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)

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(9) Olymaikolun, A. et al.:  SARS-CoV-2 spike glycoprotein S1 induces neuroinflammation in BV-2 microglia,

(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.

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(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.

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