Impairment of the cholinergic anti-inflammatory pathway in older subjects with severe COVID-19

Pomara, Nunzio; Imbimbo, Bruno P.

doi:10.1016/j.mehy.2020.110274

Cited by 7 publications

(7 citation statements)

References 9 publications

(10 reference statements)

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“…As discussed by Osman (2020), CAP constitutes a neural mechanism that modulates inflammation through the release of acetylcholine (ACh), that have led to increased AChE synthesis to decompose higher levels of this neurotransmitter [see details in Tracey (2007)]. This mechanism has been reported in different studies involving patients infected with the new coronavirus (Bonaz et al, 2020; Mazloom et al, 2020; Pomara et al, 2020), strengthening the presumption that this mechanism may constitute another similar physiological response between SARS-CoV-2 non-host and host organisms. Besides, it is plausible to assume not only that the peptide composition of the SARS-CoV-2 Spike protein participates in the CAP activation (both in humans and in the evaluated tadpoles) but also that the neuroimmune system of the tadpoles has an essential role in responding to exposure of peptides PSPD2001, PSPD2002 and PSPD2003.…”

Section: Resultsmentioning

confidence: 99%

An insight into neurotoxic and toxicity of spike fragments SARS-CoV-2 by exposure environment: A threat to aquatic health?

Charlie-Silva

Araújo

Guimarães

et al. 2021

Preprint

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The Spike protein (S protein) is a critical component in the infection of the new coronavirus (SARS-CoV-2). The objective of this work was to evaluate whether peptides from S protein could cause negative impact in the aquatic animals. The aquatic toxicity of SARS-CoV-2 spike protein peptides derivatives has been evaluated in tadpoles (n = 50 tadpoles / 5 replicates of 10 animals) from species Physalaemus cuvieri (Leptodactylidae). After synthesis, purification, and characterization of peptides (PSDP2001, PSDP2002, PSDP2003) an aquatic contamination has been simulatedwith these peptides during 24 hours of exposure in two concentrations (100 and 500 ng/mL). The control group (“C”) was composed of tadpoles kept in polyethylene containers containing de-chlorinated water. Oxidative stress, antioxidant biomarkers and neurotoxicity activity were assessed. In both concentrations, PSPD2002 and PSPD2003 increased catalase and superoxide dismutase antioxidants enzymes activities, as well as oxidative stress (nitrite levels, hydrogen peroxide and reactive oxygen species). All three peptides also increased acetylcholinesterase activity in the highest concentration. These peptides showed molecular interactions in silico with acetylcholinesterase and antioxidant enzymes. Aquatic particle contamination of SARS-CoV-2 has neurotoxics effects in P. cuvieri tadpoles. These findings indicate that the COVID-19 can constitute environmental impact or biological damage potential.HIGHLIGHTSSARS-CoV-2 spike protein peptides (PSDP) were synthesized, purified, and characterized by solid phase peptide synthesis.PSDP peptides promoted REDOX imbalance and acute neurotoxicity in tadpoles (Physalaemus cuvieri)In silico studies have shown interactionsbetween peptides and acetylcholinesterase and antioxidant enzymesAquatic particle contamination of SARS-CoV-2 can constitute additional environmental damageGRAPHICAL ABSTRACT

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Section: Resultsmentioning

confidence: 99%

An insight into neurotoxic and toxicity of spike fragments SARS-CoV-2 by exposure environment: A threat to aquatic health?

Charlie-Silva

Araújo

Guimarães

et al. 2021

Preprint

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“…The heavy viral infection within the brain stem of deceased patients suggests that the neuroinvasive potential of SARS-CoV2 is likely to be partially responsible for COVID-19 acute respiratory failure. This finding favors treatment modalities involving the vagus nerve and the cholinergic anti-inflammatory pathway (CAP), which was supported by several research teams (Bara et al, 2020;Bonaz et al, 2020;De Virgiliis and Di Giovanni, 2020;Leitzke et al, 2020;Mazloom, 2020;Pomara and Imbimbo, 2020;Rangon et al, 2020;Staats et al, 2020;Tornero et al, 2020;Azabou et al, 2021;Mastitskaya et al, 2021).…”

Section: Introductionmentioning

confidence: 70%

Auricular Neuromodulation for Mass Vagus Nerve Stimulation: Insights From SOS COVID-19 a Multicentric, Randomized, Controlled, Double-Blind French Pilot Study

Rangon

Barruet²,

Mazouni³

et al. 2021

Front. Physiol.

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Importance: An exacerbated inflammatory response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is believed to be one of the major causes of the morbidity and mortality of the coronavirus disease 2019 (COVID-19). Neuromodulation therapy, based on vagus nerve stimulation, was recently hypothesized to control both the SARS-CoV-2 replication and the ensuing inflammation likely through the inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells pathway and could improve the clinical outcomes as an adjunct treatment. We proposed to test it by the stimulation of the auricular branch of the vagus nerve, i.e., auricular neuromodulation (AN), a non-invasive procedure through the insertion of semipermanent needles on the ears.Objective: The aim of this study was to assess the effect of AN on the clinical outcomes in patients affected by COVID-19.Design, Setting, and Participants: A multicenter, randomized, placebo-controlled, double-blind clinical trial included 31 patients with respiratory failure due to COVID-19 requiring hospitalization. Within 72 h after admission, patients received either AN (n = 14) or sham neuromodulation (SN, n = 15) in addition to the conventional treatments.Main Outcome and Measures: The primary endpoint of the study was the rate of a clinical benefit conferred by AN at Day 14 (D14) as assessed by a 7-point Clinical Progression Scale. The secondary endpoint of the study was the impact of AN on the rate of transfer to the intensive care unit (ICU) and on the survival rate at D14.Results: The AN procedure was well-tolerated without any reported side effects but with no significant improvement for the measures of both primary (p > 0.3) and secondary (p > 0.05) endpoints at the interim analysis. None of the AN-treated patients died but one in the SN group did (81 years). Two AN-treated patients (73 and 79 years, respectively) and one SN-treated patient (59 years) were transferred to ICU. Remarkably, AN-treated patients were older with more representation by males than in the SN arm (i.e., the median age of 75 vs. 65 years, 79% male vs. 47%).Conclusion: The AN procedure, which was used within 72 h after the admission of patients with COVID-19, was safe and could be successfully implemented during the first two waves of COVID-19 in France. Nevertheless, AN did not significantly improve the outcome of the patients in our small preliminary study. It is pertinent to explore further to validate AN as the non-invasive mass vagal stimulation solution for the forthcoming pandemics.Clinical Trial Registration: [https://clinicaltrials.gov/], identifier [NCT04341415].

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“…Associations between cholinergic neuro-immunological function and COVID-19 hyperinflammation have been discussed recently [ 26 ]. Pomara and Imbimbo describe the association between older age and Alzheimer’s disease as well as a downregulated cholinergic anti-inflammatory pathway [ 34 ]. A deficiency or loss of cholinergic reaction could explain an increase in proinflammatory cytokines and the COVID-19-associated high mortality in elderly patients [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

“…Pomara and Imbimbo describe the association between older age and Alzheimer’s disease as well as a downregulated cholinergic anti-inflammatory pathway [ 34 ]. A deficiency or loss of cholinergic reaction could explain an increase in proinflammatory cytokines and the COVID-19-associated high mortality in elderly patients [ 34 ]. The authors do not specify at which age a patient has to be considered old, and therefore at what age a downregulated cholinergic anti-inflammatory pathway is to be assumed.…”

Section: Discussionmentioning

confidence: 99%

“…Direct cholinergic stimulation with nicotine remained ruled out due to the unfavorable side effect profile [ 4 ]. Cholinergic immunomodulation with cholinesterase inhibitors such as physostigmine could potentially be used to treat severely ill COVID-19 patients [ 34 ]. An appropriate therapy response could then possibly be monitored by bedside BChE measurement.…”

Section: Discussionmentioning

confidence: 99%

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Critically Ill COVID-19 Patients Show Reduced Point of Care-Measured Butyrylcholinesterase Activity—A Prospective, Monocentric Observational Study

et al. 2022

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A biomarker for risk stratification and disease severity assessment in SARS-CoV-2 infections has not yet been established. Point of care testing (POCT) of butyrylcholinesterase (BChE) enables early detection of systemic inflammatory responses and correlates with disease severity in sepsis and burns. In acute care or resource-limited settings, POCT facilitates rapid clinical decision making, a particularly beneficial aspect in the management of pandemic situations. In this prospective observational study, POCT-measured BChE activity was assessed in 52 critically ill COVID-19 patients within 24 h of ICU admission and on the third and seventh day after ICU admission. Forty (77%) of these patients required venovenous extracorporeal membrane oxygenation (vvECMO). In critically ill COVID-19 patients, BChE activity is significantly decreased compared with healthy subjects, but also compared with other inflammatory conditions such as sepsis, burns, or trauma. POCT BChE activity reflects the severity of organ dysfunction and allows prediction of 28-day mortality in critically ill COVID-19 patients. Implementing early POCT BChE measurement could facilitate risk stratification and support admission and transfer decisions in resource-limited settings.

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Impairment of the cholinergic anti-inflammatory pathway in older subjects with severe COVID-19

Cited by 7 publications

References 9 publications

An insight into neurotoxic and toxicity of spike fragments SARS-CoV-2 by exposure environment: A threat to aquatic health?

An insight into neurotoxic and toxicity of spike fragments SARS-CoV-2 by exposure environment: A threat to aquatic health?

Auricular Neuromodulation for Mass Vagus Nerve Stimulation: Insights From SOS COVID-19 a Multicentric, Randomized, Controlled, Double-Blind French Pilot Study

Critically Ill COVID-19 Patients Show Reduced Point of Care-Measured Butyrylcholinesterase Activity—A Prospective, Monocentric Observational Study

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