Long Neuro-COVID-19: Current Mechanistic Views and Therapeutic Perspectives
Abstract
:1. Introduction
2. Current Hypotheses
- A-1: Inflammation
- A-2: Immunity
- A-3: Long Neuro-COVID-19 (Long Neuro-COVID) and neuropeptides
3. Insights into the Role of the SARS-CoV-2 Nucleoprotein in COVID-19 and Long COVID
Hormone/Neuropeptide | Target | Receptor | Antagonist | Symptom(s) | References |
---|---|---|---|---|---|
Cholecystokinin (CCK) | Gut and brain and vagus nerve | CCKR1 and R2, CBRs receptors | - Pancreas dysfunction as CCK is a satiety hormone - Synaptic deficits: CCK is involved in synaptic transmission via the activation of muscarinic acetylcholine receptors | [15,51,57,73,78,79] | |
Met/Proenkephalin | Brain/ inhibition of replication | Opioid receptors | Naltrexone | Pain reduction, increased gut dysbiosis, neurodegenerescence | [7,12,44,53,54,78,81,82,83,84] |
Substance P | Olfactory neurons Trigeminal nerve lymph node | Neurokinin receptor-1 (NK-1R) | Aprepitant | Pain transmission, headache, brain fog, depression, thromboembolism, pro-inflammatory effects, and viral latency (although the latter requires further study). | [24,50,76,85,86] |
Folate/heme/iron | Heart, blood hemoglobin | Folate receptor, iron metabolism, Fe storage ferritin | Brain fog, shortness of breath, ferroptosis, fibrosis | [7,38,39,87] |
4. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Appendix A
- Key Statements Are All Supported by Literature References
References
- Khullar, D.; Zhang, Y.; Zang, C.; Xu, Z.; Wang, F.; Weiner, M.G.; Carton, T.W.; Rothman, R.L.; Block, J.P.; Kaushal, R. Racial/Ethnic Disparities in Post-acute Sequelae of SARS-CoV-2 Infection in New York: An EHR-Based Cohort Study from the RECOVER Program. J. Gen. Intern. Med. 2023, 38, 1127–1136. [Google Scholar] [CrossRef] [PubMed]
- Zang, C.; Hou, Y.; Schenck, E.; Xu, Z.; Zhang, Y.; Xu, J.; Bian, J.; Morozyuk, D.; Khullar, D.; Nordvig, A.; et al. Risk Factors and Predictive Modeling for Post-Acute Sequelae of SARS-CoV-2 Infection: Findings from EHR Cohorts of the RECOVER Initiative. Commun. Med. 2024, 4. [Google Scholar] [CrossRef] [PubMed]
- Zang, C.; Hou, Y.; Schenck, E.J.; Xu, Z.; Zhang, Y.; Xu, J.; Bian, J.; Morozyuk, D.; Khullar, D.; Nordvig, A.S.; et al. Identification of risk factors of Long COVID and predictive modeling in the RECOVER EHR cohorts. Commun. Med. 2024, 4, 130. [Google Scholar] [CrossRef] [PubMed]
- Thompson, E.J.; Williams, D.M.; Walker, A.J.; Mitchell, R.E.; Niedzwiedz, C.L.; Yang, T.C.; Huggins, C.F.; Kwong, A.S.F.; Silverwood, R.J.; Di Gessa, G.; et al. Long COVID burden and risk factors in 10 UK longitudinal studies and electronic health records. Nat. Commun. 2022, 13, 3528. [Google Scholar] [CrossRef]
- Laracy, J.C.; Kamboj, M.; Vardhana, S.A. Long and persistent COVID-19 in patients with hematologic malignancies: From bench to bedside. Curr. Opin. Infect. Dis. 2022, 35, 271–279. [Google Scholar] [CrossRef]
- Peluso, M.J.; Deitchman, A.N.; Torres, L.; Iyer, N.S.; Munter, S.E.; Nixon, C.C.; Donatelli, J.; Thanh, C.; Takahashi, S.; Hakim, J.; et al. Long-term SARS-CoV-2-specific immune and inflammatory responses in individuals recovering from COVID-19 with and without post-acute symptoms. Cell Rep. 2021, 36, 109518. [Google Scholar] [CrossRef]
- Henri, J.; Minder, L.; Mohanasundaram, K.; Dilly, S.; Goupil-Lamy, A.; Di Primo, C.; Schwok, A.S. Neuropeptides, New Ligands of SARS-CoV-2 Nucleoprotein, a Potential Link between Replication, Inflammation and Neurotransmission. Molecules 2022, 27, 8094. [Google Scholar] [CrossRef]
- Hanson, B.A.; Visvabharathy, L.; Ali, S.T.; Kang, A.K.; Patel, T.R.; Clark, J.R.; Lim, P.H.; Orban, Z.S.; Hwang, S.S.; Mattoon, D.; et al. Plasma Biomarkers of Neuropathogenesis in Hospitalized Patients With COVID-19 and Those With Postacute Sequelae of SARS-CoV-2 Infection. Neurol. Neuroimmunol. Neuroinflamm. 2022, 9, e1151. [Google Scholar] [CrossRef]
- Visvabharathy, L.; Hanson, B.A.; Orban, Z.S.; Lim, P.H.; Palacio, N.M.; Jimenez, M.; Clark, J.R.; Graham, E.L.; Liotta, E.M.; Tachas, G.; et al. Neuro-PASC is characterized by enhanced CD4+ and diminished CD8+ T cell responses to SARS-CoV-2 Nucleocapsid protein. Front. Immunol. 2023, 14, 1155770. [Google Scholar] [CrossRef]
- Molnar, T.; Varnai, R.; Schranz, D.; Zavori, L.; Peterfi, Z.; Sipos, D.; Tőkés-Füzesi, M.; Illes, Z.; Buki, A.; Csecsei, P. Severe Fatigue and Memory Impairment Are Associated with Lower Serum Level of Anti-SARS-CoV-2 Antibodies in Patients with Post-COVID Symptoms. J. Clin. Med. 2021, 10, 4337. [Google Scholar] [CrossRef]
- Varnai, R.; Molnar, T.; Zavori, L.; Tőkés-Füzesi, M.; Illes, Z.; Kanizsai, A.; Csecsei, P. Serum Level of Anti-Nucleocapsid, but Not Anti-Spike Antibody, Is Associated with Improvement of Long COVID Symptoms. Vaccines 2022, 10, 165. [Google Scholar] [CrossRef] [PubMed]
- Burtscher, J.; Bean, C.; Zangrandi, L.; Kmiec, I.; Agostinho, A.; Scorrano, L.; Gnaiger, E.; Schwarzer, C. Proenkephalin Derived Peptides Are Involved in the Modulation of Mitochondrial Respiratory Control During Epileptogenesis. Front. Mol. Neurosci. 2018, 11, 351. [Google Scholar] [CrossRef] [PubMed]
- Chowdhury, B.; Sahoo, B.M.; Jena, A.P.; Hiramani, K.; Behera, A.; Acharya, B. NOX-2 Inhibitors may be Potential Drug Candidates for the Management of COVID-19 Complications. Curr. Drug Res. Rev. 2024, 16, 128–133. [Google Scholar] [CrossRef]
- Foo, J.; Bellot, G.; Pervaiz, S.; Alonso, S. Mitochondria-mediated oxidative stress during viral infection. Trends Microbiol. 2022, 30, 679–692. [Google Scholar] [CrossRef]
- Hao, L.; Shi, M.; Ma, J.; Shao, S.; Yuan, Y.; Liu, J.; Yu, Z.; Zhang, Z.; Hölscher, C. A Cholecystokinin Analogue Ameliorates Cognitive Deficits and Regulates Mitochondrial Dynamics via the AMPK/Drp1 Pathway in APP/PS1 Mice. J. Prev. Alzheimer’s Dis. 2024, 11, 382–401. [Google Scholar] [CrossRef]
- Keeney, M.T.; Hoffman, E.K.; Farmer, K.; Bodle, C.R.; Fazzari, M.; Zharikov, A.; Castro, S.L.; Hu, X.; Mortimer, A.; Kofler, J.K.; et al. NADPH oxidase 2 activity in Parkinson’s disease. Neurobiol. Dis. 2022, 170, 105754. [Google Scholar] [CrossRef]
- Pileggi, C.A.; Parmar, G.; Elkhatib, H.; Stewart, C.M.; Alecu, I.; Côté, M.; Bennett, S.A.; Sandhu, J.K.; Cuperlovic-Culf, M.; Harper, M.-E. The SARS-CoV-2 spike glycoprotein interacts with MAO-B and impairs mitochondrial energetics. Curr. Res. Neurobiol. 2023, 5, 100112. [Google Scholar] [CrossRef]
- Stefano, G.B.; Büttiker, P.; Weissenberger, S.; Martin, A.; Ptacek, R.; Kream, R.M. Editorial: The Pathogenesis of Long-Term Neuropsychiatric COVID-19 and the Role of Microglia, Mitochondria, and Persistent Neuroinflammation: A Hypothesis. Med Sci. Monit. 2021, 27, e933015. [Google Scholar] [CrossRef]
- Yu, H.; Yang, L.; Han, Z.; Zhou, X.; Zhang, Z.; Sun, T.; Zheng, F.; Yang, J.; Guan, F.; Xie, J.; et al. SARS-CoV-2 nucleocapsid protein enhances the level of mitochondrial reactive oxygen species. J. Med Virol. 2023, 95, e29270. [Google Scholar] [CrossRef] [PubMed]
- Chen, B.; Julg, B.; Mohandas, S.; Bradfute, S.B.; RECOVER Mechanistic Pathways Task Force. Viral persistence, reactivation, and mechanisms of long COVID. eLife 2023, 12, e86015. [Google Scholar] [CrossRef]
- De Melo, G.D.; Lazarini, F.; Levallois, S.; Hautefort, C.; Michel, V.; Larrous, F.; Verillaud, B.; Aparicio, C.; Wagner, S.; Gheusi, G.; et al. COVID-19–related anosmia is associated with viral persistence and inflammation in human olfactory epithelium and brain infection in hamsters. Sci. Transl. Med. 2021, 13, eabf8396. [Google Scholar] [CrossRef] [PubMed]
- De Melo, G.D.; Perraud, V.; Alvarez, F.; Vieites-Prado, A.; Kim, S.; Kergoat, L.; Coleon, A.; Trüeb, B.S.; Tichit, M.; Piazza, A.; et al. Neuroinvasion and anosmia are independent phenomena upon infection with SARS-CoV-2 and its variants. Nat. Commun. 2023, 14, 4485. [Google Scholar] [CrossRef] [PubMed]
- Sherif, Z.A.; Gomez, C.R.; Connors, T.J.; Henrich, T.J.; Reeves, W.B.; RECOVER Mechanistic Pathway Task Force. Pathogenic mechanisms of post-acute sequelae of SARS-CoV-2 infection (PASC). eLife 2023, 12, e86002. [Google Scholar] [CrossRef]
- Janket, S.-J.; Fraser, D.D.; E Baird, A.; Tamimi, F.; Sohaei, D.; A Conte, H.; Prassas, I.; Diamandis, E.P. Tachykinins and the potential causal factors for post-COVID-19 condition. Lancet Microbe 2023, 4, e642–e650. [Google Scholar] [CrossRef] [PubMed]
- Lauritano, D.; Mastrangelo, F.; D’ovidio, C.; Ronconi, G.; Caraffa, A.; Gallenga, C.E.; Frydas, I.; Kritas, S.K.; Trimarchi, M.; Carinci, F.; et al. Activation of Mast Cells by Neuropeptides: The Role of Pro-Inflammatory and Anti-Inflammatory Cytokines. Int. J. Mol. Sci. 2023, 24, 4811. [Google Scholar] [CrossRef]
- Mehboob, R.; Kurdi, M.; Bamaga, A.; Aldardeir, N.; Nasief, H.; Moshref, L.H.; Alsinani, T.; Rayes, A.O.; Jabbad, R.H. Substance P/Neurokinin-1 Receptor, Trigeminal Ganglion, Latency, and Coronavirus Infection-Is There Any Link? Front. Med. 2021, 8, 727593. [Google Scholar] [CrossRef]
- Anderson, G.; Carbone, A.; Mazzoccoli, G. Aryl Hydrocarbon Receptor Role in Co-Ordinating SARS-CoV-2 Entry and Symptomatology: Linking Cytotoxicity Changes in COVID-19 and Cancers; Modulation by Racial Discrimination Stress. Biology 2020, 9, 249. [Google Scholar] [CrossRef]
- Turski, W.A.; Wnorowski, A.; Turski, G.N.; Turski, C.A.; 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, 343–354. [Google Scholar] [CrossRef]
- Shi, J.; Du, T.; Wang, J.; Tang, C.; Lei, M.; Yu, W.; Yang, Y.; Ma, Y.; Huang, P.; Chen, H.; et al. Aryl hydrocarbon receptor is a proviral host factor and a candidate pan-SARS-CoV-2 therapeutic target. Sci. Adv. 2023, 9, eadf0211. [Google Scholar] [CrossRef]
- Amici, C.; Di Caro, A.; Ciucci, A.; Chiappa, L.; Castilletti, C.; Martella, V.; Decaro, N.; Buonavoglia, C.; Capobianchi, M.R.; Santoro, M.G. Indomethacin Has a Potent Antiviral Activity against Sars Coronavirus. Antivir. Ther. 2006, 11, 1021–1030. [Google Scholar] [CrossRef]
- Lejal, N.; Tarus, B.; Bouguyon, E.; Chenavas, S.; Bertho, N.; Delmas, B.; Ruigrok, R.W.H.; Di Primo, C.; Slama-Schwok, A. Structure-Based Discovery of the Novel Antiviral Properties of Naproxen against the Nucleoprotein of Influenza A Virus. Antimicrob. Agents Chemother. 2013, 57, 2231–2242. [Google Scholar] [CrossRef]
- Ravichandran, R.; Mohan, S.K.; Sukumaran, S.K.; Kamaraj, D.; Daivasuga, S.S.; Ravi, S.O.A.S.; Vijayaraghavalu, S.; Kumar, R.K. An open label randomized clinical trial of Indomethacin for mild and moderate hospitalised COVID-19 patients. Sci. Rep. 2022, 12, 6413. [Google Scholar] [CrossRef]
- Terrier, O.; Dilly, S.; Pizzorno, A.; Chalupska, D.; Humpolickova, J.; Bouřa, E.; Berenbaum, F.; Quideau, S.; Lina, B.; Fève, B.; et al. Antiviral Properties of the NSAID Drug Naproxen Targeting the Nucleoprotein of SARS-CoV-2 Coronavirus. Molecules 2021, 26, 2593. [Google Scholar] [CrossRef] [PubMed]
- Ehrlich, A.; Ioannidis, K.; Nasar, M.; Abu Alkian, I.; Daskal, Y.; Atari, N.; Kliker, L.; Rainy, N.; Hofree, M.; Tikva, S.S.; et al. Efficacy and safety of metabolic interventions for the treatment of severe COVID-19: In vitro, observational, and non-randomized open-label interventional study. eLife 2023, 12, e79946. [Google Scholar] [CrossRef] [PubMed]
- Li, M.; Tan, H.-E.; Lu, Z.; Tsang, K.S.; Chung, A.J.; Zuker, C.S. Gut–brain circuits for fat preference. Nature 2022, 610, 722–730. [Google Scholar] [CrossRef]
- Qian, Y.; Lei, T.; Patel, P.S.; Lee, C.H.; Monaghan-Nichols, P.; Xin, H.-B.; Qiu, J.; Fu, M. Direct Activation of Endothelial Cells by SARS-CoV-2 Nucleocapsid Protein Is Blocked by Simvastatin. J. Virol. 2021, 95, e0139621. [Google Scholar] [CrossRef] [PubMed]
- Tan, H.-E.; Sisti, A.C.; Jin, H.; Vignovich, M.; Villavicencio, M.; Tsang, K.S.; Goffer, Y.; Zuker, C.S. The gut–brain axis mediates sugar preference. Nature 2020, 580, 511–516. [Google Scholar] [CrossRef] [PubMed]
- Ishikura, T.; Nakano, T.; Kitano, T.; Tokuda, T.; Sumi-Akamaru, H.; Naka, T. Serum ferritin level during hospitalization is associated with Brain Fog after COVID-19. Sci. Rep. 2023, 13, 13095. [Google Scholar] [CrossRef]
- Kronstein-Wiedemann, R.; Stadtmüller, M.; Traikov, S.; Georgi, M.; Teichert, M.; Yosef, H.; Wallenborn, J.; Karl, A.; Schütze, K.; Wagner, M.; et al. SARS-CoV-2 Infects Red Blood Cell Progenitors and Dysregulates Hemoglobin and Iron Metabolism. Stem Cell Rev. Rep. 2022, 18, 1809–1821. [Google Scholar] [CrossRef]
- Lejal, N.; Truchet, S.; Bechor, E.; Bouguyon, E.; Khedkar, V.; Bertho, N.; Vidic, J.; Adenot, P.; Solier, S.; Pick, E.; et al. Turning off NADPH oxidase-2 by impeding p67phox activation in infected mouse macrophages reduced viral entry and inflammation. Biochim. et Biophys. Acta (BBA) Gen. Subj. 2018, 1862, 1263–1275. [Google Scholar] [CrossRef]
- Dilly, S.; Romero, M.; Solier, S.; Feron, O.; Dessy, C.; Schwok, A.S. Targeting M2 Macrophages with a Novel NADPH Oxidase Inhibitor. Antioxidants 2023, 12, 440. [Google Scholar] [CrossRef]
- Terrier, O.D.S.; Pizzorno, A.; Henri, J.; Berenbaum, F.; Lina, B.; Fève, B.; Adnet, F.; Sabbah, M.; Rosa-Calatrava, M.; Maréchal, V.; et al. Broad-spectrum antiviral activity of naproxen: From Influenza A to SARS-CoV-2 Coronavirus. BioRxiv 2020. [Google Scholar] [CrossRef]
- Wang, Y.; Tsai, C.-H.; Wang, Y.-C.; Yen, L.-C.; Chang, Y.-W.; Sun, J.-R.; Lin, T.-Y.; Chiu, C.-H.; Chao, Y.-C.; Chang, F.-Y. SARS-CoV-2 nucleocapsid protein, rather than spike protein, triggers a cytokine storm originating from lung epithelial cells in patients with COVID-19. Infection 2023, 52, 955–983. [Google Scholar] [CrossRef] [PubMed]
- Xu, X.; Gao, Y.; Wen, L.; Zhai, Z.; Zhang, S.; Shan, F.; Feng, J. Methionine enkephalin regulates microglia polarization and function. Int. Immunopharmacol. 2016, 40, 90–97. [Google Scholar] [CrossRef] [PubMed]
- Wu, W.; Wang, W.; Liang, L.; Chen, J.; Sun, S.; Wei, B.; Zhong, Y.; Huang, X.-R.; Liu, J.; Wang, X.; et al. SARS-CoV-2 N protein induced acute kidney injury in diabetic db/db mice is associated with a Mincle-dependent M1 macrophage activation. Front. Immunol. 2023, 14, 1264447. [Google Scholar] [CrossRef] [PubMed]
- Cohen, K.W.; Linderman, S.L.; Moodie, Z.; Czartoski, J.; Lai, L.; Mantus, G.; Norwood, C.; Nyhoff, L.E.; Edara, V.V.; Floyd, K.; et al. Longitudinal analysis shows durable and broad immune memory after SARS-CoV-2 infection with persisting antibody responses and memory B and T cells. Cell Rep. Med. 2021, 2, 100354. [Google Scholar] [CrossRef]
- Le Bert, N.; Tan, A.T.; Kunasegaran, K.; Tham, C.Y.L.; Hafezi, M.; Chia, A.; Chng, M.H.Y.; Lin, M.; Tan, N.; Linster, M.; et al. SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls. Nature 2020, 584, 457–462. [Google Scholar] [CrossRef]
- Glynne, P.; Tahmasebi, N.; Gant, V.; Gupta, R. Long COVID following Mild SARS-CoV-2 Infection: Characteristic T Cell Alterations and Response to Antihistamines. J. Investig. Med. 2021, 70, 61–67. [Google Scholar] [CrossRef] [PubMed]
- Theoharides, T.C.; Kempuraj, D. Role of SARS-CoV-2 Spike-Protein-Induced Activation of Microglia and Mast Cells in the Pathogenesis of Neuro-COVID. Cells 2023, 12, 688. [Google Scholar] [CrossRef]
- Mehboob, R.; Oehme, P.; Pfaff, G. The role of Substance P in the defense line of the respiratory tract and neurological manifestations post COVID-19 infection. Front. Neurol. 2023, 14, 1052811. [Google Scholar] [CrossRef]
- Barde, S.; Aguila, J.; Zhong, W.; Solarz, A.; Mei, I.; Prud’Homme, J.; Palkovits, M.; Turecki, G.; Mulder, J.; Uhlén, M.; et al. Substance P, NPY, CCK and their receptors in five brain regions in major depressive disorder with transcriptomic analysis of locus coeruleus neurons. Eur. Neuropsychopharmacol. 2024, 78, 54–63. [Google Scholar] [CrossRef]
- Casello, S.M.; Flores, R.J.; Yarur, H.E.; Wang, H.; Awanyai, M.; Arenivar, M.A.; Jaime-Lara, R.B.; Bravo-Rivera, H.; Tejeda, H.A. Neuropeptide System Regulation of Prefrontal Cortex Circuitry: Implications for Neuropsychiatric Disorders. Front. Neural Circuits 2022, 16, 796443. [Google Scholar] [CrossRef] [PubMed]
- Fu, D.; Liu, H.; Zhu, J.; Xu, H.; Yao, J. [D-Ala2, D-Leu5] Enkephalin Inhibits TLR4/NF-κB Signaling Pathway and Protects Rat Brains against Focal Ischemia-Reperfusion Injury. Mediat. Inflamm. 2021, 2021, 6661620. [Google Scholar] [CrossRef] [PubMed]
- Papasidero, I.D.; Valli, G.; Marin, D.; Del Sasso, A.; De Magistris, A.; Cennamo, E.; Casalboni, S.; De Marco, F.; Rocchi, R.; Beumo, B.N.; et al. Utility of Measuring Circulating Bio-Adrenomedullin and Proenkephalin for 30-Day Mortality Risk Prediction in Patients with COVID-19 and Non-COVID-19 Interstitial Pneumonia in the Emergency Department. Medicina 2022, 58, 1852. [Google Scholar] [CrossRef]
- Podvin, S.; Jiang, Z.; Boyarko, B.; Rossitto, L.-A.; O’donoghue, A.; Rissman, R.A.; Hook, V. Dysregulation of Neuropeptide and Tau Peptide Signatures in Human Alzheimer’s Disease Brain. ACS Chem. Neurosci. 2022, 13, 1992–2005. [Google Scholar] [CrossRef]
- Yang, A.C.; Kern, F.; Losada, P.M.; Agam, M.R.; Maat, C.A.; Schmartz, G.P.; Fehlmann, T.; Stein, J.A.; Schaum, N.; Lee, D.P.; et al. Dysregulation of brain and choroid plexus cell types in severe COVID-19. Nature 2021, 595, 565–571. [Google Scholar] [CrossRef] [PubMed]
- Karson, M.A.; Tang, A.-H.; Milner, T.A.; Alger, B.E. Synaptic Cross Talk between Perisomatic-Targeting Interneuron Classes Expressing Cholecystokinin and Parvalbumin in Hippocampus. J. Neurosci. 2009, 29, 4140–4154. [Google Scholar] [CrossRef]
- Antar, A.A.R.; Yu, T.; O Demko, Z.; Hu, C.; Tornheim, J.A.; Blair, P.W.; Thomas, D.L.; Manabe, Y.C. Long COVID brain fog and muscle pain are associated with longer time to clearance of SARS-CoV-2 RNA from the upper respiratory tract during acute infection. Front. Immunol. 2023, 14, 1147549. [Google Scholar] [CrossRef]
- 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, 815–827. [Google Scholar] [CrossRef]
- DeMarino, C.; Lee, M.-H.; Cowen, M.; Steiner, J.P.; Inati, S.; Shah, A.H.; Zaghloul, K.A.; Nath, A. Detection of SARS-CoV-2 Nucleocapsid and Microvascular Disease in the Brain. Neurology 2023, 100, 624–628. [Google Scholar] [CrossRef]
- Li, C.; Song, W.; Chan, J.F.-W.; Chen, Y.; Liu, F.; Ye, Z.; Lam, A.H.-C.; Cai, J.; Lee, A.C.-Y.; Wong, B.H.-Y.; et al. Intranasal infection by SARS-CoV-2 Omicron variants can induce inflammatory brain damage in newly weaned hamsters. Emerg. Microbes Infect. 2023, 12, 2207678. [Google Scholar] [CrossRef] [PubMed]
- Mehboob, R.; Lavezzi, A.M. Neuropathological explanation of minimal COVID-19 infection rate in newborns, infants and children—A mystery so far. New insight into the role of Substance P. J. Neurol. Sci. 2020, 420, 117276. [Google Scholar] [CrossRef]
- Lichtenberger, L.M.; Szabo, S. A closer look at endothelial injury-induced platelet hyperactivity and the use of aspirin in the treatment of COVID infection. Inflammopharmacology 2022, 30, 1475–1476. [Google Scholar] [CrossRef] [PubMed]
- Mikuteit, M.; Baskal, S.; Klawitter, S.; Dopfer-Jablonka, A.; Behrens, G.M.N.; Müller, F.; Schröder, D.; Klawonn, F.; Steffens, S.; Tsikas, D. Amino acids, post-translational modifications, nitric oxide, and oxidative stress in serum and urine of long COVID and ex COVID human subjects. Amino Acids 2023, 55, 1173–1188. [Google Scholar] [CrossRef] [PubMed]
- Henrich, T.J.; Deeks, S.G.; Peluso, M.J.; Meyer, N.J.; Wherry, E.J.; Abramoff, B.A.; Cherry, S.; Thaiss, C.A.; Levy, M.; Wong, A.C.; et al. Serotonin reduction in post-acute sequelae of viral infection. Cell 2023, 186, 4851–4867.e20. [Google Scholar] [CrossRef]
- Spudich, S.; Nath, A. Nervous system consequences of COVID-19. Science 2022, 375, 267–269. [Google Scholar] [CrossRef]
- Ogata, A.F.; Maley, A.M.; Wu, C.; Gilboa, T.; Norman, M.; Lazarovits, R.; Mao, C.-P.; Newton, G.; Chang, M.; Nguyen, K.; et al. Ultra-Sensitive Serial Profiling of SARS-CoV-2 Antigens and Antibodies in Plasma to Understand Disease Progression in COVID-19 Patients with Severe Disease. Clin. Chem. 2020, 66, 1562–1572. [Google Scholar] [CrossRef] [PubMed]
- Chen, K.; Xiao, F.; Hu, D.; Ge, W.; Tian, M.; Wang, W.; Pan, P.; Wu, K.; Wu, J. SARS-CoV-2 Nucleocapsid Protein Interacts with RIG-I and Represses RIG-Mediated IFN-β Production. Viruses 2021, 13, 47. [Google Scholar] [CrossRef]
- Mu, J.; Xu, J.; Zhang, L.; Shu, T.; Wu, D.; Huang, M.; Ren, Y.; Li, X.; Geng, Q.; Xu, Y.; et al. SARS-CoV-2-encoded nucleocapsid protein acts as a viral suppressor of RNA interference in cells. Sci. China Life Sci. 2020, 63, 1413–1416. [Google Scholar] [CrossRef]
- Oh, S.J.; Shin, O.S. SARS-CoV-2 Nucleocapsid Protein Targets RIG-I-Like Receptor Pathways to Inhibit the Induction of Interferon Response. Cells 2021, 10, 530. [Google Scholar] [CrossRef]
- Xia, J.; Tang, W.; Wang, J.; Lai, D.; Xu, Q.; Huang, R.; Hu, Y.; Gong, X.; Fan, J.; Shu, Q.; et al. SARS-CoV-2 N Protein Induces Acute Lung Injury in Mice via NF-ĸB Activation. Front. Immunol. 2021, 12, 791753. [Google Scholar] [CrossRef] [PubMed]
- Yang, R.-C.; Huang, K.; Zhang, H.-P.; Li, L.; Zhang, Y.-F.; Tan, C.; Chen, H.-C.; Jin, M.-L.; Wang, X.-R. SARS-CoV-2 productively infects human brain microvascular endothelial cells. J. Neuroinflamm. 2022, 19, 149. [Google Scholar] [CrossRef] [PubMed]
- Park, M.-K.; Han, Y.; Kim, M.S.; Seo, E.; Kang, S.; Park, S.-Y.; Koh, H.; Kim, D.K.; Lee, H.-J. Reduction of Food Intake by Fenofibrate is Associated with Cholecystokinin Release in Long-Evans Tokushima Rats. Korean J. Physiol. Pharmacol. 2012, 16, 181–186. [Google Scholar] [CrossRef]
- Mancini, M.; Natoli, S.; Gardoni, F.; Di Luca, M.; Pisani, A. Dopamine Transmission Imbalance in Neuroinflammation: Perspectives on Long-Term COVID-19. Int. J. Mol. Sci. 2023, 24, 5618. [Google Scholar] [CrossRef] [PubMed]
- Sotoyama, H.; Namba, H.; Tohmi, M.; Nawa, H. Schizophrenia Animal Modeling with Epidermal Growth Factor and Its Homologs: Their Connections to the Inflammatory Pathway and the Dopamine System. Biomolecules 2023, 13, 372. [Google Scholar] [CrossRef]
- Schirinzi, T.; Lattanzi, R.; Maftei, D.; Grillo, P.; Zenuni, H.; Boffa, L.; Albanese, M.; Simonetta, C.; Bovenzi, R.; Maurizi, R.; et al. Substance P and Prokineticin-2 are overexpressed in olfactory neurons and play differential roles in persons with persistent post-COVID-19 olfactory dysfunction. Brain Behav. Immun. 2022, 108, 302–308. [Google Scholar] [CrossRef]
- O’Kelly, B.; Vidal, L.; McHugh, T.; Woo, J.; Avramovic, G.; Lambert, J.S. Safety and efficacy of low dose naltrexone in a long covid cohort; an interventional pre-post study. Brain Behav. Immun. Health 2022, 24, 100485. [Google Scholar] [CrossRef]
- Gall, C.; Lauterborn, J.; Burks, D.; Seroogy, K. Co-localization of enkephalin and cholecystokinin in discrete areas of rat brain. Brain Res. 1987, 403, 403–408. [Google Scholar] [CrossRef]
- Loonam, T.M.; Noailles, P.A.; Yu, J.; Zhu, J.P.; A Angulo, J. Substance P and cholecystokinin regulate neurochemical responses to cocaine and methamphetamine in the striatum. Life Sci. 2003, 73, 727–739. [Google Scholar] [CrossRef]
- Jalodia, R.; Antoine, D.; Braniff, R.G.; Dutta, R.K.; Ramakrishnan, S.; Roy, S. Opioid-Use, COVID-19 Infection, and Their Neurological Implications. Front. Neurol. 2022, 13, 884216. [Google Scholar] [CrossRef]
- Corder, G.; Castro, D.C.; Bruchas, M.R.; Scherrer, G. Endogenous and Exogenous Opioids in Pain. Annu. Rev. Neurosci. 2018, 41, 453–473. [Google Scholar] [CrossRef] [PubMed]
- Deng, Z.; Chen, X.; Zhang, R.; Kong, L.; Fang, Y.; Guo, J.; Shen, B.; Zhang, L. Delta opioid peptide [D-ala2, D-leu5]-Enkephalin’s ability to enhance mitophagy via TRPV4 to relieve ischemia/reperfusion injury in brain microvascular endothelial cells. Stroke Vasc. Neurol. 2024, svn-2023. [Google Scholar] [CrossRef]
- Heles, M.; Mrozkova, P.; Sulcova, D.; Adamek, P.; Spicarova, D.; Palecek, J. Chemokine CCL2 prevents opioid-induced inhibition of nociceptive synaptic transmission in spinal cord dorsal horn. J. Neuroinflamm. 2021, 18, 279. [Google Scholar] [CrossRef] [PubMed]
- Niemela, V.; Landtblom, A.; Nyholm, D.; Kneider, M.; Constantinescu, R.; Paucar, M.; Svenningsson, P.; Abujrais, S.; Burman, J.; Shevchenko, G.; et al. Proenkephalin Decreases in Cerebrospinal Fluid with Symptom Progression of Huntington’s Disease. Mov. Disord. 2020, 36, 481–491. [Google Scholar] [CrossRef]
- Reinoso-Arija, R.; López-Ramírez, C.; Jimenez-Ruiz, J.A.; López-Campos, J.L. Effectiveness of aprepitant in post-acute COVID19 syndrome. Clin. Case Rep. 2021, 9, e04646. [Google Scholar] [CrossRef]
- Di Stadio, A.; Brenner, M.J.; De Luca, P.; Albanese, M.; D’ascanio, L.; Ralli, M.; Roccamatisi, D.; Cingolani, C.; Vitelli, F.; Camaioni, A.; et al. Olfactory Dysfunction, Headache, and Mental Clouding in Adults with Long-COVID-19: What Is the Link between Cognition and Olfaction? A Cross-Sectional Study. Brain Sci. 2022, 12, 154. [Google Scholar] [CrossRef]
- Zheng, Y.; Cai, Z.; Wang, S.; Zhang, X.; Qian, J.; Hong, S.; Li, H.; Wang, M.; Yang, J.; Yi, Q. Macrophages are an abundant component of myeloma microenvironment and protect myeloma cells from chemotherapy drug–induced apoptosis. Blood 2009, 114, 3625–3628. [Google Scholar] [CrossRef]
- Fontes-Dantas, F.L.; Fernandes, G.G.; Gutman, E.G.; De Lima, E.V.; Antonio, L.S.; Hammerle, M.B.; Mota-Araujo, H.P.; Colodeti, L.C.; Araújo, S.M.; Froz, G.M.; et al. SARS-CoV-2 Spike protein induces TLR4-mediated long-term cognitive dysfunction recapitulating post-COVID-19 syndrome in mice. Cell Rep. 2023, 42, 112189. [Google Scholar] [CrossRef] [PubMed]
- Proal, A.D.; VanElzakker, M.B.; Aleman, S.; Bach, K.; Boribong, B.P.; Buggert, M.; Cherry, S.; Chertow, D.S.; Davies, H.E.; Dupont, C.L.; et al. SARS-CoV-2 reservoir in post-acute sequelae of COVID-19 (PASC). Nat. Immunol. 2023, 24, 1616–1627. [Google Scholar] [CrossRef]
- Herskovitz, J.; Gendelman, H.E. HIV and the Macrophage: From Cell Reservoirs to Drug Delivery to Viral Eradication. J. Neuroimmune Pharmacol. 2018, 14, 52–67. [Google Scholar] [CrossRef]
- Barbosa-Silva, M.C.; Lima, M.N.; Battaglini, D.; Robba, C.; Pelosi, P.; Rocco, P.R.M.; Maron-Gutierrez, T. Infectious disease-associated encephalopathies. Crit. Care 2021, 25, 236. [Google Scholar] [CrossRef] [PubMed]
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Slama Schwok, A.; Henri, J. Long Neuro-COVID-19: Current Mechanistic Views and Therapeutic Perspectives. Biomolecules 2024, 14, 1081. https://doi.org/10.3390/biom14091081
Slama Schwok A, Henri J. Long Neuro-COVID-19: Current Mechanistic Views and Therapeutic Perspectives. Biomolecules. 2024; 14(9):1081. https://doi.org/10.3390/biom14091081
Chicago/Turabian StyleSlama Schwok, Anny, and Julien Henri. 2024. "Long Neuro-COVID-19: Current Mechanistic Views and Therapeutic Perspectives" Biomolecules 14, no. 9: 1081. https://doi.org/10.3390/biom14091081