Cholinergic dysfunction in COVID-19: frantic search and hoping for the best

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.

SIRT1 pathway in Parkinson’s disease: a faraway snapshot but so close

“…Mutations in the expression of lamin A protein induce a series of disorders called laminopathies including premature aging syndrome, cardiomyopathy, muscular dystrophy, and neuropathy. Evidence from in vitro and in vivo findings illustrated that lamin A protein is necessary for SIRT1 expression and activation (Nadwa et al 2022 ). Lamin A protein is regarded as a potent SIRT1 agonist that mediates resveratrol-induced SIRT1 expression.…”

“…Lamin A protein is regarded as a potent SIRT1 agonist that mediates resveratrol-induced SIRT1 expression. It was (Nadwa et al 2022 ) demonstrated that SIRT1 activation by resveratrol was mediated and dependent on the activity of lamin A protein. Dysregulation of lamin A protein attenuates PGC1-α/NAD with subsequent reduction of SIRT1 activity and development of mitochondrial dysfunction (Alomair et al 2022 ).…”

Mixed storm in SARS‐CoV‐2 infection: A narrative review and new term in the Covid‐19 era

“…This normal immune response is developing in patients with asymptomatic or mild Covid‐19. 19 , 20 , 21 If there is a defect in the lymphocyte functions, the CD8 and NK cells are unable to destroy virally infected cells with subsequent prolonged immune activation and higher interaction between adaptive and innate immune responses. 22 In this state, exaggerated immune response and release of proinflammatory cytokines like tumor necrosis factor‐alpha (TNF‐α), IL‐1β and IL‐6 are developed causing CS leading to severe and critical Covid‐19.…”

“…Besides, to avoid unnecessary immune activation, the antigen‐presenting cells and cytotoxic T cells (CD8+) undergo apoptosis. This normal immune response is developing in patients with asymptomatic or mild Covid‐19 19–21 . If there is a defect in the lymphocyte functions, the CD8 and NK cells are unable to destroy virally infected cells with subsequent prolonged immune activation and higher interaction between adaptive and innate immune responses 22 .…”

Receptor-dependent effects of sphingosine-1-phosphate (S1P) in COVID-19: the black side of the moon

“…Different studies revealed that the SphK-S1P-S1PR axis plays a role in accelerating inflammation and growth of endometriotic cells by increasing the expression of IL-6 and other pro-inflammatory cytokines [ 40 ]. As well, 1P has been shown to regulate cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) expression and IL-6 secretion in various respiratory diseases [ 41 ]. However, the mechanisms underlying S1P-induced COX-2 expression and PGE2 production in human tracheal smooth muscle cells (HTSMCs) remain unclear [ 42 ].…”