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Cholinergic dysfunction in COVID-19: frantic search and hoping for the best
Eman Hassan Nadwa1,2, Hayder M Al-Kuraishy3, Ali I Al-Gareeb3
1Department of Pharmacology and Therapeutics, College of Medicine, Jouf University, Sakakah, 72345, Saudi Arabia.
Abstract:
A novel coronavirus known as severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is a potential cause of acute respiratory infection called coronavirus disease 2019 (COVID-19). The binding of SARS-CoV-2 with angiotensin-converting enzyme 2 (ACE2) induces a series of inflammatory cellular events with cytopathic effects leading to cell injury and hyperinflammation. Severe SARS-CoV-2 infection may lead to dysautonomia and sympathetic storm due to dysfunction of the autonomic nervous system (ANS). Therefore, this review aimed to elucidate the critical role of the cholinergic system (CS) in SARS-CoV-2 infection. The CS forms a multi-faceted network performing diverse functions in the body due to its distribution in the neuronal and non-neuronal cells. Acetylcholine (ACh) acts on two main types of receptors which are nicotinic receptors (NRs) and muscarinic receptors (MRs). NRs induce T cell anergy with impairment of antigen-mediated signal transduction. Nicotine through activation of T cell NRs inhibits the expression and release of the pro-inflammatory cytokines. NRs play important anti-inflammatory effects while MRs promote inflammation by inducing the release of pro-inflammatory cytokines. SARS-CoV-2 infection can affect the morphological and functional stability of CS through the disruption of cholinergic receptors. SARS-CoV-2 spike protein is similar to neurotoxins, which can bind to nicotinic acetylcholine receptors (nAChR) in the ANS and brain. Therefore, cholinergic receptors mainly nAChR and related cholinergic agonists may affect the pathogenesis of SARS-CoV-2 infection. Cholinergic dysfunction in COVID-19 is due to dysregulation of nAChR by SARS-CoV-2 promoting the central sympathetic drive with the development of the sympathetic storm. As well, nAChR activators through interaction with diverse signaling pathways can reduce the risk of inflammatory disorders in COVID-19. In addition, nAChR activators may mitigate endothelial dysfunction (ED), oxidative stress (OS), and associated coagulopathy in COVID-19. Similarly, nAChR activators may improve OS, inflammatory changes, and cytokine storm in COVID-19. Therefore, nAChR activators like varenicline in virtue of its anti-inflammatory and anti-oxidant effects with direct anti-SARS-CoV-2 effect could be effective in the management of COVID-19.
Insights
The cholinergic system, particularly nicotinic acetylcholine receptors (nAChR), plays a key role in COVID-19 pathogenesis. nAChR activators show potential in managing SARS-CoV-2 by reducing inflammation and oxidative stress.
Area of Science:
- Neuroscience
- Immunology
- Virology
Background:
- SARS-CoV-2 infection can cause severe respiratory illness (COVID-19) and lead to autonomic nervous system dysfunction.
- The cholinergic system (CS), involving acetylcholine (ACh), plays a crucial role in regulating inflammatory and physiological responses.
- Dysfunction of the CS, particularly nicotinic acetylcholine receptors (nAChR), is implicated in severe COVID-19.
Purpose of the Study:
- To elucidate the critical role of the cholinergic system in SARS-CoV-2 infection.
- To explore the impact of cholinergic receptor disruption on COVID-19 pathogenesis.
- To evaluate the therapeutic potential of cholinergic agonists in managing COVID-19.
Main Methods:
- Review of existing literature on the cholinergic system, SARS-CoV-2, and COVID-19.
- Analysis of the interaction between SARS-CoV-2 spike protein and nicotinic acetylcholine receptors.
- Examination of the anti-inflammatory and anti-oxidant effects of nAChR activators.
Main Results:
- SARS-CoV-2 infection disrupts the cholinergic system, particularly nAChRs, leading to sympathetic storm.
- nAChR activation demonstrates anti-inflammatory effects, inhibiting pro-inflammatory cytokine release.
- nAChR activators may mitigate endothelial dysfunction, oxidative stress, and coagulopathy associated with COVID-19.
Conclusions:
- Cholinergic dysfunction is a significant factor in severe COVID-19.
- nAChR activators exhibit potential therapeutic benefits for COVID-19 management.
- Agents like varenicline, with anti-inflammatory and anti-oxidant properties, warrant further investigation for treating COVID-19.
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