Melatonin Based Drugs Inhibit SARS-Cov-2 Entry Into The Brain And Prevent Damage Of Cerebral Vessels

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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 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

As of 20 December 2021, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is estimated to have infected globally approximately 270 Mio.Lpeople, including more than 5 Mio. deaths and more than 500,000 new confirmed infected cases per 24h, reported to WHO (https://covid19.who.int/).

Although COVID-19, the disease caused by the SARS-CoV- 2 virus, targets primarily the lungs leading to an acute respiratory disease, increasing evidence indicates a more widespread infection of other organs including the heart and blood vessels, kidneys, gut, and brain 1.

Among the secondary symptoms, various neurologic signs and symptoms have been reported such as headache, nausea, anosmia, myalgia, hemorrhage, syncope, seizure, and stroke 2. Many of these symptoms remain long after the acute illness has passed, a phenomenon described as “long COVID”, post COVID-19 condition 3 or Post-Acute Sequelae of SARS-CoV-2 infection (PASC) 4 5.

The estimated incidence of a neurological or psychiatric diagnosis in the following 6 months of infection is of 33% with no apparent correlation with severeness of COVID-19 in the acute phase, using electronic health records of over 236,000 patients with COVID-19 6.

Several possible mechanisms explaining the neurological symptoms and the neuro-invasive potential of SARS-CoV-2 have been discussed.

Mechanisms by which the virus accesses the brain include a direct viral infection of host endothelial cells, altering the tight junction proteins forming the blood-brain barrier (BBB) resulting in a leaky BBB (paracellular migration), or a phagocytosis by circulating immune cells followed by brain infiltration of these cells (“Trojan horse” strategy, by transcellular migration) 7, 8, 9.

Another entry gate into the central nervous system is located at the neural-mucosa interface in the olfactory mucosa 10. Much attention has been given to identify potential treatments for lung infection and to control the cytokine storm, but only very few efforts to treat or prevent symptoms of post COVID condition have been made so far.

Melatonin is 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. Additional favorable effects are its neuroprotective, anti-inflammatory and anti-oxidant actions 11.

Melatonin acts through a variety of target proteins 12 of which the two high-affinity G protein-coupled receptors, MT1 and MT2, are best-described 13. Currently marketed drugs (ramelteon, agomelatine, tasimelteon and slow-release melatonin) acting on MT1 and MT2 are indicated for insomnia, « jet-lag », and depression 14 and have been proven to show a good safety profile displaying few or no side-effects 15, 16.

Recent systems-network-pharmacology studies revealed melatonin as one of the top-scoring molecules with potential anti-COVID-19 action 17, 18.

Based on this large spectrum of action of melatonin, its potential beneficial effects to treat COVID-19 have been postulated in several review articles 19, 20, 21, 22. However, only very few experimental data from animal models or humans are currently available.

We have recently shown 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 23.

Here, we 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, we 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.

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