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image of Neuropsychiatric Manifestations of COVID-19 Disease and Post Covid Syndrome: The Role of N Acetyl-cysteine and Acetyl-L-carnitine

Abstract

COVID-19 is associated with neuropsychiatric symptoms, such as anosmia, anxiety, depression, stress-related reactions, and psychoses. The illness can cause persistent cognitive impairment and “brain fog”, suggesting chronic brain involvement. Clinical entities of ongoing symptomatic COVID-19 and Post COVID Syndrome (PCS) mainly present neuropsychiatric symptoms such as dysgeusia, headache, fatigue, anxiety, depression, sleep disturbances, and post-traumatic stress disorder. The pathophysiology of COVID-19-related brain damage is unclear, but it is linked to various mechanisms such as inflammation, oxidative stress, immune dysregulation, impaired glutamate homeostasis, glial and glymphatic damage, and hippocampal degeneration. Noteworthy is that the metabotropic receptor mGluR2 was discovered as a mechanism of internalisation of SARS-CoV-2 in Central Nervous System (CNS) cells. N-acetylcysteine (NAC) and acetyl-L-carnitine (ALC) are two supplements that have already been found effective in treating psychiatric conditions. Furthermore, NAC showed evidence in relieving cognitive symptomatology in PCS, and ALC was found effective in treating depressive symptomatology of PCS. The overlapping effects on the glutamatergic system of ALC and NAC could help treat COVID-19 psychiatric symptoms and PCS, acting through different mechanisms on the xc-mGluR2 network, with potentially synergistic effects on chronic pain and neuro-astrocyte protection. This paper aims to summarise the current evidence on the potential therapeutic role of NAC and ALC, providing an overview of the underlying molecular mechanisms and pathophysiology. It proposes a pathophysiological model explaining the effectiveness of NAC and ALC in treating COVID-19-related neuropsychiatric symptoms.

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2024-11-05
2024-12-30

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References

  1. Shivalkar S. Pingali M.S. Verma A. Singh A. Singh V. Paital B. Das D. Varadwaj P.K. Samanta S.K. Outbreak of COVID-19: A detailed overview and its consequences. Adv. Exp. Med. Biol. 2021 1353 23 45 10.1007/978‑3‑030‑85113‑2_2 35137366
    [Google Scholar]
  2. Wan D. Du T. Hong W. Chen L. Que H. Lu S. Peng X. Neurological complications and infection mechanism of SARS-CoV-2. Signal Transduct. Target. Ther. 2021 6 1 406 10.1038/s41392‑021‑00818‑7 34815399
    [Google Scholar]
  3. Rogers J.P. Chesney E. Oliver D. Pollak T.A. McGuire P. Fusar-Poli P. Zandi M.S. Lewis G. David A.S. Psychiatric and neuro-psychiatric presentations associated with severe coronavirus infections: A systematic review and meta-analysis with comparison to the COVID-19 pandemic. Lancet Psychiatry 2020 7 7 611 627 10.1016/S2215‑0366(20)30203‑0 32437679
    [Google Scholar]
  4. Aleem A. Akbar Samad A.B. Slenker A.K. Emerging variants of SARS-CoV-2 and novel therapeutics against coronavirus (COVID-19). Treasure Island, FL StatPearls 2021
    [Google Scholar]
  5. Wee L.E. Lim J.T. Tay A.T. Pang D. Dickens B. Chiew C.J. Ong B. Lye D.C.B. Tan K.B. Long-term neuropsychiatric sequelae of Delta versus Omicron SARS-CoV-2 infection. Clin. Microbiol. Infect. 2024 30 4 531 539 10.1016/j.cmi.2023.12.019 38141822
    [Google Scholar]
  6. Nalbandian A. Sehgal K. Gupta A. Madhavan M.V. McGroder C. Stevens J.S. Cook J.R. Nordvig A.S. Shalev D. Sehrawat T.S. Ahluwalia N. Bikdeli B. Dietz D. Der-Nigoghossian C. Liyanage-Don N. Rosner G.F. Bernstein E.J. Mohan S. Beckley A.A. Seres D.S. Choueiri T.K. Uriel N. Ausiello J.C. Accili D. Freedberg D.E. Baldwin M. Schwartz A. Brodie D. Garcia C.K. Elkind M.S.V. Connors J.M. Bilezikian J.P. Landry D.W. Wan E.Y. Post-acute COVID-19 syndrome. Nat. Med. 2021 27 4 601 615 10.1038/s41591‑021‑01283‑z 33753937
    [Google Scholar]
  7. Venkatesan P. NICE guideline on long COVID. Lancet Respir. Med. 2021 9 2 129 10.1016/S2213‑2600(21)00031‑X 33453162
    [Google Scholar]
  8. Schou T.M. Joca S. Wegener G. Bay-Richter C. Psychiatric and neuropsychiatric sequelae of COVID-19 - A systematic review. Brain Behav. Immun. 2021 97 328 348 10.1016/j.bbi.2021.07.018 34339806
    [Google Scholar]
  9. De Berardis D. How concerned should we be about neurotropism of SARS-Cov-2? A brief clinical consideration of the possible psychiat-ric implications. CNS Spectr. 2022 27 3 258 259 10.1017/S1092852920002175 33300484
    [Google Scholar]
  10. De Berardis D. Di Carlo F. Di Giannantonio M. Pettorruso M. Legacy of neuropsychiatric symptoms associated with past COVID-19 infection: A cause of concern. World J. Psychiatry 2022 12 6 773 778 10.5498/wjp.v12.i6.773 35978974
    [Google Scholar]
  11. Ali Awan H. Najmuddin Diwan M. Aamir A. Ali M. Di Giannantonio M. Ullah I. Shoib S. De Berardis D. SARS-CoV-2 and the brain: What do we know about the causality of ‘cognitive COVID? J. Clin. Med. 2021 10 15 3441 10.3390/jcm10153441 34362224
    [Google Scholar]
  12. Sher L. Post-COVID syndrome and suicide risk. QJM 2021 114 2 95 98 10.1093/qjmed/hcab007 33486531
    [Google Scholar]
  13. Yelin D. Margalit I. Nehme M. Bordas-Martínez J. Pistelli F. Yahav D. Guessous I. Durà-Miralles X. Carrozzi L. Shapira-Lichter I. Vetter P. Peleato-Catalan D. Tiseo G. Wirtheim E. Kaiser L. Gudiol C. Falcone M. Leibovici L. Patterns of long COVID symptoms: A multi-center cross sectional study. J. Clin. Med. 2022 11 4 898 10.3390/jcm11040898 35207171
    [Google Scholar]
  14. Irani S. Immune responses in SARS-CoV-2, SARS-CoV, and MERS-CoV infections: A comparative review. Int. J. Prev. Med. 2022 13 1 45 10.4103/ijpvm.IJPVM_429_20 35529506
    [Google Scholar]
  15. Mohamed M.S. Johansson A. Jonsson J. Schiöth H.B. Dissecting the molecular mechanisms surrounding Post-COVID-19 syndrome and neurological features. Int. J. Mol. Sci. 2022 23 8 4275 10.3390/ijms23084275 35457093
    [Google Scholar]
  16. Davis H.E. McCorkell L. Vogel J.M. Topol E.J. Long COVID: Major findings, mechanisms and recommendations. Nat. Rev. Microbiol. 2023 21 3 133 146 10.1038/s41579‑022‑00846‑2 36639608
    [Google Scholar]
  17. Han Y. Yuan K. Wang Z. Liu W.J. Lu Z.A. Liu L. Shi L. Yan W. Yuan J.L. Li J.L. Shi J. Liu Z.C. Wang G.H. Kosten T. Bao Y.P. Lu L. Neuropsychiatric manifestations of COVID-19, potential neurotropic mechanisms, and therapeutic interventions. Transl. Psychiatry 2021 11 1 499 10.1038/s41398‑021‑01629‑8 34593760
    [Google Scholar]
  18. Wostyn P. COVID-19 and chronic fatigue syndrome: Is the worst yet to come? Med. Hypotheses 2021 146 110469 10.1016/j.mehy.2020.110469 33401106
    [Google Scholar]
  19. Díez-Cirarda M. Yus-Fuertes M. Sanchez-Sanchez R. Gonzalez-Rosa J.J. Gonzalez-Escamilla G. Gil-Martínez L. Delgado-Alonso C. Gil-Moreno M.J. Valles-Salgado M. Cano-Cano F. Ojeda-Hernandez D. Gomez-Ruiz N. Oliver-Mas S. Benito-Martín M.S. Jorquera M. de la Fuente S. Polidura C. Selma-Calvo B. Arrazola J. Matias-Guiu J. Gomez-Pinedo U. Matias-Guiu J.A. Hippo-campal subfield abnormalities and biomarkers of pathologic brain changes: From SARS-CoV-2 acute infection to post-COVID syndrome. EBioMedicine 2023 94 104711 10.1016/j.ebiom.2023.104711 37453364
    [Google Scholar]
  20. Wang J. Yang G. Wang X. Wen Z. Shuai L. Luo J. Wang C. Sun Z. Liu R. Ge J. He X. Hua R. Wang X. Yang X. Chen W. Zhong G. Bu Z. SARS-CoV-2 uses metabotropic glutamate receptor subtype 2 as an internalization factor to infect cells. Cell Discov. 2021 7 1 119 10.1038/s41421‑021‑00357‑z 34903715
    [Google Scholar]
  21. Nicoletti F. Bockaert J. Collingridge G.L. Conn P.J. Ferraguti F. Schoepp D.D. Wroblewski J.T. Pin J.P. Metabotropic glutamate receptors: From the workbench to the bedside. Neuropharmacology 2011 60 7-8 1017 1041 10.1016/j.neuropharm.2010.10.022 21036182
    [Google Scholar]
  22. Planas-Fontánez T.M. Dreyfus C.F. Saitta K.S. Reactive astrocytes as therapeutic targets for brain degenerative diseases: Roles played by metabotropic glutamate receptors. Neurochem. Res. 2020 45 3 541 550 10.1007/s11064‑020‑02968‑6 31983009
    [Google Scholar]
  23. Fesharaki-Zadeh A. Lowe N. Arnsten A.F.T. Clinical experience with the α2A-adrenoceptor agonist, guanfacine, and N-acetylcysteine for the treatment of cognitive deficits in “Long-COVID19”. Neuroimmunology Reports 2023 3 100154 10.1016/j.nerep.2022.100154
    [Google Scholar]
  24. Scaturro D. Vitagliani F. Di Bella V.E. Falco V. Tomasello S. Lauricella L. Letizia Mauro G. The role of acetyl-carnitine and reha-bilitation in the management of patients with Post-COVID syndrome: Case-control study. Appl. Sci. (Basel) 2022 12 8 4084 10.3390/app12084084
    [Google Scholar]
  25. Samsonia M. Kandelaki M. Baratashvili N. Gvaramia L. Neuroprotective and antioxidant potential of montelukast-acetylcysteine combination therapy for brain protection in patients with COVID-19 induced pneumonia. Georgian Med. News 2023 335 335 111 118 37042600
    [Google Scholar]
  26. Stefanou M.I. Palaiodimou L. Bakola E. Smyrnis N. Papadopoulou M. Paraskevas G.P. Rizos E. Boutati E. Grigoriadis N. Krogias C. Giannopoulos S. Tsiodras S. Gaga M. Tsivgoulis G. Neurological manifestations of long-COVID syndrome: A narrative review. Ther. Adv. Chronic Dis. 2022 13 76890 10.1177/20406223221076890 35198136
    [Google Scholar]
  27. De Flora S. Balansky R. La Maestra S. Rationale for the use of N‐acetylcysteine in both prevention and adjuvant therapy of COVID‐19. FASEB J. 2020 34 10 13185 13193 10.1096/fj.202001807 32780893
    [Google Scholar]
  28. Fesharaki Zadeh A. Arnsten A.F.T. Wang M. Scientific rationale for the treatment of cognitive deficits from long COVID. Neurol. Int. 2023 15 2 725 742 10.3390/neurolint15020045 37368329
    [Google Scholar]
  29. Veleri S. Neurotropism of SARS-CoV-2 and neurological diseases of the central nervous system in COVID-19 patients. Exp. Brain Res. 2022 240 1 9 25 10.1007/s00221‑021‑06244‑z 34694467
    [Google Scholar]
  30. Meinhardt J. Radke J. Dittmayer C. Franz J. Thomas C. Mothes R. Laue M. Schneider J. Brünink S. Greuel S. Lehmann M. Hassan O. Aschman T. Schumann E. Chua R.L. Conrad C. Eils R. Stenzel W. Windgassen M. Rößler L. Goebel H.H. Gelder-blom H.R. Martin H. Nitsche A. Schulz-Schaeffer W.J. Hakroush S. Winkler M.S. Tampe B. Scheibe F. Körtvélyessy P. Rein-hold D. Siegmund B. Kühl A.A. Elezkurtaj S. Horst D. Oesterhelweg L. Tsokos M. Ingold-Heppner B. Stadelmann C. Drosten C. Corman V.M. Radbruch H. Heppner F.L. 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 10.1038/s41593‑020‑00758‑5 33257876
    [Google Scholar]
  31. Baysal-Kirac L. Uysal H. COVID-19 associate neurological complications. Neurol. Sci. Neurophysiol. 2020 37 1 1 3 10.4103/NSN.NSN_28_20
    [Google Scholar]
  32. Bostancıklıoğlu M. SARS-CoV2 entry and spread in the lymphatic drainage system of the brain. Brain Behav. Immun. 2020 87 122 123 10.1016/j.bbi.2020.04.080 32360606
    [Google Scholar]
  33. Hirabara S.M. Serdan T.D.A. Gorjao R. Masi L.N. Pithon-Curi T.C. Covas D.T. Curi R. Durigon E.L. SARS-COV-2 Variants: Differences and potential of immune evasion. Front. Cell. Infect. Microbiol. 2022 11 781429 10.3389/fcimb.2021.781429 35118007
    [Google Scholar]
  34. Zeisel A. Muñoz-Manchado A.B. Codeluppi S. Lönnerberg P. La Manno G. Juréus A. Marques S. Munguba H. He L. Betsholtz C. Rolny C. Castelo-Branco G. Hjerling-Leffler J. Linnarsson S. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq. Science 2015 347 6226 1138 1142 10.1126/science.aaa1934 25700174
    [Google Scholar]
  35. Zhang Y. Archie S.R. Ghanwatkar Y. Sharma S. Nozohouri S. Burks E. Mdzinarishvili A. Liu Z. Abbruscato T.J. Potential role of astrocyte angiotensin converting enzyme 2 in the neural transmission of COVID-19 and a neuroinflammatory state induced by smoking and vaping. Fluids Barriers CNS 2022 19 1 46 10.1186/s12987‑022‑00339‑7 35672716
    [Google Scholar]
  36. Pellegrini L. Bonfio C. Chadwick J. Begum F. Skehel M. Lancaster M.A. Human CNS barrier-forming organoids with cerebrospinal fluid production. Science 2020 369 6500 eaaz5626 10.1126/science.aaz5626
    [Google Scholar]
  37. Mao L.M. Bodepudi A. Chu X.P. Wang J.Q. Group I. Group I metabotropic glutamate receptors and interacting partners: An Update. Int. J. Mol. Sci. 2022 23 2 840 10.3390/ijms23020840 35055030
    [Google Scholar]
  38. Wang X. Wen Z. Cao H. Luo J. Shuai L. Wang C. Ge J. Wang X. Bu Z. Wang J. Transferrin receptor protein 1 cooperates with mGluR2 to mediate the internalization of rabies virus and SARS-CoV-2. J. Virol. 2023 97 2 e01611 e01622 10.1128/jvi.01611‑22 36779763
    [Google Scholar]
  39. Spampinato S.F. Copani A. Nicoletti F. Sortino M.A. Caraci F. Metabotropic glutamate receptors in glial cells: A new potential target for neuroprotection? Front. Mol. Neurosci. 2018 11 414 10.3389/fnmol.2018.00414 30483053
    [Google Scholar]
  40. Huang L. Xiao W. Wang Y. Li J. Gong J. Tu E. Long L. Xiao B. Yan X. Wan L. Metabotropic glutamate receptors (mGluRs) in epileptogenesis: An update on abnormal mGluRs signaling and its therapeutic implications. Neural Regen. Res. 2024 19 2 360 368 10.4103/1673‑5374.379018 37488891
    [Google Scholar]
  41. Andrews M.G. Mukhtar T. Eze U.C. Simoneau C.R. Ross J. Parikshak N. Wang S. Zhou L. Koontz M. Velmeshev D. Siebert C.V. Gemenes K.M. Tabata T. Perez Y. Wang L. Mostajo-Radji M.A. de Majo M. Donohue K.C. Shin D. Salma J. Pollen A.A. Nowakowski T.J. Ullian E. Kumar G.R. Winkler E.A. Crouch E.E. Ott M. Kriegstein A.R. Tropism of SARS-CoV-2 for hu-man cortical astrocytes. Proc. Natl. Acad. Sci. USA 2022 119 30 e2122236119 e2122236119 10.1073/pnas.2122236119 35858406
    [Google Scholar]
  42. Hirunpattarasilp C. James G. Kwanthongdee J. Freitas F. Huo J. Sethi H. Kittler J.T. Owens R.J. McCoy L.E. Attwell D. SARS-CoV-2 triggers pericyte-mediated cerebral capillary constriction. Brain 2023 146 2 727 738 10.1093/brain/awac272 35867861
    [Google Scholar]
  43. Jackson C.B. Farzan M. Chen B. Choe H. Mechanisms of SARS-CoV-2 entry into cells. Nat. Rev. Mol. Cell Biol. 2022 23 1 3 20 10.1038/s41580‑021‑00418‑x 34611326
    [Google Scholar]
  44. Jarius S. Pache F. Körtvelyessy P. Jelčić I. Stettner M. Franciotta D. Keller E. Neumann B. Ringelstein M. Senel M. Regeniter A. Kalantzis R. Willms J.F. Berthele A. Busch M. Capobianco M. Eisele A. Reichen I. Dersch R. Rauer S. Sandner K. Ayzen-berg I. Gross C.C. Hegen H. Khalil M. Kleiter I. Lenhard T. Haas J. Aktas O. Angstwurm K. Kleinschnitz C. Lewerenz J. Tumani H. Paul F. Stangel M. Ruprecht K. Wildemann B. Cerebrospinal fluid findings in COVID-19: A multicenter study of 150 lumbar punctures in 127 patients. J. Neuroinflammation 2022 19 1 19 10.1186/s12974‑021‑02339‑0 35057809
    [Google Scholar]
  45. Iliff J.J. Wang M. Liao Y. Plogg B.A. Peng W. Gundersen G.A. A paravascular pathway facilitates CSF flow through the brain parenchy-ma and the clearance of interstitial solutes, including amyloid β. Sci. Transl. Med. 2012 4 147 147ra111 10.1126/scitranslmed.3003748
    [Google Scholar]
  46. Wu L. Zhang Z. Liang X. Wang Y. Cao Y. Li M. Zhou F. Glymphatic system dysfunction in recovered patients with mild COVID-19: A DTI-ALPS study. iScience 2024 27 1 108647 10.1016/j.isci.2023.108647 38155770
    [Google Scholar]
  47. Koehler R.C. Roman R.J. Harder D.R. Astrocytes and the regulation of cerebral blood flow. Trends Neurosci. 2009 32 3 160 169 10.1016/j.tins.2008.11.005 19162338
    [Google Scholar]
  48. Masamoto K. Unekawa M. Watanabe T. Toriumi H. Takuwa H. Kawaguchi H. Kanno I. Matsui K. Tanaka K.F. Tomita Y. Suzuki N. Unveiling astrocytic control of cerebral blood flow with optogenetics. Sci. Rep. 2015 5 1 11455 10.1038/srep11455 26076820
    [Google Scholar]
  49. Jessen N.A. Munk A.S.F. Lundgaard I. Nedergaard M. The glymphatic system: A beginner’s guide. Neurochem. Res. 2015 40 12 2583 2599 10.1007/s11064‑015‑1581‑6 25947369
    [Google Scholar]
  50. Kubotera H. Ikeshima-Kataoka H. Hatashita Y. Allegra Mascaro A.L. Pavone F.S. Inoue T. Astrocytic endfeet re-cover blood ves-sels after removal by laser ablation. Sci. Rep. 2019 9 1 1263 10.1038/s41598‑018‑37419‑4 30718555
    [Google Scholar]
  51. Hu B. Huang S. Yin L. The cytokine storm and COVID‐19. J. Med. Virol. 2021 93 1 250 256 10.1002/jmv.26232 32592501
    [Google Scholar]
  52. Selickman J. Vrettou C.S. Mentzelopoulos S.D. Marini J.J. COVID-19-Related ARDS: Key mechanistic features and treatments. J. Clin. Med. 2022 11 16 4896 10.3390/jcm11164896 36013135
    [Google Scholar]
  53. Hasanvand A. COVID-19 and the role of cytokines in this disease. Inflammopharmacology 2022 30 3 789 798 10.1007/s10787‑022‑00992‑2 35505267
    [Google Scholar]
  54. Nikkhoo B. Mohammadi M. Hasani S. Sigari N. Borhani A. Ramezani C. Charajoo A. Badri S. Rostami F. Etemadi M. Rah-mani K. Elevated interleukin (IL)-6 as a predictor of disease severity among COVID-19 patients: A prospective cohort study. BMC Infect. Dis. 2023 23 1 311 10.1186/s12879‑023‑08294‑w 37161412
    [Google Scholar]
  55. Guo J. Wang S. Xia H. Shi D. Chen Y. Zheng S. Chen Y. Gao H. Guo F. Ji Z. Huang C. Luo R. Zhang Y. Zuo J. Chen Y. Xu Y. Xia J. Zhu C. Xu X. Qiu Y. Sheng J. Xu K. Li L. Cytokine signature associated with disease severity in COVID-19. Front. Immunol. 2021 12 681516 10.3389/fimmu.2021.681516 34489933
    [Google Scholar]
  56. Del Valle D.M. Kim-Schulze S. Huang H.H. Beckmann N.D. Nirenberg S. Wang B. Lavin Y. Swartz T.H. Madduri D. Stock A. Marron T.U. Xie H. Patel M. Tuballes K. Van Oekelen O. Rahman A. Kovatch P. Aberg J.A. Schadt E. Jagannath S. Ma-zumdar M. Charney A.W. Firpo-Betancourt A. Mendu D.R. Jhang J. Reich D. Sigel K. Cordon-Cardo C. Feldmann M. Parekh S. Merad M. Gnjatic S. An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat. Med. 2020 26 10 1636 1643 10.1038/s41591‑020‑1051‑9 32839624
    [Google Scholar]
  57. Montazersaheb S. Hosseiniyan Khatibi S.M. Hejazi M.S. Tarhriz V. Farjami A. Ghasemian Sorbeni F. Farahzadi R. Ghasemnejad T. COVID-19 infection: An overview on cytokine storm and related interventions. Virol. J. 2022 19 1 92 10.1186/s12985‑022‑01814‑1 35619180
    [Google Scholar]
  58. Tan S. Chen W. Kong G. Wei L. Xie Y. Peripheral inflammation and neurocognitive impairment: Correlations, underlying mecha-nisms, and therapeutic implications. Front. Aging Neurosci. 2023 15 1305790 10.3389/fnagi.2023.1305790 38094503
    [Google Scholar]
  59. Redza-Dutordoir M. Averill-Bates D.A. Activation of apoptosis signalling pathways by reactive oxygen species. Biochim. Biophys. Acta Mol. Cell Res. 2016 1863 12 2977 2992 10.1016/j.bbamcr.2016.09.012 27646922
    [Google Scholar]
  60. Maes M. Galecki P. Chang Y.S. Berk M. A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness. Prog. Neuropsychopharmacol. Biol. Psychiatry 2011 35 3 676 692 10.1016/j.pnpbp.2010.05.004 20471444
    [Google Scholar]
  61. Correia A.S. Cardoso A. Vale N. Oxidative stress in depression: The link with the stress response, neuroinflammation, serotonin, neu-rogenesis and synaptic plasticity. Antioxidants 2023 12 2 470 10.3390/antiox12020470 36830028
    [Google Scholar]
  62. Liu X. Fang Y. Xu J. Yang T. Xu J. He J. Liu W. Yu X. Wen Y. Zhang N. Li C. Oxidative stress, dysfunctional energy me-tabolism, and destabilizing neurotransmitters altered the cerebral metabolic profile in a rat model of simulated heliox saturation diving to 4.0 MPa. PLoS One 2023 18 3 e0282700 e0282700 10.1371/journal.pone.0282700 36917582
    [Google Scholar]
  63. Kong X. Gong Z. Zhang L. Sun X. Ou Z. Xu B. Huang J. Long D. He X. Lin X. Li Q. Xu L. Xuan A. JAK2/STAT3 signal-ing mediates IL-6-inhibited neurogenesis of neural stem cells through DNA demethylation/methylation. Brain Behav. Immun. 2019 79 159 173 10.1016/j.bbi.2019.01.027 30763768
    [Google Scholar]
  64. Vallières L. Campbell I.L. Gage F.H. Sawchenko P.E. Reduced hippocampal neurogenesis in adult transgenic mice with chronic astro-cytic production of interleukin-6. J. Neurosci. 2002 22 2 486 492 10.1523/JNEUROSCI.22‑02‑00486.2002 11784794
    [Google Scholar]
  65. Schwerk C. Tenenbaum T. Kim K.S. Schroten H. The choroid plexus—a multi-role player during infectious diseases of the CNS. Front. Cell. Neurosci. 2015 9 80 10.3389/fncel.2015.00080 25814932
    [Google Scholar]
  66. Yirmiya R. Goshen I. Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav. Immun. 2011 25 2 181 213 10.1016/j.bbi.2010.10.015 20970492
    [Google Scholar]
  67. Schousboe A. Bak L.K. Waagepetersen H.S. Astrocytic control of biosynthesis and turnover of the neurotransmitters glutamate and GABA. Front. Endocrinol. (Lausanne) 2013 4 102 10.3389/fendo.2013.00102 23966981
    [Google Scholar]
  68. Schousboe A. Metabolic signaling in the brain and the role of astrocytes in control of glutamate and GABA neurotransmission. Neurosci. Lett. 2019 689 11 13 10.1016/j.neulet.2018.01.038 29378296
    [Google Scholar]
  69. Kalivas P.W. The glutamate homeostasis hypothesis of addiction. Nat. Rev. Neurosci. 2009 10 8 561 572 10.1038/nrn2515 19571793
    [Google Scholar]
  70. Massie A. Boillée S. Hewett S. Knackstedt L. Lewerenz J. Main path and byways: Non‐vesicular glutamate release by system Xc− as an important modifier of glutamatergic neurotransmission. J. Neurochem. 2015 135 6 1062 1079 10.1111/jnc.13348 26336934
    [Google Scholar]
  71. Shih A.Y. Erb H. Sun X. Toda S. Kalivas P.W. Murphy T.H. Cystine/glutamate exchange modulates glutathione supply for neuro-protection from oxidative stress and cell proliferation. J. Neurosci. 2006 26 41 10514 10523 10.1523/JNEUROSCI.3178‑06.2006 17035536
    [Google Scholar]
  72. Moran M.M. McFarland K. Melendez R.I. Kalivas P.W. Seamans J.K. Cystine/glutamate exchange regulates metabotropic glutamate receptor presynaptic inhibition of excitatory transmission and vulnerability to cocaine seeking. J. Neurosci. 2005 25 27 6389 6393 10.1523/JNEUROSCI.1007‑05.2005 16000629
    [Google Scholar]
  73. Hol E.M. Pekny M. Glial fibrillary acidic protein (GFAP) and the astrocyte intermediate filament system in diseases of the central nerv-ous system. Curr. Opin. Cell Biol. 2015 32 121 130 10.1016/j.ceb.2015.02.004 25726916
    [Google Scholar]
  74. Kanberg N. Simrén J. Edén A. Andersson L.M. Nilsson S. Ashton N.J. Sundvall P.D. Nellgård B. Blennow K. Zetterberg H. Gisslén M. Neurochemical signs of astrocytic and neuronal injury in acute COVID-19 normalizes during long-term follow-up. EBioMedicine 2021 70 103512 10.1016/j.ebiom.2021.103512 34333238
    [Google Scholar]
  75. Matschke J. Lütgehetmann M. Hagel C. Sperhake J.P. Schröder A.S. Edler C. Mushumba H. Fitzek A. Allweiss L. Dandri M. Dottermusch M. Heinemann A. Pfefferle S. Schwabenland M. Sumner Magruder D. Bonn S. Prinz M. Gerloff C. Püschel K. Krasemann S. Aepfelbacher M. Glatzel M. Neuropathology of patients with COVID-19 in Germany: A post-mortem case series. Lancet Neurol. 2020 19 11 919 929 10.1016/S1474‑4422(20)30308‑2 33031735
    [Google Scholar]
  76. Deigendesch N. Sironi L. Kutza M. Wischnewski S. Fuchs V. Hench J. Frank A. Nienhold R. Mertz K.D. Cathomas G. Matter M.S. Siegemund M. Tolnay M. Schirmer L. Pröbstel A.K. Tzankov A. Frank S. Correlates of critical illness-related encephalopathy predominate postmortem COVID-19 neuropathology. Acta Neuropathol. 2020 140 4 583 586 10.1007/s00401‑020‑02213‑y 32851506
    [Google Scholar]
  77. Cosentino G. Todisco M. Hota N. Della Porta G. Morbini P. Tassorelli C. Pisani A. Neuropathological findings from COVID‐19 patients with neurological symptoms argue against a direct brain invasion of SARS‐CoV‐2: A critical systematic review. Eur. J. Neurol. 2021 28 11 3856 3865 10.1111/ene.15045 34339563
    [Google Scholar]
  78. Villarreal A. Vidos C. Monteverde Busso M. Cieri M.B. Ramos A.J. Pathological neuroinflammatory conversion of reactive astro-cytes is induced by microglia and involves chromatin remodeling. Front. Pharmacol. 2021 12 689346 10.3389/fphar.2021.689346 34234677
    [Google Scholar]
  79. Ribeiro D.E. Oliveira-Giacomelli Á. Glaser T. Arnaud-Sampaio V.F. Andrejew R. Dieckmann L. Baranova J. Lameu C. Ratajczak M.Z. Ulrich H. Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology. Mol. Psychiatry 2021 26 4 1044 1059 10.1038/s41380‑020‑00965‑3 33328588
    [Google Scholar]
  80. Loane D.J. Kumar A. Stoica B.A. Cabatbat R. Faden A.I. Progressive neurodegeneration after experimental brain trauma: Association with chronic microglial activation. J. Neuropathol. Exp. Neurol. 2014 73 1 14 29 10.1097/NEN.0000000000000021 24335533
    [Google Scholar]
  81. Fernández-Castañeda A. Lu P. Geraghty A.C. Song E. Lee M.H. Wood J. O’Dea M.R. Dutton S. Shamardani K. Nwangwu K. Mancusi R. Yalçın B. Taylor K.R. Acosta-Alvarez L. Malacon K. Keough M.B. Ni L. Woo P.J. Contreras-Esquivel D. Toland A.M.S. Gehlhausen J.R. Klein J. Takahashi T. Silva J. Israelow B. Lucas C. Mao T. Peña-Hernández M.A. Tabachnikova A. Homer R.J. Tabacof L. Tosto-Mancuso J. Breyman E. Kontorovich A. McCarthy D. Quezado M. Vogel H. Hefti M.M. Perl D.P. Liddelow S. Folkerth R. Putrino D. Nath A. Iwasaki A. Monje M. Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation. Cell 2022 185 14 2452 2468.e16 10.1016/j.cell.2022.06.008 35768006
    [Google Scholar]
  82. Boldrini M. Canoll P.D. Klein R.S. How COVID-19 affects the brain. JAMA Psychiatry 2021 78 6 682 683 10.1001/jamapsychiatry.2021.0500 33769431
    [Google Scholar]
  83. Buckingham S.C. Campbell S.L. Haas B.R. Montana V. Robel S. Ogunrinu T. Sontheimer H. Glutamate release by primary brain tumors induces epileptic activity. Nat. Med. 2011 17 10 1269 1274 10.1038/nm.2453 21909104
    [Google Scholar]
  84. Soria F.N. Pérez-Samartín A. Martin A. Gona K.B. Llop J. Szczupak B. Chara J.C. Matute C. Domercq M. Extrasynaptic gluta-mate release through cystine/glutamate antiporter contributes to ischemic damage. J. Clin. Invest. 2014 124 8 3645 3655 10.1172/JCI71886 25036707
    [Google Scholar]
  85. Dringen R. Brandmann M. Hohnholt M.C. Blumrich E.M. Glutathione-dependent detoxification processes in astrocytes. Neurochem. Res. 2015 40 12 2570 2582 10.1007/s11064‑014‑1481‑1 25428182
    [Google Scholar]
  86. Yesilkaya U.H. Sen M. Balcioglu Y.H. COVID-19-related cognitive dysfunction may be associated with transient disruption in the DLPFC glutamatergic pathway. J. Clin. Neurosci. 2021 87 153 155 10.1016/j.jocn.2021.03.007 33863524
    [Google Scholar]
  87. García-Sánchez C. Calabria M. Grunden N. Pons C. Arroyo J.A. Gómez-Anson B. Lleó A. Alcolea D. Belvís R. Morollón N. Mur I. Pomar V. Domingo P. Neuropsychological deficits in patients with cognitive complaints after COVID‐19. Brain Behav. 2022 12 3 e2508 10.1002/brb3.2508 35137561
    [Google Scholar]
  88. Lu Y. Li X. Geng D. Mei N. Wu P.Y. Huang C.C. Jia T. Zhao Y. Wang D. Xiao A. Yin B. Cerebral micro-structural changes in COVID-19 patients - an MRI-based 3-month follow-up study. EClinicalMedicine 2020 25 100484 10.1016/j.eclinm.2020.100484 32838240
    [Google Scholar]
  89. Perica M.I. Ravindranath O. Calabro F.J. Foran W. Luna B. Hippocampal-Prefrontal connectivity prior to the COVID-19 pandemic predicts stress reactivity. Biol. Psychiatry Glob. Open Sci. 2021 1 4 283 290 10.1016/j.bpsgos.2021.06.010 34849503
    [Google Scholar]
  90. Bird C.M. Burgess N. The hippocampus and memory: Insights from spatial processing. Nat. Rev. Neurosci. 2008 9 3 182 194 10.1038/nrn2335 18270514
    [Google Scholar]
  91. Scholler P. Nevoltris D. de Bundel D. Bossi S. Moreno-Delgado D. Rovira X. Møller T.C. El Moustaine D. Mathieu M. Blanc E. McLean H. Dupuis E. Mathis G. Trinquet E. Daniel H. Valjent E. Baty D. Chames P. Rondard P. Pin J.P. Allosteric nano-bodies uncover a role of hippocampal mGlu2 receptor homodimers in contextual fear consolidation. Nat. Commun. 2017 8 1 1967 10.1038/s41467‑017‑01489‑1 29213077
    [Google Scholar]
  92. Ritchie K. Chan D. Watermeyer T. The cognitive consequences of the COVID-19 epidemic: Collateral damage. Brain Commun. 2022 2 2 fcaa069 10.1093/braincomms/fcaa069
    [Google Scholar]
  93. Soung A.L. Vanderheiden A. Nordvig A.S. Sissoko C.A. Canoll P. Mariani M.B. Jiang X. Bricker T. Rosoklija G.B. Arango V. Underwood M. Mann J.J. Dwork A.J. Goldman J.E. Boon A.C.M. Boldrini M. Klein R.S. COVID-19 induces CNS cytokine ex-pression and loss of hippocampal neurogenesis. Brain 2022 145 12 4193 4201 10.1093/brain/awac270 36004663
    [Google Scholar]
  94. Jin L.E. Wang M. Galvin V.C. Lightbourne T.C. Conn P.J. Arnsten A.F.T. Paspalas C.D. mGluR2 versus mGluR3 metabotropic glutamate receptors in primate dorsolateral prefrontal cortex: Postsynaptic mGluR3 strengthen working memory networks. Cereb. Cortex 2018 28 3 974 987 10.1093/cercor/bhx005 28108498
    [Google Scholar]
  95. Ma J. Hu Z. Yue H. Luo Y. Wang C. Wu X. Gu Y. Wang L. GRM2 regulates functional integration of adult-born DGCs by para-doxically modulating MEK/ERK1/2 pathway. J. Neurosci. 2023 43 16 2822 2836 10.1523/JNEUROSCI.1886‑22.2023 36878727
    [Google Scholar]
  96. Alenina N. Bader M. ACE2 in brain physiology and pathophysiology: Evidence from transgenic animal models. Neurochem. Res. 2019 44 6 1323 1329 10.1007/s11064‑018‑2679‑4 30443713
    [Google Scholar]
  97. Xia H. Lazartigues E. Angiotensin‐converting enzyme 2 in the brain: Properties and future directions. J. Neurochem. 2008 107 6 1482 1494 10.1111/j.1471‑4159.2008.05723.x 19014390
    [Google Scholar]
  98. Hashimoto T. Perlot T. Rehman A. Trichereau J. Ishiguro H. Paolino M. Sigl V. Hanada T. Hanada R. Lipinski S. Wild B. Camargo S.M.R. Singer D. Richter A. Kuba K. Fukamizu A. Schreiber S. Clevers H. Verrey F. Rosenstiel P. Penninger J.M. ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. Nature 2012 487 7408 477 481 10.1038/nature11228 22837003
    [Google Scholar]
  99. Klempin F. Mosienko V. Matthes S. Villela D.C. Todiras M. Penninger J.M. Bader M. Santos R.A.S. Alenina N. Depletion of angiotensin-converting enzyme 2 reduces brain serotonin and impairs the running-induced neurogenic response. Cell. Mol. Life Sci. 2018 75 19 3625 3634 10.1007/s00018‑018‑2815‑y 29679094
    [Google Scholar]
  100. Bartolomucci A. Carola V. Pascucci T. Puglisi-Allegra S. Cabib S. Lesch K.P. Parmigiani S. Palanza P. Gross C. Increased vul-nerability to psychosocial stress in heterozygous serotonin transporter knockout mice. Dis. Model. Mech. 2010 3 7-8 459 470 10.1242/dmm.004614 20371729
    [Google Scholar]
  101. Wang L.A. de Kloet A.D. Smeltzer M.D. Cahill K.M. Hiller H. Bruce E.B. Pioquinto D.J. Ludin J.A. Katovich M.J. Raizada M.K. Krause E.G. Coupling corticotropin-releasing-hormone and angiotensin converting enzyme 2 dampens stress responsiveness in male mice. Neuropharmacology 2018 133 85 93 10.1016/j.neuropharm.2018.01.025 29360543
    [Google Scholar]
  102. Wenzel J. Lampe J. Müller-Fielitz H. Schuster R. Zille M. Müller K. Krohn M. Körbelin J. Zhang L. Özorhan Ü. Neve V. Wagner J.U.G. Bojkova D. Shumliakivska M. Jiang Y. Fähnrich A. Ott F. Sencio V. Robil C. Pfefferle S. Sauve F. Coêlho C.F.F. Franz J. Spiecker F. Lembrich B. Binder S. Feller N. König P. Busch H. Collin L. Villaseñor R. Jöhren O. Altmeppen H.C. Pasparakis M. Dimmeler S. Cinatl J. Püschel K. Zelic M. Ofengeim D. Stadelmann C. Trottein F. Nogueiras R. Hilgenfeld R. Glatzel M. Prevot V. Schwaninger M. The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells. Nat. Neurosci. 2021 24 11 1522 1533 10.1038/s41593‑021‑00926‑1 34675436
    [Google Scholar]
  103. Johansson A. Mohamed M.S. Moulin T.C. Schiöth H.B. Neurological manifestations of COVID-19: A comprehensive literature re-view and discussion of mechanisms. J. Neuroimmunol. 2021 358 577658 10.1016/j.jneuroim.2021.577658 34304141
    [Google Scholar]
  104. Everaerd D. Vissers P. van Helvoort M. Schellekens A. van de Maat J. Hoogerwerf J. Tendolkar I. Acute neuropsychiatric symp-toms during COVID-19. J. Nerv. Ment. Dis. 2023 211 10 779 783 10.1097/NMD.0000000000001700 37557068
    [Google Scholar]
  105. Chhabra N. Grill M.F. Singh R.B.H. Post-COVID Headache: A Literature Review. Curr. Pain Headache Rep. 2022 26 11 835 842 10.1007/s11916‑022‑01086‑y 36197571
    [Google Scholar]
  106. Belvis R. Headaches During COVID‐19: My clinical case and review of the literature. Headache 2020 60 7 1422 1426 10.1111/head.13841 32413158
    [Google Scholar]
  107. Caronna E. van den Hoek T.C. Bolay H. Garcia-Azorin D. Gago-Veiga A.B. Valeriani M. Takizawa T. Messlinger K. Shapiro R.E. Goadsby P.J. Ashina M. Tassorelli C. Diener H.C. Terwindt G.M. Pozo-Rosich P. Headache attributed to SARS-CoV-2 infec-tion, vaccination and the impact on primary headache disorders of the COVID-19 pandemic: A comprehensive review. Cephalalgia 2023 43 1 10.1177/03331024221131337 36606562
    [Google Scholar]
  108. Huang C. Huang L. Wang Y. Li X. Ren L. Gu X. Kang L. Guo L. Liu M. Zhou X. Luo J. Huang Z. Tu S. Zhao Y. Chen L. Xu D. Li Y. Li C. Peng L. Li Y. Xie W. Cui D. Shang L. Fan G. Xu J. Wang G. Wang Y. Zhong J. Wang C. Wang J. Zhang D. Cao B. RETRACTED: 6-month consequences of COVID-19 in patients discharged from hospital: A cohort study. Lancet 2021 397 10270 220 232 10.1016/S0140‑6736(20)32656‑8 33428867
    [Google Scholar]
  109. Mazza M.G. Palladini M. Villa G. Agnoletto E. Harrington Y. Vai B. Benedetti F. Prevalence of depression in SARS-CoV-2 infect-ed patients: An umbrella review of meta-analyses. Gen. Hosp. Psychiatry 2023 80 17 25 10.1016/j.genhosppsych.2022.12.002 36535239
    [Google Scholar]
  110. Mazza M.G. De Lorenzo R. Conte C. Poletti S. Vai B. Bollettini I. Melloni E.M.T. Furlan R. Ciceri F. Rovere-Querini P. Bene-detti F. Anxiety and depression in COVID-19 survivors: Role of inflammatory and clinical predictors. Brain Behav. Immun. 2020 89 594 600 10.1016/j.bbi.2020.07.037 32738287
    [Google Scholar]
  111. Taquet M. Luciano S. Geddes J.R. Harrison P.J. Bidirectional associations between COVID-19 and psychiatric disorder: Retrospective cohort studies of 62 354 COVID-19 cases in the USA. Lancet Psychiatry 2021 8 2 130 140 10.1016/S2215‑0366(20)30462‑4 33181098
    [Google Scholar]
  112. Taquet M. Sillett R. Zhu L. Mendel J. Camplisson I. Dercon Q. Harrison P.J. Neurological and psychiatric risk trajectories after SARS-CoV-2 infection: An analysis of 2-year retrospective cohort studies including 1 284 437 patients. Lancet Psychiatry 2022 9 10 815 827 10.1016/S2215‑0366(22)00260‑7 35987197
    [Google Scholar]
  113. Nordvig A.S. Fong K.T. Willey J.Z. Thakur K.T. Boehme A.K. Vargas W.S. Smith C.J. Elkind M.S.V. Potential neurologic mani-festations of COVID-19. Neurol. Clin. Pract. 2021 11 2 e135 e146 10.1212/CPJ.0000000000000897 33842082
    [Google Scholar]
  114. Heneka M.T. Golenbock D. Latz E. Morgan D. Brown R. Immediate and long-term consequences of COVID-19 infections for the development of neurological disease. Alzheimers Res. Ther. 2020 12 1 69 10.1186/s13195‑020‑00640‑3 32498691
    [Google Scholar]
  115. Sakusic A. Rabinstein A.A. Cognitive outcomes after critical illness. Curr. Opin. Crit. Care 2018 24 5 410 414 10.1097/MCC.0000000000000527 30036191
    [Google Scholar]
  116. Patel U.K. Mehta N. Patel A. Patel N. Ortiz J.F. Khurana M. Urhoghide E. Parulekar A. Bhriguvanshi A. Patel N. Mistry A.M. Patel R. Arumaithurai K. Shah S. Long-term neurological sequelae among severe COVID-19 patients: A systematic review and meta-analysis. Cureus 2022 14 9 e29694 e29694 10.7759/cureus.29694 36321004
    [Google Scholar]
  117. Kedor C. Freitag H. Meyer-Arndt L. Wittke K. Hanitsch L.G. Zoller T. Steinbeis F. Haffke M. Rudolf G. Heidecker B. Bob-bert T. Spranger J. Volk H.D. Skurk C. Konietschke F. Paul F. Behrends U. Bellmann-Strobl J. Scheibenbogen C. A prospective observational study of post-COVID-19 chronic fatigue syndrome following the first pandemic wave in Germany and biomarkers associat-ed with symptom severity. Nat. Commun. 2022 13 1 5104 10.1038/s41467‑022‑32507‑6 36042189
    [Google Scholar]
  118. Komaroff A.L. Lipkin W.I. ME/CFS and Long COVID share similar symptoms and biological abnormalities: Road map to the literature. Front. Med. (Lausanne) 2023 10 1187163 10.3389/fmed.2023.1187163 37342500
    [Google Scholar]
  119. Comella P.H. Gonzalez-Kozlova E. Kosoy R. Charney A.W. Peradejordi I.F. Chandrasekar S. A Molecular network approach re-veals shared cellular and molecular signatures between chronic fatigue syndrome and other fatiguing illnesses. MedRxiv 2021 10.1101/2021.01.29.21250755
    [Google Scholar]
  120. Martinez-Banaclocha M. N-Acetyl-Cysteine: Modulating the cysteine redox proteome in neurodegenerative diseases. Antioxidants 2022 11 2 416 10.3390/antiox11020416
    [Google Scholar]
  121. Devrim-Lanpir A. Hill L. Knechtle B. How N-Acetylcysteine supplementation affects redox regulation, especially at mitohormesis and sarcohormesis level: Current perspective. Antioxidants 2021 10 2 153 10.3390/antiox10020153
    [Google Scholar]
  122. Schwalfenberg G.K. N-Acetylcysteine: A review of clinical usefulness (an Old Drug with New Tricks). J. Nutr. Metab. 2021 2021 1 13 10.1155/2021/9949453 34221501
    [Google Scholar]
  123. Asanuma M. Miyazaki I. Glutathione and related molecules in parkinsonism. Int. J. Mol. Sci. 2021 22 16 8689 10.3390/ijms22168689 34445395
    [Google Scholar]
  124. Ferreira F.R. Biojone C. Joca S.R.L. Guimarães F.S. Antidepressant-like effects of N-acetyl-L-cysteine in rats. Behav. Pharmacol. 2008 19 7 747 750 10.1097/FBP.0b013e3283123c98 18797252
    [Google Scholar]
  125. Berk M. Dean O. Cotton S.M. Gama C.S. Kapczinski F. Fernandes B.S. Kohlmann K. Jeavons S. Hewitt K. Allwang C. Cobb H. Bush A.I. Schapkaitz I. Dodd S. Malhi G.S. The efficacy of N-acetylcysteine as an adjunctive treatment in bipolar depression: An open label trial. J. Affect. Disord. 2011 135 1-3 389 394 10.1016/j.jad.2011.06.005 21719110
    [Google Scholar]
  126. Raza H. John A. Shafarin J. NAC attenuates LPS-induced toxicity in aspirin-sensitized mouse macrophages via suppression of oxida-tive stress and mitochondrial dysfunction. PLoS One 2014 9 7 e103379 e103379 10.1371/journal.pone.0103379 25075522
    [Google Scholar]
  127. Tardiolo G. Bramanti P. Mazzon E. Overview on the effects of N-acetylcysteine in neurodegenerative diseases. Molecules 2018 23 12 3305 10.3390/molecules23123305 30551603
    [Google Scholar]
  128. Porcu M. Urbano M.R. Verri W.A. Jr Barbosa D.S. Baracat M. Vargas H.O. Machado R.C.B.R. Pescim R.R. Nunes S.O.V. Ef-fects of adjunctive N-acetylcysteine on depressive symptoms: Modulation by baseline high-sensitivity C-reactive protein. Psychiatry Res. 2018 263 268 274 10.1016/j.psychres.2018.02.056 29605103
    [Google Scholar]
  129. Dean O. Giorlando F. Berk M. N-acetylcysteine in psychiatry: Current therapeutic evidence and potential mechanisms of action. J. Psychiatry Neurosci. 2011 36 2 78 86 10.1503/jpn.100057 21118657
    [Google Scholar]
  130. Rapado-Castro M. Berk M. Venugopal K. Bush A.I. Dodd S. Dean O.M. Towards stage specific treatments: Effects of duration of illness on therapeutic response to adjunctive treatment with N-acetyl cysteine in schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry 2015 57 69 75 10.1016/j.pnpbp.2014.10.002 25315856
    [Google Scholar]
  131. Gleixner A.M. Hutchison D.F. Sannino S. Bhatia T.N. Leak L.C. Flaherty P.T. Wipf P. Brodsky J.L. Leak R.K. N-acetyl-L-cysteine protects astrocytes against proteotoxicity without recourse to glutathione. Mol. Pharmacol. 2017 92 5 564 575 10.1124/mol.117.109926 28830914
    [Google Scholar]
  132. Halasi M. Wang M. Chavan T.S. Gaponenko V. Hay N. Gartel A.L. ROS inhibitor N -acetyl- L -cysteine antagonizes the activity of proteasome inhibitors. Biochem. J. 2013 454 2 201 208 10.1042/BJ20130282 23772801
    [Google Scholar]
  133. Pedre B. Barayeu U. Ezeriņa D. Dick T.P. The mechanism of action of N-acetylcysteine (NAC): The emerging role of H2S and sulfane sulfur species. Pharmacol. Ther. 2021 228 107916 10.1016/j.pharmthera.2021.107916 34171332
    [Google Scholar]
  134. Aldini G. Altomare A. Baron G. Vistoli G. Carini M. Borsani L. Sergio F. N-Acetylcysteine as an antioxidant and disulphide breaking agent: The reasons why. Free Radic. Res. 2018 52 7 751 762 10.1080/10715762.2018.1468564 29742938
    [Google Scholar]
  135. Soto M.E. Manzano-Pech L. Palacios-Chavarría A. Valdez-Vázquez R.R. Guarner-Lans V. Pérez-Torres I. N-Acetyl Cysteine Re-stores the Diminished Activity of the Antioxidant Enzymatic System Caused by SARS-CoV-2 Infection: Preliminary Findings. Pharmaceuticals (Basel) 2023 16 4 591 10.3390/ph16040591 37111348
    [Google Scholar]
  136. Zhou Y. Wang H. Zhou X. Fang J. Zhu L. Ding K. N-acetylcysteine amide provides neuroprotection via Nrf2-ARE pathway in a mouse model of traumatic brain injury. Drug Des. Devel. Ther. 2018 12 4117 4127 10.2147/DDDT.S179227 30584276
    [Google Scholar]
  137. Xia Z. Nagareddy P.R. Guo Z. Zhang W. Mcneill J.H. Antioxidant N -acetylcysteine restores systemic nitric oxide availability and corrects depressions in arterial blood pressure and heart rate in diabetic rats. Free Radic. Res. 2006 40 2 175 184 10.1080/10715760500484336 16390827
    [Google Scholar]
  138. Krzyzanowska W. Pomierny B. Budziszewska B. Filip M. Pera J. N-Acetylcysteine and Ceftriaxone as Preconditioning Strategies in Focal Brain Ischemia: Influence on Glutamate Transporters Expression. Neurotox. Res. 2016 29 4 539 550 10.1007/s12640‑016‑9602‑z 26861954
    [Google Scholar]
  139. Minarini A. Ferrari S. Galletti M. Giambalvo N. Perrone D. Rioli G. Galeazzi G.M. N -acetylcysteine in the treatment of psychiatric disorders: Current status and future prospects. Expert Opin. Drug Metab. Toxicol. 2017 13 3 279 292 10.1080/17425255.2017.1251580 27766914
    [Google Scholar]
  140. Ooi B.K. Chan K.G. Goh B.H. Yap W.H. The role of natural products in targeting cardiovascular diseases via Nrf2 pathway: Novel molecular mechanisms and therapeutic approaches. Front. Pharmacol. 2018 9 1308 10.3389/fphar.2018.01308 30498447
    [Google Scholar]
  141. Blanco Ayala T. Ramírez Ortega D. Ovalle Rodríguez P. Pineda B. Pérez de la Cruz G. González Esquivel D. Schwarcz R. Sathy-asaikumar K.V. Jiménez Anguiano A. Pérez de la Cruz V. Subchronic n-acetylcysteine treatment decreases brain kynurenic acid levels and improves cognitive performance in mice. Antioxidants 2021 10 2 147 10.3390/antiox10020147 33498402
    [Google Scholar]
  142. Hashimoto K. Tsukada H. Nishiyama S. Fukumoto D. Kakiuchi T. Shimizu E. Iyo M. Protective effects of N-acetyl-L-cysteine on the reduction of dopamine transporters in the striatum of monkeys treated with methamphetamine. Neuropsychopharmacology 2004 29 11 2018 2023 10.1038/sj.npp.1300512 15199373
    [Google Scholar]
  143. Janáky R. Dohovics R. Saransaari P. Oja S.S. Modulation of [3H]dopamine release by glutathione in mouse striatal slices. Neurochem. Res. 2007 32 8 1357 1364 10.1007/s11064‑007‑9315‑z 17401648
    [Google Scholar]
  144. Yan C.Y.I. Greene L.A. Prevention of PC12 cell death by N-acetylcysteine requires activation of the Ras pathway. J. Neurosci. 1998 18 11 4042 4049 10.1523/JNEUROSCI.18‑11‑04042.1998 9592085
    [Google Scholar]
  145. Sun L. Gu L. Wang S. Yuan J. Yang H. Zhu J. Zhang H. N-acetylcysteine protects against apoptosis through modulation of group I metabotropic glutamate receptor activity. PLoS One 2012 7 3 e32503 e32503 10.1371/journal.pone.0032503 22442667
    [Google Scholar]
  146. Zhang F. Lau S.S. Monks T.J. The cytoprotective effect of N-acetyl-L-cysteine against ROS-induced cytotoxicity is independent of its ability to enhance glutathione synthesis. Toxicol. Sci. 2011 120 1 87 97 10.1093/toxsci/kfq364 21135414
    [Google Scholar]
  147. Heinemann S.D. Posimo J.M. Mason D.M. Hutchison D.F. Leak R.K. Synergistic stress exacerbation in hippocampal neurons: Evi-dence favoring the dual‐hit hypothesis of neurodegeneration. Hippocampus 2016 26 8 980 994 10.1002/hipo.22580 26934478
    [Google Scholar]
  148. Posimo J.M. Titler A.M. Choi H.J.H. Unnithan A.S. Leak R.K. Neocortex and allocortex respond differentially to cellular stress in vitro and aging in vivo. PLoS One 2013 8 3 e58596 e58596 10.1371/journal.pone.0058596 23536801
    [Google Scholar]
  149. Unnithan A.S. Jiang Y. Rumble J.L. Pulugulla S.H. Posimo J.M. Gleixner A.M. Leak R.K. N-Acetyl cysteine prevents synergistic, severe toxicity from two hits of oxidative stress. Neurosci. Lett. 2014 560 71 76 10.1016/j.neulet.2013.12.023 24361774
    [Google Scholar]
  150. Fan C. Long Y. Wang L. Liu X. Liu Z. Lan T. Li Y. Yu S.Y. N-Acetylcysteine Rescues Hippocampal Oxidative Stress-Induced Neuronal Injury via Suppression of p38/JNK Signaling in Depressed Rats. Front. Cell. Neurosci. 2020 14 554613 10.3389/fncel.2020.554613 33262689
    [Google Scholar]
  151. Lanté F. Meunier J. Guiramand J. De Jesus Ferreira M.C. Cambonie G. Aimar R. Cohen-Solal C. Maurice T. Vignes M. Bar-banel G. Late N ‐acetylcysteine treatment prevents the deficits induced in the offspring of dams exposed to an immune stress during ges-tation. Hippocampus 2008 18 6 602 609 10.1002/hipo.20421 18306297
    [Google Scholar]
  152. Bradlow R.C.J. Berk M. Kalivas P.W. Back S.E. Kanaan R.A. The potential of N-Acetyl-L-Cysteine (NAC) in the treatment of psy-chiatric disorders. CNS Drugs 2022 36 5 451 482 10.1007/s40263‑022‑00907‑3 35316513
    [Google Scholar]
  153. Fen F. Zhang J. Wang Z. Wu Q. Zhou X. Efficacy and safety of N acetylcysteine therapy for idiopathic pulmonary fibrosis: An up-dated systematic review and meta analysis. Exp. Ther. Med. 2019 18 1 802 816 10.3892/etm.2019.7579 31258714
    [Google Scholar]
  154. Panahi Y. Ghanei M. Rahimi M. Samim A. Vahedian-Azimi A. Atkin S.L. Sahebkar A. Evaluation the efficacy and safety of N‐acetylcysteine inhalation spray in controlling the symptoms of patients with COVID‐19: An open‐label randomized controlled clinical trial. J. Med. Virol. 2023 95 1 e28393 e28393 10.1002/jmv.28393 36495185
    [Google Scholar]
  155. Celorrio M. Rhodes J. Vadivelu S. Davies M. Friess S.H. N-acetylcysteine reduces brain injury after delayed hypoxemia following traumatic brain injury. Exp. Neurol. 2021 335 113507 10.1016/j.expneurol.2020.113507 33065076
    [Google Scholar]
  156. Izzo L.T. Trefely S. Demetriadou C. Drummond J.M. Mizukami T. Kuprasertkul N. Farria A.T. Nguyen P.T.T. Murali N. Reich L. Kantner D.S. Shaffer J. Affronti H. Carrer A. Andrews A. Capell B.C. Snyder N.W. Wellen K.E. Acetylcarnitine shut-tling links mitochondrial metabolism to histone acetylation and lipogenesis. Sci. Adv. 2023 9 18 eadf0115 10.1126/sciadv.adf0115 37134161
    [Google Scholar]
  157. Longo N. Frigeni M. Pasquali M. Carnitine transport and fatty acid oxidation. Biochim. Biophys. Acta Mol. Cell Res. 2016 1863 10 2422 2435 10.1016/j.bbamcr.2016.01.023 26828774
    [Google Scholar]
  158. Jones L.L. McDonald D.A. Borum P.R. Acylcarnitines: Role in brain. Prog. Lipid Res. 2010 49 1 61 75 10.1016/j.plipres.2009.08.004 19720082
    [Google Scholar]
  159. Matias-Guiu J.A. Delgado-Alonso C. Díez-Cirarda M. Martínez-Petit Á. Oliver-Mas S. Delgado-Álvarez A. Cuevas C. Valles-Salgado M. Gil M.J. Yus M. Gómez-Ruiz N. Polidura C. Pagán J. Matías-Guiu J. Ayala J.L. Neuropsychological predictors of fa-tigue in post-COVID syndrome. J. Clin. Med. 2022 11 13 3886 10.3390/jcm11133886 35807173
    [Google Scholar]
  160. Koleničová V. Vňuková M.S. Anders M. Fišerová M. Raboch J. Ptáček R. A review article on exercise intolerance in long COVID: Unmasking the causes and optimizing treatment strategies. Med. Sci. Monit. 2023 29 e941079 e941079 10.12659/MSM.941079 37897034
    [Google Scholar]
  161. Fathizadeh H. Milajerdi A. Reiner Ž. Amirani E. Asemi Z. Mansournia M.A. Hallajzadeh J. The effects of L-carnitine supplemen-tation on indicators of inflammation and oxidative stress: A systematic review and meta-analysis of randomized controlled trials. J. Diabetes Metab. Disord. 2020 19 2 1879 1894 10.1007/s40200‑020‑00627‑9 33520867
    [Google Scholar]
  162. Chiechio S. Canonico P. Grilli M. L-acetylcarnitine: A mechanistically distinctive and potentially rapid-acting antidepressant drug. Int. J. Mol. Sci. 2017 19 1 11 10.3390/ijms19010011 29267192
    [Google Scholar]
  163. Ferreira G.C. McKenna M.C. l-Carnitine and acetyl-l-carnitine roles and neuroprotection in developing brain. Neurochem. Res. 2017 42 6 1661 1675 10.1007/s11064‑017‑2288‑7 28508995
    [Google Scholar]
  164. Spalding K.L. Bergmann O. Alkass K. Bernard S. Salehpour M. Huttner H.B. Boström E. Westerlund I. Vial C. Buchholz B.A. Possnert G. Mash D.C. Druid H. Frisén J. Dynamics of hippocampal neurogenesis in adult humans. Cell 2013 153 6 1219 1227 10.1016/j.cell.2013.05.002 23746839
    [Google Scholar]
  165. Nasca C. Bigio B. Zelli D. de Angelis P. Lau T. Okamoto M. Soya H. Ni J. Brichta L. Greengard P. Neve R.L. Lee F.S. McEwen B.S. Role of the astroglial glutamate exchanger xct in ventral hippocampus in resilience to stress. Neuron 2017 96 2 402 413.e5 10.1016/j.neuron.2017.09.020 29024663
    [Google Scholar]
  166. Notartomaso S. Mascio G. Bernabucci M. Zappulla C. Scarselli P. Cannella M. Imbriglio T. Gradini R. Battaglia G. Bruno V. Nicoletti F. Analgesia induced by the epigenetic drug, L-acetylcarnitine, outlasts the end of treatment in mouse models of chronic inflam-matory and neuropathic pain. Mol. Pain 2017 13 10.1177/1744806917697009 28326943
    [Google Scholar]
  167. Sarzi-Puttini P. Giorgi V. Di Lascio S. Fornasari D. Acetyl-L-carnitine in chronic pain: A narrative review. Pharmacol. Res. 2021 173 105874 10.1016/j.phrs.2021.105874 34500063
    [Google Scholar]
  168. Nasca C. Bigio B. Zelli D. Nicoletti F. McEwen B.S. Mind the gap: Glucocorticoids modulate hippocampal glutamate tone underlying individual differences in stress susceptibility. Mol. Psychiatry 2015 20 6 755 763 10.1038/mp.2014.96 25178162
    [Google Scholar]
  169. Nasca C. Xenos D. Barone Y. Caruso A. Scaccianoce S. Matrisciano F. Battaglia G. Mathé A.A. Pittaluga A. Lionetto L. Sim-maco M. Nicoletti F. L -acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors. Proc. Natl. Acad. Sci. USA 2013 110 12 4804 4809 10.1073/pnas.1216100110 23382250
    [Google Scholar]
  170. Onofrj M. Ciccocioppo F. Varanese S. di Muzio A. Calvani M. Chiechio S. Osio M. Thomas A. Acetyl- L -carnitine: From a biological curiosity to a drug for the peripheral nervous system and beyond. Expert Rev. Neurother. 2013 13 8 925 936 10.1586/14737175.2013.814930 23965166
    [Google Scholar]
  171. Liu T. Deng K. Xue Y. Yang R. Yang R. Gong Z. Tang M. Carnitine and Depression. Front. Nutr. 2022 9 853058 10.3389/fnut.2022.853058 35369081
    [Google Scholar]
  172. Li S. Li Q. Li Y. Li L. Tian H. Sun X. Acetyl-L-carnitine in the treatment of peripheral neuropathic pain: A systematic review and meta-analysis of randomized controlled trials. PLoS One 2015 10 3 e0119479 e0119479 10.1371/journal.pone.0119479 25751285
    [Google Scholar]
  173. Bigio B. Azam S. Mathé A.A. Nasca C. The neuropsychopharmacology of acetyl-L-carnitine (LAC): basic, translational and therapeu-tic implications. Discov. Ment. Health 2024 4 1 2 10.1007/s44192‑023‑00056‑z 38169018
    [Google Scholar]
  174. Wang S.M. Han C. Lee S.J. Patkar A.A. Masand P.S. Pae C.U. A review of current evidence for acetyl-l-carnitine in the treatment of depression. J. Psychiatr. Res. 2014 53 30 37 10.1016/j.jpsychires.2014.02.005 24607292
    [Google Scholar]
  175. Bersani G. Meco G. Denaro A. Liberati D. Colletti C. Nicolai R. Bersani F.S. Koverech A. l-Acetylcarnitine in dysthymic disorder in elderly patients: A double-blind, multicenter, controlled randomized study vs. fluoxetine. Eur. Neuropsychopharmacol. 2013 23 10 1219 1225 10.1016/j.euroneuro.2012.11.013 23428336
    [Google Scholar]
  176. Veronese N. Stubbs B. Solmi M. Ajnakina O. Carvalho A.F. Maggi S. Acetyl-l-carnitine supplementation and the treatment of de-pressive symptoms: A systematic review and meta-analysis. Psychosom. Med. 2018 80 2 154 159 10.1097/PSY.0000000000000537 29076953
    [Google Scholar]
  177. Ames B.N. Liu J. Delaying the mitochondrial decay of aging with acetylcarnitine. Ann. N. Y. Acad. Sci. 2004 1033 1 108 116 10.1196/annals.1320.010 15591008
    [Google Scholar]
  178. Chen N. Yang M. Zhou M. Xiao J. Guo J. He L. L-carnitine for cognitive enhancement in people without cognitive impairment. Cochrane Libr. 2017 2017 3 CD009374 CD009374 10.1002/14651858.CD009374.pub3 28349514
    [Google Scholar]
  179. Cuccurazzu B. Bortolotto V. Valente M.M. Ubezio F. Koverech A. Canonico P.L. Grilli M. Upregulation of mGlu2 receptors via NF-κB p65 acetylation is involved in the Proneurogenic and antidepressant effects of acetyl-L-carnitine. Neuropsychopharmacology 2013 38 11 2220 2230 10.1038/npp.2013.121 23670591
    [Google Scholar]
  180. Foreman P.J. Perez-Polo J.R. Angelucci L. Ramacci M.T. Taglialatela G. Effects of acetyl-l-carnitine treatment and stress exposure on the nerve growth factor receptor (p75NGFR) mRNA level in the central nervous system of aged rats. Prog. Neuropsychopharmacol. Biol. Psychiatry 1995 19 1 117 133 10.1016/0278‑5846(94)00109‑U 7708926
    [Google Scholar]
  181. Taglialatela G. Navarra D. Cruciani R. Ramacci M. Alemà G. Angelucci L. Acetyl-l-carnitine treatment increases nerve growth factor levels and choline acetyltransferase activity in the central nervous system of aged rats. Exp. Gerontol. 1994 29 1 55 66 10.1016/0531‑5565(94)90062‑0 8187841
    [Google Scholar]
  182. Piovesan P. Pacifici L. Taglialatela G. Ramacci M.T. Angelucci L. Acetyl-l-carnitine treatment increases choline acetyltransferase activity and NGF levels in the CNS of adult rats following total fimbria-fornix transection. Brain Res. 1994 633 1-2 77 82 10.1016/0006‑8993(94)91524‑5 8137174
    [Google Scholar]
  183. Pourshahidi S. Shamshiri A.R. Derakhshan S. Mohammadi S. Ghorbani M. The effect of acetyl-L-carnitine (ALCAR) on peripheral nerve regeneration in animal models: A systematic review. Neurochem. Res. 2023 48 8 2335 2344 10.1007/s11064‑023‑03911‑1 37037995
    [Google Scholar]
  184. Doležal V. Tuček S. Utilization of citrate, acetylcarnitine, acetate, pyruvate and glucose for the synthesis of acetylcholine in rat brain slices. J. Neurochem. 1981 36 4 1323 1330 10.1111/j.1471‑4159.1981.tb00569.x 6790669
    [Google Scholar]
  185. Traina G. The neurobiology of acetyl-L-carnitine. Front. Biosci. 2016 21 7 1314 1329 10.2741/4459 27100509
    [Google Scholar]
  186. Traina G. Federighi G. Brunelli M. Scuri R. Cytoprotective effect of acetyl-L-carnitine evidenced by analysis of gene expression in the rat brain. Mol. Neurobiol. 2009 39 2 101 106 10.1007/s12035‑009‑8056‑1 19199082
    [Google Scholar]
  187. He J. Li Z. Xia P. Shi A. FuChen, X.; Zhang, J.; Yu, P. Ferroptosis and ferritinophagy in diabetes complications. Mol. Metab. 2022 60 101470 10.1016/j.molmet.2022.101470 35304332
    [Google Scholar]
  188. Li C. Ou R. Wei Q. Shang H. Carnitine and COVID-19 susceptibility and severity: A mendelian randomization study. Front. Nutr. 2021 8 780205 10.3389/fnut.2021.780205 34901126
    [Google Scholar]
  189. Arnsten A.F.T. Datta D. Wang M. The genie in the bottle-magnified calcium signaling in dorsolateral prefrontal cortex. Mol. Psychiatry 2021 26 8 3684 3700 10.1038/s41380‑020‑00973‑3 33319854
    [Google Scholar]
  190. McEwen B.S. Gray J.D. Nasca C. Recognizing resilience: Learning from the effects of stress on the brain. Neurobiol. Stress 2015 1 1 11 10.1016/j.ynstr.2014.09.001 25506601
    [Google Scholar]
  191. Arnsten A.F.T. Woo E. Yang S. Wang M. Datta D. Unusual molecular regulation of dorsolateral prefrontal cortex layer III synapses increases vulnerability to genetic and environmental insults in Schizophrenia. Biol. Psychiatry 2022 92 6 480 490 10.1016/j.biopsych.2022.02.003 35305820
    [Google Scholar]
  192. Arnsten A.F.T. Wang M. The evolutionary expansion of mGluR3-NAAG-GCPII signaling: Relevance to human intelligence and cognitive disorders. Am. J. Psychiatry 2020 177 12 1103 1106 10.1176/appi.ajp.2020.20101458 33256450
    [Google Scholar]
  193. Knoll M.D. Wonodi C. Oxford–AstraZeneca COVID-19 vaccine efficacy. Lancet 2021 397 10269 72 74 10.1016/S0140‑6736(20)32623‑4 33306990
    [Google Scholar]
  194. Yang S. Datta D. Elizabeth Woo; Duque, A.; Morozov, Y.M.; Arellano, J.; Slusher, B.S.; Wang, M.; Arnsten, A.F.T. Inhibition of glu-tamate-carboxypeptidase-II in dorsolateral prefrontal cortex: Potential therapeutic target for neuroinflammatory cognitive disorders. Mol. Psychiatry 2022 27 10 4252 4263 10.1038/s41380‑022‑01656‑x 35732693
    [Google Scholar]
  195. Neale J.H. Olszewski R.T. Zuo D. Janczura K.J. Profaci C.P. Lavin K.M. Madore J.C. Bzdega T. Advances in understanding the peptide neurotransmitter NAAG and appearance of a new member of the NAAG neuropeptide family. J. Neurochem. 2011 118 4 490 498 10.1111/j.1471‑4159.2011.07338.x 21644997
    [Google Scholar]
  196. Holmay M.J. Terpstra M. Coles L.D. Mishra U. Ahlskog M. Öz G. Cloyd J.C. Tuite P.J. N-Acetylcysteine boosts brain and blood glutathione in Gaucher and Parkinson diseases. Clin. Neuropharmacol. 2013 36 4 103 106 10.1097/WNF.0b013e31829ae713 23860343
    [Google Scholar]
  197. Scofield M.D. Heinsbroek J.A. Gipson C.D. Kupchik Y.M. Spencer S. Smith A.C.W. Roberts-Wolfe D. Kalivas P.W. The nucleus accumbens: Mechanisms of addiction across drug classes reflect the importance of glutamate homeostasis. Pharmacol. Rev. 2016 68 3 816 871 10.1124/pr.116.012484 27363441
    [Google Scholar]
  198. Kazmi N. Davey Smith G. Lewis S. Mendelian randomization analyses show that higher acetyl-carnitine and carnitine levels in blood protect against severe COVID19. SSRN 2021 10.2139/ssrn.3857663
    [Google Scholar]
  199. Vaziri-harami R. Delkash P. Can l-carnitine reduce post-COVID-19 fatigue? Ann. Med. Surg. (Lond.) 2022 73 103145 10.1016/j.amsu.2021.103145 34925826
    [Google Scholar]
  200. Cuadrado A. Martín-Moldes Z. Ye J. Lastres-Becker I. Transcription factors NRF2 and NF-κB are coordinated effectors of the Rho family, GTP-binding protein RAC1 during inflammation. J. Biol. Chem. 2014 289 22 15244 15258 10.1074/jbc.M113.540633 24759106
    [Google Scholar]
  201. Wardyn J.D. Ponsford A.H. Sanderson C.M. Dissecting molecular cross-talk between Nrf2 and NF-κB response pathways. Biochem. Soc. Trans. 2015 43 4 621 626 10.1042/BST20150014 26551702
    [Google Scholar]
  202. Khodakarami A. Adibfar S. Karpisheh V. Abolhasani S. Jalali P. Mohammadi H. Gholizadeh Navashenaq J. Hojjat-Farsangi M. Jadidi-Niaragh F. The molecular biology and therapeutic potential of Nrf2 in leukemia. Cancer Cell Int. 2022 22 1 241 10.1186/s12935‑022‑02660‑5 35906617
    [Google Scholar]
  203. Cacciatore I. Cornacchia C. Pinnen F. Mollica A. Di Stefano A. Prodrug approach for increasing cellular glutathione levels. Molecules 2010 15 3 1242 1264 10.3390/molecules15031242 20335977
    [Google Scholar]
  204. Helbing D.L. Dommaschk E.M. Danyeli L.V. Liepinsh E. Refisch A. Sen Z.D. Zvejniece L. Rocktäschel T. Stabenow L.K. Schiöth H.B. Walter M. Dambrova M. Besteher B. Conceptual foundations of acetylcarnitine supplementation in neuropsychiatric long COVID syndrome: A narrative review. Eur. Arch. Psychiatry Clin. Neurosci. 2024 2024 01734 3 10.1007/s00406‑023‑01734‑3 38172332
    [Google Scholar]
  205. Tenório M.C.S. Graciliano N.G. Moura F.A. Oliveira A.C.M. Goulart M.O.F. N-Acetylcysteine (NAC): Impacts on Human Health. Antioxidants 2021 10 6 967 10.3390/antiox10060967 34208683
    [Google Scholar]
  206. Tavares-Júnior J.W.L. de Souza A.C.C. Borges J.W.P. Oliveira D.N. Siqueira-Neto J.I. Sobreira-Neto M.A. Braga-Neto P. COVID-19 associated cognitive impairment: A systematic review. Cortex 2022 152 77 97 10.1016/j.cortex.2022.04.006 35537236
    [Google Scholar]
  207. Ooi S.L. Green R. Pak S.C. N-Acetylcysteine for the Treatment of Psychiatric Disorders: A Review of Current Evidence. BioMed Res. Int. 2018 2018 1 8 10.1155/2018/2469486 30426004
    [Google Scholar]
  208. Mohiuddin M. Pivetta B. Gilron I. Khan J.S. Efficacy and safety of N-acetylcysteine for the management of chronic pain in adults: A systematic review and meta-analysis. Pain Med. 2021 22 12 2896 2907 10.1093/pm/pnab042 33560443
    [Google Scholar]
  209. Morris G. Puri B.K. Walker A.J. Maes M. Carvalho A.F. Walder K. Mazza C. Berk M. Myalgic encephalomyelitis/chronic fatigue syndrome: From pathophysiological insights to novel therapeutic opportunities. Pharmacol. Res. 2019 148 104450 10.1016/j.phrs.2019.104450 31509764
    [Google Scholar]
  210. Vermeulen R.C.W. Scholte H.R. Exploratory open label, randomized study of acetyl- and propionylcarnitine in chronic fatigue syn-drome. Psychosom. Med. 2004 66 2 276 282 10.1097/01.psy.0000116249.60477.e9 15039515
    [Google Scholar]
  211. Altay O. Arif M. Li X. Yang H. Aydın M. Alkurt G. Kim W. Akyol D. Zhang C. Dinler-Doganay G. Turkez H. Shoaie S. Nielsen J. Borén J. Olmuscelik O. Doganay L. Uhlén M. Mardinoglu A. Combined metabolic activators accelerates recovery in mild‐to‐moderate COVID‐19. Adv. Sci. (Weinh.) 2021 8 17 2101222 10.1002/advs.202101222 34180141
    [Google Scholar]
  212. Valdés A. Moreno L.O. Rello S.R. Orduña A. Bernardo D. Cifuentes A. Metabolomics study of COVID-19 patients in four differ-ent clinical stages. Sci. Rep. 2022 12 1 1650 10.1038/s41598‑022‑05667‑0 35102215
    [Google Scholar]
  213. Micheletto C. Izquierdo J.L. Avdeev S.N. Rada Escobar R.A. Pacheco Gallego M.C. N-acetylcysteine as a therapeutic approach to post-COVID-19 pulmonary fibrosis adjunctive treatment. Eur. Rev. Med. Pharmacol. Sci. 2022 26 13 4872 4880 10.26355/eurrev_202207_29212 35856379
    [Google Scholar]
  214. Rastgoo S. Fateh S.T. Nikbaf-Shandiz M. Rasaei N. Aali Y. Zamani M. Shiraseb F. Asbaghi O. The effects of L-carnitine sup-plementation on inflammatory and anti-inflammatory markers in adults: A systematic review and dose–response meta-analysis. Inflammopharmacology 2023 31 5 2173 2199 10.1007/s10787‑023‑01323‑9 37656233
    [Google Scholar]
  215. Alhasaniah A.H. l-carnitine: Nutrition, pathology, and health benefits. Saudi J. Biol. Sci. 2023 30 2 103555 10.1016/j.sjbs.2022.103555 36632072
    [Google Scholar]
  216. Badawi A. Hypercytokinemia and Pathogen–Host Interaction in COVID-19. J. Inflamm. Res. 2020 13 255 261 10.2147/JIR.S259096 32606886
    [Google Scholar]
  217. Poe F.L. Corn J. N-Acetylcysteine: A potential therapeutic agent for SARS-CoV-2. Med. Hypotheses 2020 143 109862 10.1016/j.mehy.2020.109862 32504923
    [Google Scholar]
  218. Zawawi A. Naser A.Y. Alwafi H. Minshawi F. Profile of circulatory cytokines and chemokines in human coronaviruses: A systematic review and meta-analysis. Front. Immunol. 2021 12 666223 10.3389/fimmu.2021.666223 34046036
    [Google Scholar]
  219. Truini A. Piroso S. Pasquale E. Notartomaso S. Stefano G.D. Lattanzi R. Battaglia G. Nicoletti F. Cruccu G. N-acetylcysteine, a drug that enhances the endogenous activation of group- II metabotropic glutamate receptors, inhibits nociceptive transmission in humans Mol. Pain, 2015 11 s12990-015-0009 10.1186/s12990‑015‑0009‑2 25889381
    [Google Scholar]
  220. Naureen Z. Dautaj A. Nodari S. Fioretti F. Dhuli K. Anpilogov K. Lorusso L. Paolacci S. Michelini S. Guda T. Kallazi M. Bertelli M. Proposal of a food supplement for the management of post-COVID syndrome. Eur. Rev. Med. Pharmacol. Sci. 2021 25 1 67 73 10.26355/eurrev_202112_27335 34890036
    [Google Scholar]
  221. Bellamine A. Pham T.N.Q. Jain J. Wilson J. Sahin K. Dallaire F. Seidah N.G. Durkee S. Radošević K. Cohen É.A. L-carnitine tartrate downregulates the ace2 receptor and limits sars-cov-2 infection. Nutrients 2021 13 4 1297 10.3390/nu13041297 33919991
    [Google Scholar]
  222. Sadowska A.M. N -Acetylcysteine mucolysis in the management of chronic obstructive pulmonary disease. Ther. Adv. Respir. Dis. 2012 6 3 127 135 10.1177/1753465812437563 22361928
    [Google Scholar]
  223. Dai J. Teng X. Jin S. Wu Y. The antiviral roles of hydrogen sulfide by blocking the interaction between SARS‐CoV‐2 and its potential cell surface receptors. Oxid. Med. Cell. Longev. 2021 2021 1 7866992 10.1155/2021/7866992 34497683
    [Google Scholar]
  224. Guo Q. Jin Y. Chen X. Ye X. Shen X. Lin M. Zeng C. Zhou T. Zhang J. NF-κB in biology and targeted therapy: New insights and translational implications. Signal Transduct. Target. Ther. 2024 9 1 53 10.1038/s41392‑024‑01757‑9 38433280
    [Google Scholar]
  225. Naushad S.M. Mandadapu G. Ramaiah M.J. Almajhdi F.N. Hussain T. The role of TLR7 agonists in modulating COVID-19 severity in subjects with loss-of-function TLR7 variants. Sci. Rep. 2023 13 1 13078 10.1038/s41598‑023‑40114‑8 37567916
    [Google Scholar]
  226. McCarty M.F. DiNicolantonio J.J. Nutraceuticals have potential for boosting the type 1 interferon response to RNA viruses including influenza and coronavirus. Prog. Cardiovasc. Dis. 2020 63 3 383 385 10.1016/j.pcad.2020.02.007 32061635
    [Google Scholar]
  227. Shibanuma M. Kuroki T. Nose K. Inhibition by N ‐acetyl‐ L ‐cysteine of interleukin‐6 mRNA induction and activation of NFκB by tumor necrosis factor α in a mouse fibroblastic cell line, Balb/3T3. FEBS Lett. 1994 353 1 62 66 10.1016/0014‑5793(94)01014‑5 7926024
    [Google Scholar]
  228. Wong K.K. Lee S.W.H. Kua K.P. N-acetylcysteine as adjuvant therapy for covid-19 – a perspective on the current state of the evidence. J. Inflamm. Res. 2021 14 2993 3013 10.2147/JIR.S306849 34262324
    [Google Scholar]
  229. Kim K. Lee S.G. Kegelman T.P. Su Z.Z. Das S.K. Dash R. Dasgupta S. Barral P.M. Hedvat M. Diaz P. Reed J.C. Stebbins J.L. Pellecchia M. Sarkar D. Fisher P.B. Role of Excitatory Amino Acid Transporter‐2 (EAAT2) and glutamate in neurodegeneration: Opportunities for developing novel therapeutics. J. Cell. Physiol. 2011 226 10 2484 2493 10.1002/jcp.22609 21792905
    [Google Scholar]
  230. Talbot K. Madden V.J. Jones S.L. Moseley G.L. The sensory and affective components of pain: Are they differentially modifiable dimensions or inseparable aspects of a unitary experience? A systematic review. Br. J. Anaesth. 2019 123 2 e263 e272 10.1016/j.bja.2019.03.033 31053232
    [Google Scholar]
  231. Huang R. Wu J. Ma Y. Kang K. Molecular Mechanisms of Ferroptosis and Its Role in Viral Pathogenesis. Viruses 2023 15 12 2373 10.3390/v15122373 38140616
    [Google Scholar]
  232. Wang J. Zhu J. Ren S. Zhang Z. Niu K. Li H. Wu W. Peng C. The role of ferroptosis in virus infections. Front. Microbiol. 2023 14 1279655 10.3389/fmicb.2023.1279655 38075884
    [Google Scholar]
  233. Lu Y. Zhu Q. Fox D.M. Gao C. Stanley S.A. Luo K. SARS-CoV-2 down-regulates ACE2 through lysosomal degradation. Mol. Biol. Cell 2022 33 14 ar147 ar147 10.1091/mbc.E22‑02‑0045 36287912
    [Google Scholar]
  234. Wang X. Wang M. Xu T. Feng Y. Shao Q. Han S. Chu X. Xu Y. Lin S. Zhao Q. Wu B. Structural insights into dimerization and activation of the mGlu2–mGlu3 and mGlu2–mGlu4 heterodimers. Cell Res. 2023 33 10 762 774 10.1038/s41422‑023‑00830‑2 37286794
    [Google Scholar]
  235. Bridges R.J. Natale N.R. Patel S.A. System x c‐ cystine/glutamate antiporter: An update on molecular pharmacology and roles within the CNS. Br. J. Pharmacol. 2012 165 1 20 34 10.1111/j.1476‑5381.2011.01480.x 21564084
    [Google Scholar]
  236. Chiang W. Stout A. Yanchik-Slade F. Li H. Terrando N. Nilsson B.L. Gelbard H.A. Krauss T.D. Quantum Dot Biomimetic for SARS-CoV-2 to Interrogate Blood–Brain Barrier Damage Relevant to NeuroCOVID Brain Inflammation. ACS Appl. Nano Mater. 2023 6 16 15094 15107 10.1021/acsanm.3c02719 37649833
    [Google Scholar]
  237. Bradbury J. Wilkinson S. Schloss J. Nutritional Support During Long COVID: A Systematic Scoping Review. J. Integr. Complement. Med. 2023 29 11 695 704 10.1089/jicm.2022.0821 37102680
    [Google Scholar]
  238. Reuter S.E. Evans, AM Carnitine and Acylcarnitines. Clin. Pharmacokinet. 2012 51 9 553 572 10.1007/BF03261931
    [Google Scholar]
  239. Li W. Xu Z. Niu T. Xie Y. Zhao Z. Li D. He Q. Sun W. Shi K. Guo W. Chang Z. Liu K. Fan Z. Qi J. Gao G.F. Key mechanistic features of the trade-off between antibody escape and host cell binding in the SARS-CoV-2 Omicron variant spike proteins. EMBO J. 2024 43 8 1484 1498 10.1038/s44318‑024‑00062‑z 38467833
    [Google Scholar]
  240. Stępień T. Tarka S. Chmura N. Grzegorczyk M. Acewicz A. Felczak P. Wierzba-Bobrowicz T. Influence of SARS-CoV-2 on Adult Human Neurogenesis. Cells 2023 12 2 244 10.3390/cells12020244 36672177
    [Google Scholar]
  241. Borsini A. Merrick B. Edgeworth J. Mandal G. Srivastava D.P. Vernon A.C. Nebbia G. Thuret S. Pariante C.M. Neurogenesis is disrupted in human hippocampal progenitor cells upon exposure to serum samples from hospitalized COVID-19 patients with neurologi-cal symptoms. Mol. Psychiatry 2022 27 12 5049 5061 10.1038/s41380‑022‑01741‑1 36195636
    [Google Scholar]
  242. Zorzo C. Solares L. Mendez M. Mendez-Lopez M. Hippocampal alterations after SARS-CoV-2 infection: A systematic review. Behav. Brain Res. 2023 455 114662 10.1016/j.bbr.2023.114662 37703951
    [Google Scholar]
/content/journals/cn/10.2174/011570159X343115241030094848
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Neuropsychiatric Manifestations of COVID-19 Disease and Post Covid Syndrome: The Role of N Acetyl-cysteine and Acetyl-L-carnitine
Bentham Science Publishers ; https://doi.org/10.2174/011570159X343115241030094848
/content/journals/cn/10.2174/011570159X343115241030094848
/content/journals/cn/10.2174/011570159X343115241030094848
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  • Article Type:     Review Article
Keywords: N-acetylcysteine ; SARS-CoV-2 ; anxiety ; circumventricular organs

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