the regulation of the biological master clock in the hypothalamus and sleep on-set.
 
Melatonin also possesses neuroprotective, anti-inflammatory and anti-oxidant properties. https://pubmed.ncbi.nlm.nih.gov/31379746/
 
The hormone melatonin acts through a variety of target proteins of which the two high-affinity G protein-coupled receptors, MT1 and MT2, are best-described. https://www.frontiersin.org/articles/10.3389/fendo.2019.00791/full
https://pubmed.ncbi.nlm.nih.gov/27314810/
 
At present, melatonin-based drugs like ramelteon, agomelatine, tasimelteon and slow-release melatonin acting on MT1 and MT2 are indicated for insomnia, ‘jet-lag’, and depression and have been proven to show a good safety profile displaying few or no side-effects.
 
Thailand Medical News had already covered its potential as a key COVID-19 supplement since May 2020. https://www.thailandmedical.news/news/breaking-covid-19-supplements-melatonin-helps-lessen-severity-risk-in-covid-19-patients-by-preventing-cytokine-storms
 
https://www.thailandmedical.news/news/melatonin-and-covid-19:-more-studies-emerging-that-melatonin-is-useful-as-an-adjuvant-treatment-for-covid-19-due-to-its-anti-inflammatory-properties-
 
https://www.thailandmedical.news/news/melatonin-covid-19-columbia-university-study-shows-that-melatonin-increases-survival-rates-of-covid-19-patients-on-ventilators
 
https://www.thailandmedical.news/news/covid-19-supplements-cleveland-clinic-study-highlights-efficacy-of-melatonin-to-help-treat-covid-19
 
https://www.thailandmedical.news/news/covid-19-supplements-yet-another-study-indicates-that-melatonin-can-prevent-severe-covid-19
 
Recent systems-network-pharmacology studies revealed melatonin as one of the top-scoring molecules with potential anti-COVID-19 action.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240149
 
https://pubmed.ncbi.nlm.nih.gov/32194980/
 
To date, based on this large spectrum of action of melatonin, its potential beneficial effects to treat COVID-19 have been postulated in several review articles.
https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC7415199/
 
https://pubmed.ncbi.nlm.nih.gov/33256258/
 
https://pubmed.ncbi.nlm.nih.gov/33759236/
 
https://www.melatonin-research.net/index.php/MR/article/view/136/812
 
It should be noted however that only very few experimental data from animal models or humans are currently available.

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The same study team recently showed that melatonin treatment of K18-hACE2 mice (expressing the human ACE2 receptor) delayed the occurrence of severe clinical outcome and improved survival, associated with a dampening of virus-induced type I and type III interferon production in the lungs. https://onlinelibrary.wiley.com/doi/10.1111/jpi.12772
 
In this new COVID-19-Supplements study, the research team show that daily injection of melatonin and melatonergic compounds largely diminishes SARS-CoV-2 infection of the brain in the K18-hACE2 COVID-19 mouse model, which displays high level of viral brain penetrance, by reducing viral entry through brain endothelial cells and damage of cerebral small vessels. This goes along with a concomitant reduction of neuroinflammatory markers and of markers of immune cell infiltration.
 
Furthermore,the study team identified a new binding target of melatonin, as melatonin reduces the entry of SARS-CoV-2 into brain cells by binding to ACE2, the SARS-CoV-2 cell entry receptor.
 
In order to evaluate the potential beneficial effect of melatonin and the two clinically used melatonin receptor ligands agomelatine (AgoMLT) and ramelteon (RML) on SARS-CoV-2 infection in the brain, the study team chose the K18-hACE2 mice, a robust model of brain infection by SARS-CoV-2.
 
For melatonin, two doses were chosen, 10 mg/kg (MLT10) and 50 mg/kg (MLT50), aiming to maintain levels high over time as melatonin has a short plasma half-life of 20-30 minutes. Intra-peritoneal treatment of mice with compounds started two days before intranasal infection of mice and was repeated daily until sacrifice at day 7 post infection (DPI7) at the latest. Lungs and brain were collected for biochemical and histological analysis.
 
The study findings showed that melatonin treatment improves the clinical score and decreases viral load in the brain.
 
The findings showed decreased expression of the N-protein in treated mice by microscope imaging of brain slices and the difference was even more pronounced in the heavily infected hypothalamic region of the brain.
 
These study findings indicate that treatment with melatonin drugs decreases infection of the brain by SARS-CoV-2, even in the K18-hACE2 mouse model highly susceptible to brain infection.
 
The study also found that melatonin diminishes brain inflammation and inhibits virus-induced damage of cerebral small vessels.
 
The study findings indicate that vascular endothelia might be the target of melatonin and its derivatives mediating their protective effects against brain infection.
 
The study findings show that brain endothelial cells are potential melatonin target cells for receptor-mediated melatonin effects and that melatonin decreases the expression of the endogenous ACE2 and NFκB pathway genes in these cells thus potentially contributing to the protective effect of melatonin on cerebral small vessels. However, downregulation of mouse Ace2 cannot explain the reduction of virus entry in K18-hACE2 mice, which is dependent on human ACE2 expressed under the control of the K18 promoter and the latter is not downregulated by melatonin, suggesting another inhibitory mechanism by melatonin.
 
The study data indicate that melatonin binds to an allosteric binding site at ACE2 and modulates the RBD-ACE2 complex by modifying the position of helix ACE2 19-52 helix that contacts RBD, directly impacting on viral cell entry.
 
The study findings demonstrate that melatonin is able to prevent brain infection by the SARS-CoV-2 coronavirus and also prevent Long term COVID-19 issues associated with brain disturbances or damage induced by the SARS-CoV-2 pathogen.
 
It should also be noted that past studies have showed that melatonin has excellent potential as a prophylactic and therapeutic compound as one observational study show that its usage was associated with a 52% reduced likelihood of positive SARS-CoV-2 PCR test in African Americans. https://pubmed.ncbi.nlm.nih.gov/33156843/
 
It has also been found that the treatment protocol involving melatonin with fluvoxamine, (fluvoxamine helps increase plasma melatonin levels), has reduced the need for hospitalization in high-risk ambulatory patients with COVID-19. https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(21)00448-4/fulltext
 
Hence collectively, these new findings along with past studies highlight a therapeutic potential of melatonin in COVID-19.
 
When taking into consideration the reduction in brain infection and the decrease in the central inflammatory response with melatonin treatment, it is predicted that long-term neurological disorders associated with Long COVID could be avoided/attenuated with melatonin treatment.

Emerging preliminary studies from ongoing studies in Germany and Denmark that will soon be published also show that melatonin works well with the Omicron variant in terms of preventing SARS-CoV-2 infections and also viral persistence.
 
Melatonin is a supplement that can be obtained without a prescription. And is sold as an OTC drug in many pharmacies. It is cheap and has a safe profile when taken correctly. We however do not recommend readers to self-prescribe and start taking melatonin unless they have consulted a licensed doctor first.
 
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