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Possible impact of intranasal proinsulin c-peptide on the course of COVID-19 infection: the role of the cholinergic anti-inflammatory pathway measured by Heart Rate Variability (HRV) and the importance of microglia, the resident immune cells in the brain

The increase of the inflammatory markers CRP and Il-6 predict the unfavorable course of the covid-19 infection. (1) (2) The decrease of HRV by more than 40% precedes a 50% increase in CRP during the next 72 hours according to a small study. (3) The sudden decrease of HRV may signal the weakening or collapse of the cholinergic anti-inflammatory pathway. It is supposed that by strengthening this pathway the cytokine storm could be prevented or at least mitigated. (4)(5)(6) In an animal study it was shown that increased vagus nerve activity, measured by (RMSSD), the parasympathetic part of the HRV, the brain inflammatory processes, and the resulting brain damages can be mitigated. (7) This is highly significant, because – besides the cytokines –  the spike protein of covid-19 can cross the blood-brain barrier and induce inflammatory processes in the brain leading to neuroinflammation and neurological disorders. (8) (9) (10) Elderly patients with chronic diseases have impaired vagus nerve activity that may exacerbate the covid-19 disease course. (11) For this reason, methods increasing the vagal tone may be beneficial for the treatment or prevention of the severe consequences of covid-19 infection. One of the most promising methods is the intranasal administration of proinsulin c peptide. Systemic administration of C can increase the vagus nerve activity according to clinical trials on insulin-dependent diabetes mellitus patients, that are among the most affected people regarding the mortality of covid-19 caused disease. (12) (13) Proinsulin c peptide administered directly into the brain seems to have even a more pronounced effect on the parasympathetic nervous system. (14) Intranasal application of proinsulin c peptide is effectively transferring the peptide into the brain. (15)

The resident immune cells in the CNS, the microglia, are often activated in patients severely affected by the disease according to autopsic investigations. (16) The hyperactivity of the molecular scissor, cofilin, that regulates the shape and dynamical change of the actin cytoskeleton is responsible for the overactivation of microglia. The reduction of the hyperactivity of the cofilin is leading to the cessation of the overactivity of microglia. (17)(18) Interestingly, proinsulin c peptide, besides increasing HRV, is also able to inactivate cofilin in lymphocytes that may serve as a model for microglia and neurons also. (19)


(1) Gorham J, Moreau A, Corazza F, Peluso L, Ponthieux F, Talamonti M, Izzi A, Nagant C, Ndieugnou Djangang N, Garufi A, Creteur J, Taccone FS. Interleukine-6 in critically ill COVID-19 patients: A retrospective analysis. PLoS One. 2020 Dec 31;15(12):e0244628. doi: 10.1371/journal.pone.0244628. PMID: 33382773; PMCID: PMC7774924.

(2) Ahnach M, Zbiri S, Nejjari S, Ousti F, Elkettani C. C-reactive protein as an early predictor of COVID-19 severity. J Med Biochem. 2020 Oct 2;39(4):500-507. doi: 10.5937/jomb0-27554. PMID: 33312067; PMCID: PMC7710381.

(3) Frederick Hasty, MD, Guillermo García, MD, Col Héctor Dávila, MD, MSS, MC, USAR (Ret.), S Howard Wittels, MD, Stephanie Hendricks, BA, Stephanie Chong, DNP, CRNA, ARNP, Heart Rate Variability as a Possible Predictive Marker for Acute Inflammatory Response in COVID-19 Patients, Military Medicine, , usaa405, https://doi.org/10.1093/milmed/usaa405

(4) Huston JM, Tracey KJ. The pulse of inflammation: heart rate variability, the cholinergic anti-inflammatory pathway and implications for therapy. J Intern Med. 2011 Jan;269(1):45-53. doi: 10.1111/j.1365-2796.2010.02321.x. PMID: 21158977; PMCID: PMC4527046.

(5) Haarala A, Kähönen M, Eklund C, Jylhävä J, Koskinen T, Taittonen L, Huupponen R, Lehtimäki T, Viikari J, Raitakari OT, Hurme M. Heart rate variability is independently associated with C-reactive protein but not with Serum amyloid A. The Cardiovascular Risk in Young Finns Study. Eur J Clin Invest. 2011 Sep;41(9):951-7. doi: 10.1111/j.1365-2362.2011.02485.x. Epub 2011 Feb 17. PMID: 21323913.

(6) Sajadieh A, Nielsen OW, Rasmussen V, Hein HO, Hansen JF. C-reactive protein, heart rate variability and prognosis in community subjects with no apparent heart disease. J Intern Med. 2006 Oct;260(4):377-87. doi: 10.1111/j.1365-2796.2006.01701.x. PMID: 16961675.

(7) Frasch MG, Szynkaruk M, Prout AP, Nygard K, Cao M, Veldhuizen R, Hammond R, Richardson BS. Decreased neuroinflammation correlates to higher vagus nerve activity fluctuations in near-term ovine fetuses: a case for the afferent cholinergic anti-inflammatory pathway? J Neuroinflammation. 2016 May 10;13(1):103. doi: 10.1186/s12974-016-0567-x. PMID: 27165310; PMCID: PMC4894374.

(8) Rhea, E.M., Logsdon, A.F., Hansen, K.M. et al. The S1 protein of SARS-CoV-2 crosses the blood–brain barrier in mice. Nat Neurosci (2020). https://doi.org/10.1038/s41593-020-00771-8

(9) Olymaikolun, A. et al.:  SARS-CoV-2 spike glycoprotein S1 induces neuroinflammation in BV-2 microglia, https://doi.org/10.1101/2020.12.29.424619

(10) Achar, A.; Ghosh, C. COVID-19-Associated Neurological Disorders: The Potential Route of CNS Invasion and Blood-Brain Barrier Relevance. Cells 2020, 9, 2360.

(11) Prinsloo GE, Rauch HG, Derman WE. A brief review and clinical application of heart rate variability biofeedback in sports, exercise, and rehabilitation medicine. Phys Sportsmed. 2014 May;42(2):88-99. doi: 10.3810/psm.2014.05.2061. PMID: 24875976.

(12) Johansson BL, Borg K, Fernqvist-Forbes E, Odergren T, Remahl S, Wahren J. C-peptide improves autonomic nerve function in IDDM patients. Diabetologia. 1996 Jun;39(6):687-95. doi: 10.1007/BF00418540. PMID: 8781764.

(13) Barron E, Bakhai C, Kar P, Weaver A, Bradley D, Ismail H, Knighton P, Holman N, Khunti K, Sattar N, Wareham NJ, Young B, Valabhji J. Associations of type 1 and type 2 diabetes with COVID-19-related mortality in England: a whole-population study. Lancet Diabetes Endocrinol. 2020 Oct;8(10):813-822. doi: 10.1016/S2213-8587(20)30272-2. Epub 2020 Aug 13. PMID: 32798472; PMCID: PMC7426088.

(14) Okamoto S, Kimura K, Kitamura T, Cañas X, Yoshida T, Saito M. Proinsulin C peptide obviates sympathetically mediated suppression of splenic lymphocyte activity in rats. Diabetologia. 2000 Dec;43(12):1512-7. doi: 10.1007/s001250051562. PMID: 11151760.

(15) Derkach KV, Perminova AA, Buzanakov DM, Shpakov AO. Intranasal Administration of Proinsulin C-Peptide Enhances the Stimulating Effect of Insulin on Insulin System Activity in the Hypothalamus of Diabetic Rats. Bull Exp Biol Med. 2019 Jul;167(3):351-355. doi: 10.1007/s10517-019-04525-w. Epub 2019 Jul 26. PMID: 31346872.

(16) Matschke J, Lütgehetmann M, Hagel C, Sperhake JP, Schröder AS, 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 Nov;19(11):919-929. doi: 10.1016/S1474-4422(20)30308-2. Epub 2020 Oct 5. PMID: 33031735; PMCID: PMC7535629.

(17) Alhadidi Q, Shah ZA. Cofilin Mediates LPS-Induced Microglial Cell Activation and Associated Neurotoxicity Through Activation of NF-κB and JAK-STAT Pathway. Mol Neurobiol. 2018 Feb;55(2):1676-1691. doi: 10.1007/s12035-017-0432-7. Epub 2017 Feb 13. PMID: 28194647; PMCID: PMC5554748.

(18) 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.

(19) 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

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