Scientists from France have recently unveiled the utility of melatonin and melatonin-derived medicines in reducing brain entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and subsequently preventing long-term neurological consequences of coronavirus disease 2019 (COVID-19).
The study is currently available on the bioRxiv* preprint server, whilst the article undergoes peer review.
SARS-CoV-2, the causative pathogen of COVID-19, is an enveloped RNA virus of the human beta-coronavirus family. Being a respiratory virus, it primarily affects the upper and lower respiratory tracts. However, there is ample evidence suggesting that the virus also infects blood vessels, heart, kidneys, gastrointestinal (GI) tract, and brain.
Studies have shown that in more than 30% of cases, secondary neurological symptoms, including headache, anosmia, myalgia, hemorrhage, seizure, and stroke, persist for a long period of time. This condition is defined as “long COVID”.
In the current study, the scientists have investigated whether melatonin and melatonin-derived medicines can prevent the brain entry of SARS-CoV-2 in human angiotensin converting enzyme 2 (ACE2)-expressing mice.
Melatonin is an endogenous hormone secreted by the pineal gland. The hormone plays vital roles in the brain in terms of regulating the circadian clock and sleep cycle. In addition, it has antioxidant, anti-inflammatory, and neuroprotective properties.
Efficacy of melatonin treatment
The efficacy of melatonin (low-dose and high-dose) and two clinically-approved melatonin-derived medicines (agomelatine and ramelteon) was tested in SARS-CoV-2-infected mice.
The clinical evaluation indicated a significant improvement in COVID-19 related signs and symptoms (body weight, activity, fatigue, eye closure, and respiration) in melatonin-treated mice compared to untreated mice. A similar tendency was observed in mice treated with melatonin-derived medicines. The most persistent benefits were observed in mice treated with high-dose melatonin.
No significant effect of applied treatments was observed on the lung viral load. However, high-dose melatonin was found to significantly reduce the brain viral load. Other tested drugs also seemed to reduce the brain viral load.
Effect of melatonin on brain inflammation
The SARS-CoV-2 infection caused an induction in brain inflammation. The treatment with high-dose melatonin appeared to reduce the brain levels of pro-inflammatory cytokines and chemokines and the markers of infiltrating macrophages. Other treatments failed to significantly diminish brain inflammation.
Effect of melatonin on brain small vessels
In the mouse brain, SARS-CoV-2 infection significantly disrupted small vessels by inducing viral main protease-mediated apoptosis of endothelial cells. The treatments with high-dose melatonin and melatonin-derived medicines significantly prevented SARS-CoV-2-induced damages to small vessels and helped maintain overall brain vascular density.
Significantly high expressions of two melatonin receptors, MT1 and MT2, were observed in brain endothelial cells. This indicates that melatonin exerts its beneficial effects by specifically targeting endothelial cells. However, the analysis of SARS-CoV-2 entry receptors in these cells revealed that melatonin treatment did not change the expression of exogenously expressed human ACE2. This indicates that melatonin does not prevent viral entry by downregulating ACE2 expression.
Mode of action of melatonin
A series of experiments was conducted in the study to establish the mechanism by which melatonin prevents the entry of SARS-CoV-2 in the brain. The findings revealed that melatonin partially inhibits viral entry by preventing the interaction between viral spike protein and human ACE2. Specifically, melatonin was found to induce conformational changes in the spike – ACE2 complex.
The molecular dynamics simulations conducted in the study revealed the presence of a stable melatonin binding site on ACE2, which is located close to the two helices of ACE2 interacting with the spike receptor-binding domain (RBD). This novel binding site is distinct from the central catalytic site of ACE2, explaining the fact that melatonin does not directly alter the enzymatic activity of ACE2.
Mechanistically, melatonin binding to ACE2 was found to cause conformational changes in the ACE2 interface, leading to altered interaction between spike RBD and ACE2.
The study identifies melatonin as a potent inhibitor of SARS-CoV-2 entry into the brain. Melatonin binding to the allosteric binding site of ACE2 induces conformational changes in the receptor interface, which in turn prevents the interaction between spike RBD and human ACE2.
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.