Fig. 10
Melatonin as a ferroptosis inhibitor in the post-COVID-19 trajectory of aging and neurodegeneration. Melatonin as an anti-inflammatory can ease the impact of the SARS-COV-2-induced cytokine storm, which would decrease the chances of BBB disruption and passage of pro-inflammatory cytokines to the brain vicinity. Melatonin can reduce the microglial activation and polarization from M2 (anti-inflammatory) to M1 (pro-inflammatory), which increases the production of BDNF, IL-9, IL-10, and TGF-β. The lower incidencce of neuroinflammation would decrease the chances of iron dysregulation. Melatonin decreses the expression of NF-κB, which decreases the production of anti-inflammatory cytokines and NO, protecting against its harmful impact on iron molecular regulatory machinery (IRE/IRP). Melatonin also can act as iron chelator, diminishing the iron overload/neuroinflammation cycle. Melatonin decreases can activate the SLC7A11 by activating the NrF2 and depression of P53, which would accommodate production of GSH. Also, melatonin acts as an antioxidant by direct scavenging of ROS, helping production of GSH and GPX4, and iron chelation. Melatonin can interfere with the binding of spike protein to ACE2 and can act as an antagonist against Ag II, which would decrease the activation of NOX and production of H2O2. Melatonin can inhibit the process of clockophagy and prevent the deficiency of BMAL1 and CLOCK, decreasing ROS production, lipid peroxidation, and pro-inflammatory cytokines production. Melatonin can reduce lipid peroxidation by inhibiting ACSL4 and LOX, which would decrease the PUFA incorporation in cell membranes and the production of PUFAOOH. The integrated action of melatonin can perfectly protect against ferroptosis. SARS-CoV-2: severe acute respiratory syndrome coronavirus 2, BBB: blood brain barrier, BDNF: brain derived neurotrophic factor, IL-9: interleukin 9, IL-10: interleukin 10, TGF-β: tumor growth factor- β, NF-κB: nuclear factor-κB, FPN1: ferroportin, LIP: labile iron pool, iNOS: inducible nitric oxide synthase, NO: nitric oxide, IRP: iron regulatory protein, IRE: iron responsive element, mRNA: messenger ribonucleic acid, DMT1: divalent metal transporter 1, TFR1: transferrin receptors-1, Fe+2: ferrous iron, Fe+3: Ferric iron, NrF2: nuclear factor erythroid 2-related factor 2, P53: tumor protein p53, SLC7A11: Solute carrier family 7 member 11, SLC3A2: Solute carrier family 3 member 2, GSH: reduced glutathione, GPX4: glutathione peroxidase 4, H202: hydrogen peroxide, OH●: hydroxyl radical, PUFA●: polyunsaturated fatty acid lipid radical, PUFAOOH: lipid hydroperoxide radical, NOX: nicotinamide adenine dinucleotide phosphate oxidase, NADPH: nicotinamide adenine dinucleotide phosphate, ROS: reactive oxygen species, ACE2: angiotensin converting enzyme 2 receptors, Ag II: angiotensin II, ATR1: angiotensin receptor 1, BMAL1: brain and muscle ARNT-like 1 or aryl hydrocarbon receptor nuclear translocator-like protein 1, CLOCK: circadian locomotor output cycles kaput, SQSTM1/p62: sequestosome1. ACSL4: synthetase long-chain family member 4