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.