The potential of melatonin in the prevention and attenuation of oxidative hemolysis and myocardial injury from cd147 SARS-CoV-2 spike protein receptor binding

Abstract

The rapid escalation of pandemic health threats associated with the novel, pathogenic SARS-CoV-2 coronavirus poses unprecedented challenges as proven effective vaccines and drugs have yet to be produced. Refractory hypoxemia and myocardial injury have been observed as two of the major causes of fatality in COVID-19 patients. SARS-CoV-2 spike (S) protein binding to broadly expressed CD147 receptors on erythrocytes causes oxidative hemolysis that may result in refractory hypoxemia and myocardial injury. Both of these life-threatening conditions are further exacerbated by imbalance in ACE2 from spike (S) protein receptor binding. Dysregulation in the CD147-cyclophilin A signaling pathway, together with altered calcium signaling from SARS-CoV-2 ion channel activities, may contribute to hypercoagulation, thrombosis, and cardiac remodeling resulting in heart failure. Melatonin is an ancient pleiotropic molecule with recognized antioxidant properties that is essential for the protection of erythrocytes from oxidative hemolysis. Found in erythrocytes, melatonin can reverse hemolytic anemia, normalize heme synthesis, restore lymphocytes and platelet counts, and reduce vessel permeability during an acute hemolytic crisis by maintaining intracellular calcium homeostasis and reduction of oxidative stress. In acute hypoxic conditions, melatonin is cardioprotective via blunting of cardiopulmonary response to hypoxia and suppressing hypoxia pathways. Melatonin normalizes endothelial-dependent nitric oxide production to prevent multiple organ damage from hypercoagulability, thrombosis, and hypertension associated with oxidative hemolysis and ACE2 deficiency, protecting cardiomyocytes from hypertrophy. This review discusses the full potential of melatonin as a safe and effective therapeutic intervention for the prevention and attenuation of hemoglobinopathies, refractory hypoxemia and myocardial injury during critical COVID-19 infections.

Does Evidence Exist to Blunt Inflammatory Response by Nutraceutical Supplementation during COVID-19 Pandemic? An Overview of Systematic Reviews of Vitamin D, Vitamin C, Melatonin, and Zinc

“…Melatonin is significantly involved in the complex network of psycho-neuroendocrine immunology (PNEI), stress management and aging mechanisms [ 103 ]; furthermore, this compound interacts with cortisol and with a series of immunity and inflammasome pathways, which have been shown to derange in COVID-19 [ 104 ]. This molecule has been repeatedly considered a potentially useful compound in COVID-19 patients [ 48 , 105 , 106 , 107 ]. In fact, in these cases, it may reduce the documented extremely high mitochondria oxidative stress, namely, in lung cells [ 108 ], while conferring a general antioxidant action [ 42 ].…”

“…Lastly, melatonin is known to interact with CD147, a favorite Sars-Cov-2 cell receptor which is diffused in cell walls, erythrocyte and endothelium specifically. This specific feature has been regarded as a protective mechanism against a few pathologic pathways which may occur during COVID-19, such as hemoglobin denaturation, iron accumulation, hypoxia, cardiomyocytes injury and hypercoagulability [ 104 , 106 , 113 ]. Very preliminary clinical data correlate the better survival rate of COVID-19 intubated patients with melatonin exposure [ 114 ]; similarly, a small randomized clinical trial has shown a statistically significant improvement in clinical and instrumental findings in a group of patients treated additionally with melatonin, with a more rapid hospital discharge and return to baseline health [ 115 ].…”

Targeting Host Defense System and Rescuing Compromised Mitochondria to Increase Tolerance against Pathogens by Melatonin May Impact Outcome of Deadly Virus Infection Pertinent to COVID-19

“…Melatonin is a naturally occurring molecule assumed to be present in every species [ 19 ]. Due to its antioxidant, anti-inflammatory, as well as other properties [ 20 , 21 , 22 , 23 , 24 , 25 ], it has been speculated to be a promising molecule for treating COVID-19 patients [ 18 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ], and also other deadly viral infectious diseases [ 48 , 49 , 50 , 51 ]. A small scale clinical trial has also shown promising results [ 52 ].…”

“…The major activities of melatonin are not directed towards the virus per se and, thus, it does not kill the virus, but rather buffers the immune response of the host and increases the tolerance of the host to the virus infection [ 26 ]. Additional assumptions that melatonin may help to block virus entry into cells have also been hypothesized [ 28 , 42 ]. Regardless of this possibility, melatonin seems to reduce the severity and mortality for COVID-19.…”

COVID-19 as an oxygen-deprivation disease

“…Coronavirus disease-19 (COVID- 19) was regarded as an infective-inflammatory viral disease, which mainly affected lungs. SARS-CoV-2 virus attacked cells containing angiotensin-converting enzyme2 (ACE2), particularly surfactantproducing alveolar type II cells.…”