Legend to figures
Figure 1. The nasal cavity could be the gateway of SARS-CoV-2 to reach directly the central nervous system through and affecting the olfactory nerve and olfactory bulb neuroepithelium. Once in the brain SARS-CoV-2 would initiate the innate immune responses at early stages of the COVID-19 resulting in neurological disorders. At this point, high doses of melatonin may exert anti-inflammatory effects and acting as a buffer against enhanced immunoreactivity, which would reduce the neuropathogenesis of SARS-CoV-2 infection.
Figure 2. Hypothetical diagram of the possible targets where melatonin may act against SARS-CoV-2 infection in the CNS. SARS-CoV-2 enters neuronal cells through ACE2, as the receptor binding domain, and TMPRSS2 for spike protein (s-protein) priming. Next, SARS-CoV-2 nucleocapsid triggers clathrin-mediated endocytosis enhancing cytoplasm release. Subsequently, the single negative strand RNA [(-)gRNA] synthesized from (+)gRNA template is used to replicate more copies of viral RNAs. Afterwards, subgenomic RNAs (sgRNAs) synthesized from the (+)gRNA template encode viral structural and accessory proteins, which are assembled with newly synthesized viral RNAs to form new virions. Then, virus particles are transported in secretory vesicles to the plasma membrane and released by exocytosis. Furthermore, the entry of SARS-CoV-2 into neuronal cells may dysregulate mitochondrial metabolism increasing ROS and leading to the induction of endoplasmic reticulum stress. In this regard, melatonin’s high diffusibility allows it to enter in neuronal cells, it binds to CaM and may act on the Ca2+/CaMKII system, regulating the expression of ACE2, modulating the linking between endoplasmic reticulum stress and inflammatory response and scavenging ROS. However, in both MT1/MT2 and α7nAChR receptors, melatonin-mediated signaling may influence in reduced SARS-CoV-2 entry. When SARS-CoV-2 infects the CNS, it triggers the release of pro-inflammatory cytokines. i) TNF-α, which acts by binding to TNFR receptor recruiting TRADD. This protein binds to TRAF2 to phosphorylate and activate the IKK. Then, IKK complex phosphorylates IKBα, resulting in the translocation of NF-κβ to the nucleus, where it targets many coding genes for mediators of inflammatory responses. ii) IL-6 induces gene activation in response to cytokine receptor stimulation. STAT3 proteins dimerize and translocate to the nucleus. JAK2/STAT3 signaling is a crucial link acting as a pivotal mediator of neuroinflammation. iii) The binding of SARS-CoV-2 to the TLR (TLR3/7/9) up-regulates the proinflammatory transcription factor NF-κβ and causes the release of pro-IL-1β which is cleaved by caspase-1, followed by NLRP3 inflammasome activation. Consequently, melatonin may revert these pro-inflammatory effects by inhibiting the JAK2/STAT3 signaling pathway and NF-κβ translocation. In addition, as an anti-inflammatory agent, melatonin inhibits the activation of NLRP3 inflammasome. Stimulation (blue colored) or inhibition (red colored) by melatonin and SARS-CoV-2 are also shown.