COVID-19-Related Brain Injury: The Potential Role of Ferroptosis

References

• Habib HM, Ibrahim S, Zaim A, Ibrahim WH. The role of iron in the pathogenesis of COVID-19 and possible treatment with lactoferrin and other iron chelators. Biomed Pharmacother. 2021;136:111228. doi:10.1016/j.biopha.2021.111228
   PubMed Web of Science ®Google Scholar
• World Health Organization. Coronavirus (COVID-19) dashboard data table. Available from: https://covid19.who.int/. Accessed March 16, 2022.
   Google Scholar
• Liu JM, Tan BH, Wu S, et al. Evidence of central nervous system infection and neuroinvasive routes, as well as neurological involvement, in the lethality of SARS-CoV-2 infection. J Med Virol. 2021;93(3):1304–1313. doi:10.1002/jmv.26570
   PubMed Web of Science ®Google Scholar
• Mao L, Jin H, Wang M, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. 2020;77(6):683–690. doi:10.1001/jamaneurol.2020.1127
   PubMed Web of Science ®Google Scholar
• Najjar S, Najjar A, Chong DJ, et al. Central nervous system complications associated with SARS-CoV-2 infection: integrative concepts of pathophysiology and case reports. J Neuroinflammation. 2020;17(1):231. doi:10.1186/s12974-020-01896-0
   PubMed Web of Science ®Google Scholar
• Divani AA, Andalib S, Biller J, et al. Central nervous system manifestations associated with COVID-19. Curr Neurol Neurosci Rep. 2020;20(12):60. doi:10.1007/s11910-020-01079-7
   PubMed Web of Science ®Google Scholar
• Morgello S. Coronaviruses and the central nervous system. J Neurovirol. 2020;26(4):459–473. doi:10.1007/s13365-020-00868-7
   PubMed Web of Science ®Google Scholar
• Boldrini M, Canoll PD, Klein RS. How COVID-19 affects the brain. JAMA Psychiatry. 2021;78(6):682–683. doi:10.1001/jamapsychiatry.2021.0500
   PubMed Web of Science ®Google Scholar
• De Felice FG, Tovar-Moll F, Moll J, Munoz DP, Ferreira ST. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the central nervous system. Trends Neurosci. 2020;43(6):355–357. doi:10.1016/j.tins.2020.04.004
   PubMed Web of Science ®Google Scholar
• Kaseda ET, Levine AJ. Post-traumatic stress disorder: a differential diagnostic consideration for COVID-19 survivors. Clin Neuropsychol. 2020;34(7–8):1498–1514. doi:10.1080/13854046.2020.1811894
   PubMed Web of Science ®Google Scholar
• Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149(5):1060–1072. doi:10.1016/j.cell.2012.03.042
   PubMed Web of Science ®Google Scholar
• Wan J, Ren H, Wang J. Iron toxicity, lipid peroxidation and ferroptosis after intracerebral haemorrhage. Stroke Vasc Neurol. 2019;4(2):93–95. doi:10.1136/svn-2018-000205
   PubMedGoogle Scholar
• Weiland A, Wang Y, Wu W, et al. Ferroptosis and its role in diverse brain diseases. Mol Neurobiol. 2019;56(7):4880–4893. doi:10.1007/s12035-018-1403-3
   PubMed Web of Science ®Google Scholar
• Qu XF, Liang TY, Wu DG, et al. Acyl-CoA synthetase long chain family member 4 plays detrimental role in early brain injury after subarachnoid hemorrhage in rats by inducing ferroptosis. CNS Neurosci Ther. 2021;27(4):449–463. doi:10.1111/cns.13548
   PubMed Web of Science ®Google Scholar
• Lane DJR, Ayton S, Bush AI. Iron and Alzheimer’s disease: an update on emerging mechanisms. J Alzheimers Dis. 2018;64(s1):S379–s395. doi:10.3233/JAD-179944
   PubMed Web of Science ®Google Scholar
• Mahoney-Sánchez L, Bouchaoui H, Ayton S, et al. Ferroptosis and its potential role in the physiopathology of Parkinson’s disease. Prog Neurobiol. 2021;196:101890. doi:10.1016/j.pneurobio.2020.101890
   PubMed Web of Science ®Google Scholar
• Yang M, Lai CL. SARS-CoV-2 infection: can ferroptosis be a potential treatment target for multiple organ involvement? Cell Death Discov. 2020;6:130. doi:10.1038/s41420-020-00369-w
   PubMed Web of Science ®Google Scholar
• Fitsiori A, Pugin D, Thieffry C, Lalive P, Vargas MI. COVID-19 is associated with an unusual pattern of brain microbleeds in critically ill patients. J Neuroimaging. 2020;30(5):593–597. doi:10.1111/jon.12755
   PubMed Web of Science ®Google Scholar
• Rodriguez-Morales AJ, Cardona-Ospina JA, Gutiérrez-Ocampo E, et al. Clinical, laboratory and imaging features of COVID-19: a systematic review and meta-analysis. Travel Med Infect Dis. 2020;34:101623. doi:10.1016/j.tmaid.2020.101623
   PubMed Web of Science ®Google Scholar
• Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020;323(11):1061–1069. doi:10.1001/jama.2020.1585
   PubMed Web of Science ®Google Scholar
• Beltrán-Corbellini Á, Chico-García JL, Martínez-Poles J, et al. Acute-onset smell and taste disorders in the context of COVID-19: a pilot multicentre polymerase chain reaction based case-control study. Eur J Neurol. 2020;27(9):1738–1741. doi:10.1111/ene.14273
   PubMed Web of Science ®Google Scholar
• Koralnik IJ, Tyler KL. COVID-19: a global threat to the nervous system. Ann Neurol. 2020;88(1):1–11. doi:10.1002/ana.25807
   PubMed Web of Science ®Google Scholar
• Zhou Y, Xu J, Hou Y, et al. Network medicine links SARS-CoV-2/COVID-19 infection to brain microvascular injury and neuroinflammation in dementia-like cognitive impairment. Alzheimers Res Ther. 2021;13(1):110. doi:10.1186/s13195-021-00850-3
   PubMed Web of Science ®Google Scholar
• Helms J, Kremer S, Merdji H, et al. Neurologic features in severe SARS-CoV-2 infection. N Engl J Med. 2020;382(23):2268–2270. doi:10.1056/NEJMc2008597
   PubMed Web of Science ®Google Scholar
• Jaywant A, Vanderlind WM, Alexopoulos GS, et al. Frequency and profile of objective cognitive deficits in hospitalized patients recovering from COVID-19. Neuropsychopharmacology. 2021:1–6.
   Web of Science ®Google Scholar
• Zombori L, Bacon M, Wood H, et al. Severe cortical damage associated with COVID-19 case report. Seizure. 2021;84:66–68. doi:10.1016/j.seizure.2020.11.014
   PubMed Web of Science ®Google Scholar
• Lee MH, Perl DP, Nair G, et al. Microvascular injury in the brains of patients with Covid-19. N Engl J Med. 2021;384(5):481–483. doi:10.1056/NEJMc2033369
   PubMed Web of Science ®Google Scholar
• Pajo AT, Espiritu AI, Apor A, Jamora RDG. Neuropathologic findings of patients with COVID-19: a systematic review. Neurol Sci. 2021;42(4):1255–1266. doi:10.1007/s10072-021-05068-7
   PubMed Web of Science ®Google Scholar
• Markus HS, Brainin M. COVID-19 and stroke-A global World Stroke Organization perspective. Int J Stroke. 2020;15(4):361–364. doi:10.1177/1747493020923472
   PubMed Web of Science ®Google Scholar
• Wijeratne T, Sales C, Karimi L, Crewther SG. Acute ischemic stroke in COVID-19: a case-based systematic review. Front Neurol. 2020;11:1031. doi:10.3389/fneur.2020.01031
   PubMed Web of Science ®Google Scholar
• Vogrig A, Gigli GL, Bnà C, Morassi M. Stroke in patients with COVID-19: clinical and neuroimaging characteristics. Neurosci Lett. 2021;743:135564. doi:10.1016/j.neulet.2020.135564
   PubMed Web of Science ®Google Scholar
• Li Y, Li M, Wang M, et al. Acute cerebrovascular disease following COVID-19: a single center, retrospective, observational study. Stroke Vasc Neurol. 2020;5(3):279–284. doi:10.1136/svn-2020-000431
   PubMedGoogle Scholar
• Li K, Wohlford-Lenane C, Perlman S, et al. Middle east respiratory syndrome coronavirus causes multiple organ damage and lethal disease in mice transgenic for human dipeptidyl peptidase 4. J Infect Dis. 2016;213(5):712–722. doi:10.1093/infdis/jiv499
   PubMed Web of Science ®Google Scholar
• Li Z, Liu T, Yang N, et al. Neurological manifestations of patients with COVID-19: potential routes of SARS-CoV-2 neuroinvasion from the periphery to the brain. Front Med. 2020;14(5):533–541. doi:10.1007/s11684-020-0786-5
   PubMed Web of Science ®Google Scholar
• Yachou Y, El Idrissi A, Belapasov V, Ait Benali S. Neuroinvasion, neurotropic, and neuroinflammatory events of SARS-CoV-2: understanding the neurological manifestations in COVID-19 patients. Neurol Sci. 2020;41(10):2657–2669. doi:10.1007/s10072-020-04575-3
   PubMed Web of Science ®Google Scholar
• Perrin P, Collongues N, Baloglu S, et al. Cytokine release syndrome-associated encephalopathy in patients with COVID-19. Eur J Neurol. 2021;28(1):248–258. doi:10.1111/ene.14491
   PubMed Web of Science ®Google Scholar
• Guadarrama-Ortiz P, Choreño-Parra JA, Sánchez-Martínez CM, et al. Neurological aspects of SARS-CoV-2 infection: mechanisms and manifestations. Front Neurol. 2020;11:1039. doi:10.3389/fneur.2020.01039
   PubMed Web of Science ®Google Scholar
• Michetti F, D’Ambrosi N, Toesca A, et al. The S100B story: from biomarker to active factor in neural injury. J Neurochem. 2019;148(2):168–187. doi:10.1111/jnc.14574
   PubMed Web of Science ®Google Scholar
• Kadono Y, Nakamura Y, Ogawa Y, et al. A case of COVID-19 infection presenting with a seizure following severe brain edema. Seizure. 2020;80:53–55. doi:10.1016/j.seizure.2020.06.015
   PubMed Web of Science ®Google Scholar
• Vinayagam S, Sattu K. SARS-CoV-2 and coagulation disorders in different organs. Life Sci. 2020;260:118431. doi:10.1016/j.lfs.2020.118431
   PubMed Web of Science ®Google Scholar
• Al Saiegh F, Ghosh R, Leibold A, et al. Status of SARS-CoV-2 in cerebrospinal fluid of patients with COVID-19 and stroke. J Neurol Neurosurg Psychiatry. 2020;91(8):846–848. doi:10.1136/jnnp-2020-323522
   PubMed Web of Science ®Google Scholar
• Meinhardt J, Radke J, Dittmayer C, et al. Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19. Nat Neurosci. 2021;24(2):168–175. doi:10.1038/s41593-020-00758-5
   PubMed Web of Science ®Google Scholar
• Mahalaxmi I, Kaavya J, Mohana Devi S, Balachandar V. COVID-19 and olfactory dysfunction: a possible associative approach towards neurodegenerative diseases. J Cell Physiol. 2021;236(2):763–770. doi:10.1002/jcp.29937
   PubMed Web of Science ®Google Scholar
• Chiu A, Fischbein N, Wintermark M, et al. COVID-19-induced anosmia associated with olfactory bulb atrophy. Neuroradiology. 2021;63(1):147–148. doi:10.1007/s00234-020-02554-1
   PubMed Web of Science ®Google Scholar
• Zhou L, Xu Z, Castiglione GM, et al. ACE2 and TMPRSS2 are expressed on the human ocular surface, suggesting susceptibility to SARS-CoV-2 infection. Ocul Surf. 2020;18(4):537–544. doi:10.1016/j.jtos.2020.06.007
   PubMed Web of Science ®Google Scholar
• Panariello F, Cellini L, Speciani M, De Ronchi D, Atti AR. How does SARS-CoV-2 affect the central nervous system? A working hypothesis. Front Psychiatry. 2020;11:582345. doi:10.3389/fpsyt.2020.582345
   PubMed Web of Science ®Google Scholar
• Li YC, Bai WZ, Hashikawa T. The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients. J Med Virol. 2020;92(6):552–555. doi:10.1002/jmv.25728
   PubMed Web of Science ®Google Scholar
• Virhammar J, Kumlien E, Fällmar D, et al. Acute necrotizing encephalopathy with SARS-CoV-2 RNA confirmed in cerebrospinal fluid. Neurology. 2020;95(10):445–449. doi:10.1212/WNL.0000000000010250
   PubMed Web of Science ®Google Scholar
• Bostancıklıoğlu M. Temporal correlation between neurological and gastrointestinal symptoms of SARS-CoV-2. Inflamm Bowel Dis. 2020;26(8):e89–e91. doi:10.1093/ibd/izaa131
   PubMed Web of Science ®Google Scholar
• Andriuta D, Roger PA, Thibault W, et al. COVID-19 encephalopathy: detection of antibodies against SARS-CoV-2 in CSF. J Neurol. 2020;267(10):2810–2811. doi:10.1007/s00415-020-09975-1
   PubMed Web of Science ®Google Scholar
• Satarker S, Nampoothiri M. Involvement of the nervous system in COVID-19: the bell should toll in the brain. Life Sci. 2020;262:118568. doi:10.1016/j.lfs.2020.118568
   PubMed Web of Science ®Google Scholar
• Dong M, Zhang J, Ma X, et al. ACE2, TMPRSS2 distribution and extrapulmonary organ injury in patients with COVID-19. Biomed Pharmacother. 2020;131:110678. doi:10.1016/j.biopha.2020.110678
   PubMed Web of Science ®Google Scholar
• Pezzini A, Padovani A. Lifting the mask on neurological manifestations of COVID-19. Nat Rev Neurol. 2020;16(11):636–644. doi:10.1038/s41582-020-0398-3
   PubMed Web of Science ®Google Scholar
• Aghagoli G, Gallo Marin B, Katchur NJ, et al. Neurological involvement in COVID-19 and potential mechanisms: a review. Neurocrit Care. 2021;34(3):1062–1071. doi:10.1007/s12028-020-01049-4
   PubMed Web of Science ®Google Scholar
• Terpos E, Ntanasis-Stathopoulos I, Elalamy I, et al. Hematological findings and complications of COVID-19. Am J Hematol. 2020;95(7):834–847. doi:10.1002/ajh.25829
   PubMed Web of Science ®Google Scholar
• Loganathan S, Kuppusamy M, Wankhar W, et al. Angiotensin-converting enzyme 2 (ACE2): COVID 19 gate way to multiple organ failure syndromes. Respir Physiol Neurobiol. 2021;283:103548. doi:10.1016/j.resp.2020.103548
   PubMed Web of Science ®Google Scholar
• Girija ASS, Shankar EM, Larsson M. Could SARS-CoV-2-induced hyperinflammation magnify the severity of coronavirus disease (CoViD-19) leading to acute respiratory distress syndrome? Front Immunol. 2020;11:1206. doi:10.3389/fimmu.2020.01206
   PubMed Web of Science ®Google Scholar
• Zhu H, Wang Z, Yu J, et al. Role and mechanisms of cytokines in the secondary brain injury after intracerebral hemorrhage. Prog Neurobiol. 2019;178:101610. doi:10.1016/j.pneurobio.2019.03.003
   PubMed Web of Science ®Google Scholar
• De Santis G. SARS-CoV-2: a new virus but a familiar inflammation brain pattern. Brain Behav Immun. 2020;87:95–96. doi:10.1016/j.bbi.2020.04.066
   PubMed Web of Science ®Google Scholar
• Grohmann U, Mondanelli G, Belladonna ML, et al. Amino-acid sensing and degrading pathways in immune regulation. Cytokine Growth Factor Rev. 2017;35:37–45. doi:10.1016/j.cytogfr.2017.05.004
   PubMed Web of Science ®Google Scholar
• Bouças AP, Rheinheimer J, Lagopoulos J. Why severe COVID-19 patients are at greater risk of developing depression: a molecular perspective. Neuroscientist. 2020:1073858420967892. doi:10.1177/1073858420967892
   Web of Science ®Google Scholar
• Turski WA, Wnorowski A, Turski GN, Turski CA, Turski L. AhR and IDO1 in pathogenesis of Covid-19 and the “Systemic AhR Activation Syndrome:” a translational review and therapeutic perspectives. Restor Neurol Neurosci. 2020;38(4):343–354. doi:10.3233/RNN-201042
   PubMed Web of Science ®Google Scholar
• Engin AB, Engin ED, Engin A. The effect of environmental pollution on immune evasion checkpoints of SARS-CoV-2. Environ Toxicol Pharmacol. 2021;81:103520. doi:10.1016/j.etap.2020.103520
   PubMed Web of Science ®Google Scholar
• Ng J, Papandreou A, Heales SJ, Kurian MA. Monoamine neurotransmitter disorders–clinical advances and future perspectives. Nat Rev Neurol. 2015;11(10):567–584. doi:10.1038/nrneurol.2015.172
   PubMed Web of Science ®Google Scholar
• Li J, Cao F, Yin HL, et al. Ferroptosis: past, present and future. Cell Death Dis. 2020;11(2):88. doi:10.1038/s41419-020-2298-2
   PubMed Web of Science ®Google Scholar
• Amaral EP, Costa DL, Namasivayam S, et al. A major role for ferroptosis in Mycobacterium tuberculosis-induced cell death and tissue necrosis. J Exp Med. 2019;216(3):556–570. doi:10.1084/jem.20181776
   PubMed Web of Science ®Google Scholar
• Conrad M, Kagan VE, Bayir H, et al. Regulation of lipid peroxidation and ferroptosis in diverse species. Genes Dev. 2018;32(9–10):602–619. doi:10.1101/gad.314674.118
   PubMed Web of Science ®Google Scholar
• Bogdan AR, Miyazawa M, Hashimoto K, Tsuji Y. Regulators of iron homeostasis: new players in metabolism, cell death, and disease. Trends Biochem Sci. 2016;41(3):274–286. doi:10.1016/j.tibs.2015.11.012
   PubMed Web of Science ®Google Scholar
• Gao M, Yi J, Zhu J, et al. Role of mitochondria in ferroptosis. Mol Cell. 2019;73(2):354–363.e3. doi:10.1016/j.molcel.2018.10.042
   PubMed Web of Science ®Google Scholar
• Ibrahim WH, Habib HM, Kamal H, St clair DK, Chow CK. Mitochondrial superoxide mediates labile iron level: evidence from Mn-SOD-transgenic mice and heterozygous knockout mice and isolated rat liver mitochondria. Free Radic Biol Med. 2013;65:143–149. doi:10.1016/j.freeradbiomed.2013.06.026
   PubMed Web of Science ®Google Scholar
• Xie Y, Hou W, Song X, et al. Ferroptosis: process and function. Cell Death Differ. 2016;23(3):369–379. doi:10.1038/cdd.2015.158
   PubMed Web of Science ®Google Scholar
• Sun Y, Chen P, Zhai B, et al. The emerging role of ferroptosis in inflammation. Biomed Pharmacother. 2020;127:110108. doi:10.1016/j.biopha.2020.110108
   PubMed Web of Science ®Google Scholar
• Song X, Zhu S, Chen P, et al. AMPK-mediated BECN1 phosphorylation promotes ferroptosis by directly blocking system X(c)(-) activity. Curr Biol. 2018;28(15):2388–2399.e5. doi:10.1016/j.cub.2018.05.094
   PubMed Web of Science ®Google Scholar
• Guo Y, Liu X, Liu D, et al. Inhibition of BECN1 suppresses lipid peroxidation by increasing system X(c)(-) activity in early brain injury after subarachnoid hemorrhage. J Mol Neurosci. 2019;67(4):622–631. doi:10.1007/s12031-019-01272-5
   PubMed Web of Science ®Google Scholar
• Forcina GC, Dixon SJ. GPX4 at the crossroads of lipid homeostasis and ferroptosis. Proteomics. 2019;19(18):e1800311. doi:10.1002/pmic.201800311
   PubMed Web of Science ®Google Scholar
• Stockwell BR, Friedmann Angeli JP, Bayir H, et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell. 2017;171(2):273–285. doi:10.1016/j.cell.2017.09.021
   PubMed Web of Science ®Google Scholar
• Yang WS, SriRamaratnam R, Welsch ME, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014;156(1–2):317–331. doi:10.1016/j.cell.2013.12.010
   PubMed Web of Science ®Google Scholar
• Sui X, Zhang R, Liu S, et al. RSL3 drives ferroptosis through GPX4 inactivation and ROS production in colorectal cancer. Front Pharmacol. 2018;9:1371. doi:10.3389/fphar.2018.01371
   PubMed Web of Science ®Google Scholar
• Alim I, Caulfield JT, Chen Y, et al. Selenium drives a transcriptional adaptive program to block ferroptosis and treat stroke. Cell. 2019;177(5):1262–1279.e25. doi:10.1016/j.cell.2019.03.032
   PubMed Web of Science ®Google Scholar
• Hassannia B, Wiernicki B, Ingold I, et al. Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma. J Clin Invest. 2018;128(8):3341–3355. doi:10.1172/JCI99032
   PubMed Web of Science ®Google Scholar
• Wen X, Wu J, Wang F, et al. Deconvoluting the role of reactive oxygen species and autophagy in human diseases. Free Radic Biol Med. 2013;65:402–410. doi:10.1016/j.freeradbiomed.2013.07.013
   PubMed Web of Science ®Google Scholar
• Latunde-Dada GO. Ferroptosis: role of lipid peroxidation, iron and ferritinophagy. Biochim Biophys Acta Gen Subj. 2017;1861(8):1893–1900. doi:10.1016/j.bbagen.2017.05.019
   PubMed Web of Science ®Google Scholar
• Shah R, Margison K, Pratt DA. The potency of diarylamine radical-trapping antioxidants as inhibitors of ferroptosis underscores the role of autoxidation in the mechanism of cell death. ACS Chem Biol. 2017;12(10):2538–2545. doi:10.1021/acschembio.7b00730
   PubMed Web of Science ®Google Scholar
• Feng H, Stockwell BR. Unsolved mysteries: how does lipid peroxidation cause ferroptosis? PLoS Biol. 2018;16(5):e2006203. doi:10.1371/journal.pbio.2006203
   PubMed Web of Science ®Google Scholar
• Shen L, Lin D, Li X, et al. Ferroptosis in acute central nervous system injuries: the future direction? Front Cell Dev Biol. 2020;8:594. doi:10.3389/fcell.2020.00594
   PubMed Web of Science ®Google Scholar
• Li Q, Han X, Lan X, et al. Inhibition of neuronal ferroptosis protects hemorrhagic brain. JCI Insight. 2017;2(7):e90777. doi:10.1172/jci.insight.90777
   PubMed Web of Science ®Google Scholar
• Li Q, Weiland A, Chen X, et al. Ultrastructural characteristics of neuronal death and white matter injury in mouse brain tissues after intracerebral hemorrhage: coexistence of ferroptosis, autophagy, and necrosis. Front Neurol. 2018;9:581. doi:10.3389/fneur.2018.00581
   PubMed Web of Science ®Google Scholar
• Chang CF, Cho S, Wang J. (-)-Epicatechin protects hemorrhagic brain via synergistic Nrf2 pathways. Ann Clin Transl Neurol. 2014;1(4):258–271. doi:10.1002/acn3.54
   PubMed Web of Science ®Google Scholar
• Qin D, Wang J, Le A, et al. Traumatic brain injury: ultrastructural features in neuronal ferroptosis, glial cell activation and polarization, and blood-brain barrier breakdown. Cells. 2021;10:5. doi:10.3390/cells10051009
   Web of Science ®Google Scholar
• Tang S, Gao P, Chen H, et al. The role of iron, its metabolism and ferroptosis in traumatic brain injury. Front Cell Neurosci. 2020;14:590789. doi:10.3389/fncel.2020.590789
   PubMed Web of Science ®Google Scholar
• Gao M, Monian P, Quadri N, Ramasamy R, Jiang X. Glutaminolysis and transferrin regulate ferroptosis. Mol Cell. 2015;59(2):298–308. doi:10.1016/j.molcel.2015.06.011
   PubMed Web of Science ®Google Scholar
• DeGregorio-Rocasolano N, Martí-Sistac O, Gasull T. Deciphering the iron side of stroke: neurodegeneration at the crossroads between iron dyshomeostasis, excitotoxicity, and ferroptosis. Front Neurosci. 2019;13:85. doi:10.3389/fnins.2019.00085
   PubMed Web of Science ®Google Scholar
• Zhou B, Liu J, Kang R, et al. Ferroptosis is a type of autophagy-dependent cell death. Semin Cancer Biol. 2020;66:89–100. doi:10.1016/j.semcancer.2019.03.002
   PubMed Web of Science ®Google Scholar
• Cavezzi A, Troiani E, Corrao S. COVID-19: hemoglobin, iron, and hypoxia beyond inflammation. A narrative review. Clin Pract. 2020;10(2):1271. doi:10.4081/cp.2020.1271
   PubMed Web of Science ®Google Scholar
• Liu W, Zhang S, Nekhai S, Liu S. Depriving iron supply to the virus represents a promising adjuvant therapeutic against viral survival. Curr Clin Microbiol Rep. 2020;7:13–19.
   PubMed Web of Science ®Google Scholar
• Bailey DK, Clark W, Kosman DJ. The iron chelator, PBT434, modulates transcellular iron trafficking in brain microvascular endothelial cells. PLoS One. 2021;16(7):e0254794. doi:10.1371/journal.pone.0254794
   PubMed Web of Science ®Google Scholar
• Dai S, Hua Y, Keep RF, et al. Minocycline attenuates brain injury and iron overload after intracerebral hemorrhage in aged female rats. Neurobiol Dis. 2019;126:76–84. doi:10.1016/j.nbd.2018.06.001
   PubMed Web of Science ®Google Scholar
• Li Q, Wan J, Lan X, et al. Neuroprotection of brain-permeable iron chelator VK-28 against intracerebral hemorrhage in mice. J Cereb Blood Flow Metab. 2017;37(9):3110–3123. doi:10.1177/0271678X17709186
   PubMed Web of Science ®Google Scholar
• Hua W, Chen X, Wang J, et al. Mechanisms and potential therapeutic targets for spontaneous intracerebral hemorrhage. Brain Hemorrhages. 2020;1(2):99–104. doi:10.1016/j.hest.2020.02.002
   Google Scholar
• Li Y, Feng D, Wang Z, et al. Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia/reperfusion. Cell Death Differ. 2019;26(11):2284–2299. doi:10.1038/s41418-019-0299-4
   PubMed Web of Science ®Google Scholar
• Sha W, Hu F, Xi Y, Chu Y, Bu S. Mechanism of ferroptosis and its role in type 2 diabetes mellitus. J Diabetes Res. 2021;2021:9999612. doi:10.1155/2021/9999612
   PubMed Web of Science ®Google Scholar
• Lee H, Zandkarimi F, Zhang Y, et al. Energy-stress-mediated AMPK activation inhibits ferroptosis. Nat Cell Biol. 2020;22(2):225–234. doi:10.1038/s41556-020-0461-8
   PubMed Web of Science ®Google Scholar
• Ren JX, Sun X, Yan XL, Guo ZN, Yang Y. Ferroptosis in neurological diseases. Front Cell Neurosci. 2020;14:218. doi:10.3389/fncel.2020.00218
   PubMed Web of Science ®Google Scholar
• Huang S, Li S, Feng H, Chen Y. Iron metabolism disorders for cognitive dysfunction after mild traumatic brain injury. Front Neurosci. 2021;15:587197. doi:10.3389/fnins.2021.587197
   PubMed Web of Science ®Google Scholar
• Ingold I, Berndt C, Schmitt S, et al. Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis. Cell. 2018;172(3):409–422.e21. doi:10.1016/j.cell.2017.11.048
   PubMed Web of Science ®Google Scholar
• Chen D, Fan Z, Rauh M, et al. ATF4 promotes angiogenesis and neuronal cell death and confers ferroptosis in a xCT-dependent manner. Oncogene. 2017;36(40):5593–5608. doi:10.1038/onc.2017.146
   PubMed Web of Science ®Google Scholar
• Codazzi F, Pelizzoni I, Zacchetti D, Grohovaz F. Iron entry in neurons and astrocytes: a link with synaptic activity. Front Mol Neurosci. 2015;8:18. doi:10.3389/fnmol.2015.00018
   PubMed Web of Science ®Google Scholar
• Ratan RR. The chemical biology of ferroptosis in the central nervous system. Cell Chem Biol. 2020;27(5):479–498. doi:10.1016/j.chembiol.2020.03.007
   PubMed Web of Science ®Google Scholar
• Tuo QZ, Lei P, Jackman KA, et al. Tau-mediated iron export prevents ferroptotic damage after ischemic stroke. Mol Psychiatry. 2017;22(11):1520–1530. doi:10.1038/mp.2017.171
   PubMed Web of Science ®Google Scholar
• Chen J, Wang Y, Wu J, et al. The potential value of targeting ferroptosis in early brain injury after acute CNS disease. Front Mol Neurosci. 2020;13:110. doi:10.3389/fnmol.2020.00110
   PubMed Web of Science ®Google Scholar
• Chen Y, Liu S, Li J, et al. The latest view on the mechanism of ferroptosis and its research progress in spinal cord injury. Oxid Med Cell Longev. 2020;2020:6375938. doi:10.1155/2020/6375938
   PubMed Web of Science ®Google Scholar
• Xie BS, Wang YQ, Lin Y, et al. Inhibition of ferroptosis attenuates tissue damage and improves long-term outcomes after traumatic brain injury in mice. CNS Neurosci Ther. 2019;25(4):465–475. doi:10.1111/cns.13069
   PubMed Web of Science ®Google Scholar
• Chen S, Chen Y, Zhang Y, et al. Iron metabolism and ferroptosis in epilepsy. Front Neurosci. 2020;14:601193. doi:10.3389/fnins.2020.601193
   PubMed Web of Science ®Google Scholar
• Yan N, Zhang J. Iron metabolism, ferroptosis, and the links with Alzheimer’s disease. Front Neurosci. 2019;13:1443. doi:10.3389/fnins.2019.01443
   PubMed Web of Science ®Google Scholar
• Beyrouti R, Adams ME, Benjamin L, et al. Characteristics of ischaemic stroke associated with COVID-19. J Neurol Neurosurg Psychiatry. 2020;91(8):889–891. doi:10.1136/jnnp-2020-323586
   PubMed Web of Science ®Google Scholar
• Dahan S, Segal G, Katz I, et al. Ferritin as a marker of severity in COVID-19 patients: a fatal correlation. Isr Med Assoc J. 2020;22(8):494–500.
   PubMed Web of Science ®Google Scholar
• Colafrancesco S, Alessandri C, Conti F, Priori R. COVID-19 gone bad: a new character in the spectrum of the hyperferritinemic syndrome? Autoimmun Rev. 2020;19(7):102573. doi:10.1016/j.autrev.2020.102573
   PubMed Web of Science ®Google Scholar
• Edeas M, Saleh J, Peyssonnaux C. Iron: innocent bystander or vicious culprit in COVID-19 pathogenesis? Int J Infect Dis. 2020;97:303–305. doi:10.1016/j.ijid.2020.05.110
   PubMed Web of Science ®Google Scholar
• Hernández-Fernández F, Sandoval Valencia H, Barbella-Aponte RA, et al. Cerebrovascular disease in patients with COVID-19: neuroimaging, histological and clinical description. Brain. 2020;143(10):3089–3103. doi:10.1093/brain/awaa239
   PubMed Web of Science ®Google Scholar
• Daher R, Manceau H, Karim Z. Iron metabolism and the role of the iron-regulating hormone hepcidin in health and disease. Presse Med. 2017;46(12 Pt 2):e272–e278. doi:10.1016/j.lpm.2017.10.006
   PubMed Web of Science ®Google Scholar
• Bessman NJ, Mathieu JRR, Renassia C, et al. Dendritic cell-derived hepcidin sequesters iron from the microbiota to promote mucosal healing. Science. 2020;368(6487):186–189. doi:10.1126/science.aau6481
   PubMed Web of Science ®Google Scholar
• Ehsani S. COVID-19 and iron dysregulation: distant sequence similarity between hepcidin and the novel coronavirus spike glycoprotein. Biol Direct. 2020;15(1):19. doi:10.1186/s13062-020-00275-2
   PubMed Web of Science ®Google Scholar
• Ganz T. Iron and infection. Int J Hematol. 2018;107(1):7–15. doi:10.1007/s12185-017-2366-2
   PubMed Web of Science ®Google Scholar
• Frazer DM, Anderson GJ. The regulation of iron transport. Biofactors. 2014;40(2):206–214. doi:10.1002/biof.1148
   PubMed Web of Science ®Google Scholar
• Wang J, Doré S. Heme oxygenase 2 deficiency increases brain swelling and inflammation after intracerebral hemorrhage. Neuroscience. 2008;155(4):1133–1141. doi:10.1016/j.neuroscience.2008.07.004
   PubMed Web of Science ®Google Scholar
• Wang J, Doré S. Heme oxygenase-1 exacerbates early brain injury after intracerebral haemorrhage. Brain. 2007;130(Pt 6):1643–1652. doi:10.1093/brain/awm095
   PubMed Web of Science ®Google Scholar
• Linkermann A, Stockwell BR, Krautwald S, Anders HJ. Regulated cell death and inflammation: an auto-amplification loop causes organ failure. Nat Rev Immunol. 2014;14(11):759–767. doi:10.1038/nri3743
   PubMed Web of Science ®Google Scholar
• Wu H, Wu T, Li M, Wang J. Efficacy of the lipid-soluble iron chelator 2,2’-dipyridyl against hemorrhagic brain injury. Neurobiol Dis. 2012;45(1):388–394. doi:10.1016/j.nbd.2011.08.028
   PubMed Web of Science ®Google Scholar
• Shah R, Shchepinov MS, Pratt DA. Resolving the role of lipoxygenases in the initiation and execution of ferroptosis. ACS Cent Sci. 2018;4(3):387–396. doi:10.1021/acscentsci.7b00589
   PubMed Web of Science ®Google Scholar
• Rao KV, Reddy PV, Curtis KM, Norenberg MD. Aquaporin-4 expression in cultured astrocytes after fluid percussion injury. J Neurotrauma. 2011;28(3):371–381. doi:10.1089/neu.2010.1705
   PubMed Web of Science ®Google Scholar
• Xiong XY, Wang J, Qian ZM, Yang QW. Iron and intracerebral hemorrhage: from mechanism to translation. Transl Stroke Res. 2014;5(4):429–441. doi:10.1007/s12975-013-0317-7
   PubMed Web of Science ®Google Scholar
• Zhang Z, Wu Y, Yuan S, et al. Glutathione peroxidase 4 participates in secondary brain injury through mediating ferroptosis in a rat model of intracerebral hemorrhage. Brain Res. 2018;1701:112–125. doi:10.1016/j.brainres.2018.09.012
   PubMed Web of Science ®Google Scholar
• Ingrassia R, Lanzillotta A, Sarnico I, et al. 1B/(-)IRE DMT1 expression during brain ischemia contributes to cell death mediated by NF-κB/RelA acetylation at Lys310. PLoS One. 2012;7(5):e38019. doi:10.1371/journal.pone.0038019
   PubMed Web of Science ®Google Scholar
• Chen Z, Hua S. Transcription factor-mediated signaling pathways’ contribution to the pathology of acute lung injury and acute respiratory distress syndrome. Am J Transl Res. 2020;12(9):5608–5618.
   PubMed Web of Science ®Google Scholar
• Ong WY, Go ML, Wang DY, Cheah IK, Halliwell B. Effects of antimalarial drugs on neuroinflammation-potential use for treatment of COVID-19-related neurologic complications. Mol Neurobiol. 2021;58(1):106–117. doi:10.1007/s12035-020-02093-z
   PubMed Web of Science ®Google Scholar
• Raz E, Jensen JH, Ge Y, et al. Brain iron quantification in mild traumatic brain injury: a magnetic field correlation study. AJNR Am J Neuroradiol. 2011;32(10):1851–1856. doi:10.3174/ajnr.A2637
   PubMed Web of Science ®Google Scholar
• Kagan VE, Mao G, Qu F, et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol. 2017;13(1):81–90. doi:10.1038/nchembio.2238
   PubMed Web of Science ®Google Scholar
• Fifi JT, Mocco J. COVID-19 related stroke in young individuals. Lancet Neurol. 2020;19(9):713–715. doi:10.1016/S1474-4422(20)30272-6
   PubMed Web of Science ®Google Scholar
• Wang J, Jiang C, Zhang K, et al. Melatonin receptor activation provides cerebral protection after traumatic brain injury by mitigating oxidative stress and inflammation via the Nrf2 signaling pathway. Free Radic Biol Med. 2019;131:345–355. doi:10.1016/j.freeradbiomed.2018.12.014
   PubMed Web of Science ®Google Scholar
• Magtanong L, Dixon SJ. Ferroptosis and brain injury. Dev Neurosci. 2018;40(5–6):382–395. doi:10.1159/000496922
   PubMed Web of Science ®Google Scholar
• Wu Y, Song J, Wang Y, et al. The potential role of ferroptosis in neonatal brain injury. Front Neurosci. 2019;13:115. doi:10.3389/fnins.2019.00115
   PubMed Web of Science ®Google Scholar
• Wu JR, Tuo QZ, Lei P. Ferroptosis, a recent defined form of critical cell death in neurological disorders. J Mol Neurosci. 2018;66(2):197–206. doi:10.1007/s12031-018-1155-6
   PubMed Web of Science ®Google Scholar
• Song S, Gao Y, Sheng Y, Rui T, Luo C. Targeting NRF2 to suppress ferroptosis in brain injury. Histol Histopathol. 2021;36(4):383–397. doi:10.14670/HH-18-286
   PubMed Web of Science ®Google Scholar
• Lan X, Han X, Li Q, Wang J. (-)-Epicatechin, a natural flavonoid compound, protects astrocytes against hemoglobin toxicity via Nrf2 and AP-1 signaling pathways. Mol Neurobiol. 2017;54(10):7898–7907. doi:10.1007/s12035-016-0271-y
   PubMed Web of Science ®Google Scholar
• Hodgson SH, Mansatta K, Mallett G, et al. What defines an efficacious COVID-19 vaccine? A review of the challenges assessing the clinical efficacy of vaccines against SARS-CoV-2. Lancet Infect Dis. 2021;21(2):e26–e35. doi:10.1016/S1473-3099(20)30773-8
   PubMed Web of Science ®Google Scholar
• Patone M, Handunnetthi L, Saatci D, et al. Neurological complications after first dose of COVID-19 vaccines and SARS-CoV-2 infection. Nat Med. 2021;27(12):2144–2153. doi:10.1038/s41591-021-01556-7
   PubMed Web of Science ®Google Scholar
• Drakesmith H, Pasricha SR, Cabantchik I, et al. Vaccine efficacy and iron deficiency: an intertwined pair? Lancet Haematol. 2021;8(9):e666–e669. doi:10.1016/S2352-3026(21)00201-5
   PubMed Web of Science ®Google Scholar
• Bergamaschi G, Borrelli de Andreis F, Aronico N, et al. Anemia in patients with Covid-19: pathogenesis and clinical significance. Clin Exp Med. 2021;21(2):239–246. doi:10.1007/s10238-020-00679-4
   PubMed Web of Science ®Google Scholar
• Gupta Y, Maciorowski D, Medernach B, et al. Iron dysregulation in COVID-19 and reciprocal evolution of SARS-CoV-2: natura nihil frustra facit. J Cell Biochem. 2022. doi:10.1002/jcb.30207
   Web of Science ®Google Scholar
• Zhao K, Huang J, Dai D, et al. Serum iron level as a potential predictor of coronavirus disease 2019 severity and mortality: a retrospective study. Open Forum Infect Dis. 2020;7(7):ofaa250. doi:10.1093/ofid/ofaa250
   PubMed Web of Science ®Google Scholar
• Chen C, Zhou W, Fan W, et al. Association of anemia and COVID-19 in hospitalized patients. Future Virol. 2021;16(7):459–466. doi:10.2217/fvl-2021-0044
   Web of Science ®Google Scholar
• Sonnweber T, Boehm A, Sahanic S, et al. Persisting alterations of iron homeostasis in COVID-19 are associated with non-resolving lung pathologies and poor patients’ performance: a prospective observational cohort study. Respir Res. 2020;21(1):276. doi:10.1186/s12931-020-01546-2
   PubMed Web of Science ®Google Scholar
• Tao Z, Xu J, Chen W, et al. Anemia is associated with severe illness in COVID-19: a retrospective cohort study. J Med Virol. 2021;93(3):1478–1488. doi:10.1002/jmv.26444
   PubMed Web of Science ®Google Scholar
• Faghih Dinevari M, Somi MH, Sadeghi Majd E, Abbasalizad Farhangi M, Nikniaz Z. Anemia predicts poor outcomes of COVID-19 in hospitalized patients: a prospective study in Iran. BMC Infect Dis. 2021;21(1):170. doi:10.1186/s12879-021-05868-4
   PubMed Web of Science ®Google Scholar
• Chang YL, Hung SH, Ling W, et al. Association between ischemic stroke and iron-deficiency anemia: a population-based study. PLoS One. 2013;8(12):e82952. doi:10.1371/journal.pone.0082952
   PubMed Web of Science ®Google Scholar
• Ware RE, Helms RW. Stroke with transfusions changing to hydroxyurea (SWiTCH). Blood. 2012;119(17):3925–3932. doi:10.1182/blood-2011-11-392340
   PubMed Web of Science ®Google Scholar
• Hirschhorn T, Stockwell BR. The development of the concept of ferroptosis. Free Radic Biol Med. 2019;133:130–143. doi:10.1016/j.freeradbiomed.2018.09.043
   PubMed Web of Science ®Google Scholar
• Chen X, Comish PB, Tang D, Kang R. Characteristics and biomarkers of ferroptosis. Front Cell Dev Biol. 2021;9:637162. doi:10.3389/fcell.2021.637162
   PubMed Web of Science ®Google Scholar
• Varatharaj A, Thomas N, Ellul MA, et al. Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study. Lancet Psychiatry. 2020;7(10):875–882. doi:10.1016/S2215-0366(20)30287-X
   PubMed Web of Science ®Google Scholar
• Paterson RW, Brown RL, Benjamin L, et al. The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings. Brain. 2020;143(10):3104–3120. doi:10.1093/brain/awaa240
   PubMed Web of Science ®Google Scholar
• Hao F, Tam W, Hu X, et al. A quantitative and qualitative study on the neuropsychiatric sequelae of acutely ill COVID-19 inpatients in isolation facilities. Transl Psychiatry. 2020;10(1):355. doi:10.1038/s41398-020-01039-2
   PubMed Web of Science ®Google Scholar
• Zhang J, Lu H, Zeng H, et al. The differential psychological distress of populations affected by the COVID-19 pandemic. Brain Behav Immun. 2020;87:49–50. doi:10.1016/j.bbi.2020.04.031
   PubMed Web of Science ®Google Scholar
• Giacomelli A, Pezzati L, Conti F, et al. Self-reported olfactory and taste disorders in patients with severe acute respiratory coronavirus 2 infection: a cross-sectional study. Clin Infect Dis. 2020;71(15):889–890. doi:10.1093/cid/ciaa330
   PubMed Web of Science ®Google Scholar
• Nalleballe K, Reddy Onteddu S, Sharma R, et al. Spectrum of neuropsychiatric manifestations in COVID-19. Brain Behav Immun. 2020;88:71–74. doi:10.1016/j.bbi.2020.06.020
   PubMed Web of Science ®Google Scholar
• Moriguchi T, Harii N, Goto J, et al. A first case of meningitis/encephalitis associated with SARS-Coronavirus-2. Int J Infect Dis. 2020;94:55–58. doi:10.1016/j.ijid.2020.03.062
   PubMed Web of Science ®Google Scholar
• Dinkin M, Gao V, Kahan J, et al. COVID-19 presenting with ophthalmoparesis from cranial nerve palsy. Neurology. 2020;95(5):221–223. doi:10.1212/WNL.0000000000009700
   PubMed Web of Science ®Google Scholar
• Jiang RD, Liu MQ, Chen Y, et al. Pathogenesis of SARS-CoV-2 in transgenic mice expressing human angiotensin-converting enzyme 2. Cell. 2020;182(1):50–58.e8. doi:10.1016/j.cell.2020.05.027
   PubMed Web of Science ®Google Scholar
• Chen R, Wang K, Yu J, et al. The spatial and cell-type distribution of SARS-CoV-2 receptor ACE2 in the human and mouse brains. Front Neurol. 2020;11:573095. doi:10.3389/fneur.2020.573095
   PubMed Web of Science ®Google Scholar
• Qi J, Zhou Y, Hua J, et al. The scRNA-seq expression profiling of the receptor ACE2 and the cellular protease TMPRSS2 reveals human organs susceptible to SARS-CoV-2 infection. Int J Environ Res Public Health. 2021;18(1):284. doi:10.3390/ijerph18010284
   PubMed Web of Science ®Google Scholar
• Buzhdygan TP, DeOre BJ, Baldwin-Leclair A, et al. The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in vitro models of the human blood-brain barrier. bioRxiv. 2020. doi:10.1101/2020.06.15.150912
   PubMedGoogle Scholar
• Song E, Zhang C, Israelow B, et al. Neuroinvasion of SARS-CoV-2 in human and mouse brain. J Exp Med. 2021;218(3). doi:10.1084/jem.20202135
   Web of Science ®Google Scholar
• Paniz-Mondolfi A, Bryce C, Grimes Z, et al. Central nervous system involvement by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). J Med Virol. 2020;92(7):699–702. doi:10.1002/jmv.25915
   PubMed Web of Science ®Google Scholar
• Puelles VG, Lütgehetmann M, Lindenmeyer MT, et al. Multiorgan and renal tropism of SARS-CoV-2. N Engl J Med. 2020;383(6):590–592. doi:10.1056/NEJMc2011400
   PubMed Web of Science ®Google Scholar
• Martin M, Paes VR, Cardoso EF, et al. Postmortem brain 7T MRI with minimally invasive pathological correlation in deceased COVID-19 subjects. Insights Imaging. 2022;13(1):7. doi:10.1186/s13244-021-01144-w
   PubMed Web of Science ®Google Scholar
• Shintoku R, Takigawa Y, Yamada K, et al. Lipoxygenase-mediated generation of lipid peroxides enhances ferroptosis induced by erastin and RSL3. Cancer Sci. 2017;108(11):2187–2194. doi:10.1111/cas.13380
   PubMed Web of Science ®Google Scholar