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Cofilin as the master regulator of the key covid inflammatory trigger NLRP3 and microglia activity as well as of the Shank3 protein effects: possible therapeutic implications for the brain and the body affected by Covid-19 infection

The NLRP3 inflammasome was identified as one of the most important inflammatory and apoptosis triggers in covid patients. i Its role in the inflammatory brain pathology caused by covid19 is also established. For example, the spike protein can increase the production of NRLP3 protein in microglia. ii The importance of this fact is highlighted by the Oxford study showing the loss of gray matter in the brain of covid patients even without a severe covid disease course. iii

Given the significant NRLP3 involvement of Covid-19- and spike protein pathology, we may shed light on the possible long-term consequences of Covid-19 infection or spike protein toxicity in the future.

NRLP3 activation is associated with certain types of cancers, cardiovascular disease, obesity-induced insulin resistance, several autoimmune diseases. iv v vi It is made responsible for the increased covid related mortality of obese people. vii The spike protein primes NRLP3 to increased activation in macrophages. viii

NRLP3 activation is also associated with several diseases of the Central Nervous System (CNS), such as autism, schizophrenia, Alzheimer’s, a broad spectrum of psychiatric diseases, brain injury caused by cardiac arrest. ix x xi xii xiii

One of the central mechanisms of NLRP3 activation in brain cells may be the NLRP3 dependent downregulation of the Shank family proteins. xiv Deficits in the Shank3 protein are associated and causally related to multiple neuropsychiatric diseases, such as autism, schizophrenia, bipolar disorder, Alzheimer’s. xv Patients born with Shank3 deficits are characterized by regressions, loss of skills, disturbances of mood, early dementia, and a broad spectrum of psychiatric symptoms. xvi xvii

One of the most promising therapeutic targets of rescuing Shank3 deficiency-related neuropsychiatric problems is the inhibition of overactivated cofilin. xviii xix

A natural method of inhibiting overactivated cofilin may be the intranasal administration of proinsulin c peptide. According to a study, in lymphocytes c peptide inactivates cofilin.xx

The cofilin inactivation may be a general solution of inhibiting also the overactivated NLRP3 inflammasome because the knockdown of cofilin reduced NLRP3 activation. xxi

It may be also of importance that in a neural stem cell in vitro model, Shank3 deficiency increased the expression of NLRP3 and caspase 1. xxii In this way the spike protein may affect brain development also. Indeed, in an in vitro model spike protein induced defective dendritic spines and shortened dendritic length. xxiii The effect of spike protein on the development of neuronal cells is reminiscent of the neuronal defects caused by Shank3 deficiency. xxiv In the long-term brain effects of Covid-19, it cannot be excluded, that a vicious circle is building characterized by a downregulated Shank3 due to NRLP3 activation and by activated NLRP3 due to Shank3 downregulation. The potential vicious circle may be stopped by the inactivation of cofilin in the brain by intranasal proinsulin c peptide.


i Rodrigues TS, de Sá KSG, Ishimoto AY, Becerra A, Oliveira S, Almeida L, Gonçalves AV, Perucello DB, Andrade WA, Castro R, Veras FP, Toller-Kawahisa JE, Nascimento DC, de Lima MHF, Silva CMS, Caetite DB, Martins RB, Castro IA, Pontelli MC, de Barros FC, do Amaral NB, Giannini MC, Bonjorno LP, Lopes MIF, Santana RC, Vilar FC, Auxiliadora-Martins M, Luppino-Assad R, de Almeida SCL, de Oliveira FR, Batah SS, Siyuan L, Benatti MN, Cunha TM, Alves-Filho JC, Cunha FQ, Cunha LD, Frantz FG, Kohlsdorf T, Fabro AT, Arruda E, de Oliveira RDR, Louzada-Junior P, Zamboni DS. Inflammasomes are activated in response to SARS-CoV-2 infection and are associated with COVID-19 severity in patients. J Exp Med. 2021 Mar 1;218(3):e20201707. doi: 10.1084/jem.20201707. PMID: 33231615; PMCID: PMC7684031.

ii Sepehrinezhad A, Gorji A, Sahab Negah S. SARS-CoV-2 may trigger inflammasome and pyroptosis in the central nervous system: a mechanistic view of neurotropism. Inflammopharmacology. 2021;29(4):1049-1059. doi:10.1007/s10787-021-00845-4

iii Gwenaëlle Douaud, Brain imaging before and after COVID-19 in UK Biobank, https://www.medrxiv.org/content/10.1101/2021.06.11.21258690v1.full.pdf 

iv Sharma, B.R., Kanneganti, TD. NLRP3 inflammasome in cancer and metabolic diseases. Nat Immunol 22, 550–559 (2021). https://doi.org/10.1038/s41590-021-00886-5

v Rheinheimer J, de Souza BM, Cardoso NS, Bauer AC, Crispim D. Current role of the NLRP3 inflammasome on obesity and insulin resistance: A systematic review. Metabolism. 2017 Sep;74:1-9. doi: 10.1016/j.metabol.2017.06.002. Epub 2017 Jun 11. PMID: 28764843.

vi Shen HH, Yang YX, Meng X, Luo XY, Li XM, Shuai ZW, Ye DQ, Pan HF. NLRP3: A promising therapeutic target for autoimmune diseases. Autoimmun Rev. 2018 Jul;17(7):694-702. doi: 10.1016/j.autrev.2018.01.020. Epub 2018 May 3. PMID: 29729449.

vii López-Reyes A, Martinez-Armenta C, Espinosa-Velázquez R, et al. NLRP3 Inflammasome: The Stormy Link Between Obesity and COVID-19. Front Immunol. 2020;11:570251. Published 2020 Oct 30. doi:10.3389/fimmu.2020.570251

viii heobald SJ, Simonis A, Georgomanolis T, Kreer C, Zehner M, Eisfeld HS, Albert MC, Chhen J, Motameny S, Erger F, Fischer J, Malin JJ, Gräb J, Winter S, Pouikli A, David F, Böll B, Koehler P, Vanshylla K, Gruell H, Suárez I, Hallek M, Fätkenheuer G, Jung N, Cornely OA, Lehmann C, Tessarz P, Altmüller J, Nürnberg P, Kashkar H, Klein F, Koch M, Rybniker J. Long-lived macrophage reprogramming drives spike protein-mediated inflammasome activation in COVID-19. EMBO Mol Med. 2021 Jun 16:e14150. doi: 10.15252/emmm.202114150. Epub ahead of print. PMID: 34133077.

ix Ventura L, Freiberger V, Thiesen VB, Dias P, Dutra ML, Silva BB, Schlindwein AD, Comim CM. Involvement of NLRP3 inflammasome in schizophrenia-like behaviour in young animals after maternal immune activation. Acta Neuropsychiatr. 2020 Dec;32(6):321-327. doi: 10.1017/neu.2020.27. Epub 2020 Jul 14. PMID: 32660670.

x Saresella M, Piancone F, Marventano I, Zoppis M, Hernis A, Zanette M, Trabattoni D, Chiappedi M, Ghezzo A, Canevini MP, la Rosa F, Esposito S, Clerici M. Multiple inflammasome complexes are activated in autistic spectrum disorders. Brain Behav Immun. 2016 Oct;57:125-133. doi: 10.1016/j.bbi.2016.03.009. Epub 2016 Mar 12. PMID: 26979869.

xi Feng YS, Tan ZX, Wu LY, Dong F, Zhang F. The involvement of NLRP3 inflammasome in the treatment of Alzheimer’s disease. Ageing Res Rev. 2020 Dec;64:101192. doi: 10.1016/j.arr.2020.101192. Epub 2020 Oct 13. PMID: 33059089.

xii Hylén U, Eklund D, Humble M, Bartoszek J, Särndahl E, Bejerot S. Increased inflammasome activity in markedly ill psychiatric patients: An explorative study. J Neuroimmunol. 2020 Feb 15;339:577119. doi: 10.1016/j.jneuroim.2019.577119. Epub 2019 Nov 26. PMID: 31786499.

xiii Chang Y, Zhu J, Wang D, Li H, He Y, Liu K, Wang X, Peng Y, Pan S, Huang K. NLRP3 inflammasome-mediated microglial pyroptosis is critically involved in the development of post-cardiac arrest brain injury. J Neuroinflammation. 2020 Jul 23;17(1):219. doi: 10.1186/s12974-020-01879-1. PMID: 32703306; PMCID: PMC7376727.

xiv Dong Y, Li S, Lu Y, Li X, Liao Y, Peng Z, Li Y, Hou L, Yuan Z, Cheng J. Stress-induced NLRP3 inflammasome activation negatively regulates fear memory in mice. J Neuroinflammation. 2020 Jul 7;17(1):205. doi: 10.1186/s12974-020-01842-0. PMID: 32635937; PMCID: PMC7341659.

xv Alexandrov PN, Zhao Y, Jaber V, Cong L, Lukiw WJ. Deficits in the Proline-Rich Synapse-Associated Shank3 Protein in Multiple Neuropsychiatric Disorders. Front Neurol. 2017;8:670. Published 2017 Dec 11. doi:10.3389/fneur.2017.00670

xvi Kohlenberg TM, Trelles MP, McLarney B, Betancur C, Thurm A, Kolevzon A. Psychiatric illness and regression in individuals with Phelan-McDermid syndrome. J Neurodev Disord. 2020 Feb 12;12(1):7. doi: 10.1186/s11689-020-9309-6. PMID: 32050889; PMCID: PMC7014655.

xvii Vucurovic K, Landais E, Delahaigue C, Eutrope J, Schneider A, Leroy C, Kabbaj H, Motte J, Gaillard D, Rolland AC, Doco-Fenzy M. Bipolar affective disorder and early dementia onset in a male patient with SHANK3 deletion. Eur J Med Genet. 2012 Nov;55(11):625-9. doi: 10.1016/j.ejmg.2012.07.009. Epub 2012 Aug 4. PMID: 22922660.

xviii Duffney LJ, Zhong P, Wei J, Matas E, Cheng J, Qin L, Ma K, Dietz DM, Kajiwara Y, Buxbaum JD, Yan Z. Autism-like Deficits in Shank3-Deficient Mice Are Rescued by Targeting Actin Regulators. Cell Rep. 2015 Jun 9;11(9):1400-1413. doi: 10.1016/j.celrep.2015.04.064. Epub 2015 May 28. PMID: 26027926; PMCID: PMC4464902.

xix Shaw AE, Bamburg JR. Peptide regulation of cofilin activity in the CNS: A novel therapeutic approach for treatment of multiple neurological disorders. Pharmacol Ther. 2017 Jul;175:17-27. doi: 10.1016/j.pharmthera.2017.02.031. Epub 2017 Feb 20. PMID: 28232023; PMCID: PMC5466456.

xx Aleksic M, Walcher D, Giehl K, Bach H, Grüb M, Durst R, Hombach V, Marx N. Signalling processes involved in C-peptide-induced chemotaxis of CD4-positive lymphocytes. Cell Mol Life Sci. 2009 Jun;66(11-12):1974-84. doi: 10.1007/s00018-009-9057-y. PMID: 19373435.

xxi Park YH, Kastner D, Chae JJ. Cofilin-1 is an essential redox sensor for NLRP3 inflammasome activation. Pediatr Rheumatol Online J. 2015;13(Suppl 1):O52. Published 2015 Sep 28. doi:10.1186/1546-0096-13-S1-O52

xxii Grasselli C, Carbone A, Panelli P, Giambra V, Bossi M, Mazzoccoli G, De Filippis L. Neural Stem Cells from Shank3-ko Mouse Model Autism Spectrum Disorders. Mol Neurobiol. 2020 Mar;57(3):1502-1515. doi: 10.1007/s12035-019-01811-6. Epub 2019 Nov 26. PMID: 31773410.

xxiii https://www.biorxiv.org/content/10.1101/2020.12.03.409763v1
Chiung-Ya Chen, Yu-Chi Chou, Yi-Ping Hsueh , SARS-CoV-2 D614 and G614 spike variants impair neuronal synapses and exhibit differential fusion ability

xxiv Huang G, Chen S, Chen X, et al. Uncovering the Functional Link Between SHANK3 Deletions and Deficiency in Neurodevelopment Using iPSC-Derived Human Neurons. Front Neuroanat. 2019;13:23. Published 2019 Mar 13. doi:10.3389/fnana.2019.00023

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