Activation of the Cholinergic Anti-Inflammatory Pathway as a Novel Therapeutic Strategy for COVID-19

Abstract

The outbreak of coronavirus disease 2019 (COVID-19) underlined the urgent need for alleviating cytokine storm. We propose here that activating the cholinergic anti-inflammatory pathway (CAP) is a potential therapeutic strategy. However, there is currently no approved drugs targeting the regulatory pathway. It is evident that nicotine, anisodamine and some herb medicine, activate the CAP and exert anti-inflammation action in vitro and in vivo. As the vagus nerve affects both inflammation and specific immune response, we propose that vagus nerve stimulation by invasive or non-invasive devices and acupuncture at ST36, PC6, or GV20, are also feasible approaches to activate the CAP and control COVID-19. It is worth to investigate the efficacy and safety of the strategy in patients with COVID-19.

Effectiveness of anisodamine for the treatment of critically ill patients with septic shock: a multicentre randomized controlled trial

“…The anti-shock effects of anisodamine are proposed to be mediated by activating the cholinergic anti-inflammatory pathway [ 14 ]. Anisodamine blocks muscarinic receptors, which results in rerouting of acetylcholine to the α7 nicotinic acetylcholine receptor (α7nAChR) bringing about increased acetylcholine-mediated activation of α7nAChR and the cholinergic anti-inflammatory pathway [ 33 ].…”

“…Therefore, one of the most important approaches for the successful treatment of septic shock is to ameliorate the uncontrolled inflammatory response and endothelial injury. Anisodamine has been shown to be effective in improving microcirculation and reperfusion injuries by reducing oxidative stress, apoptosis and inflammatory responses [ 12 , 13 ], as well as by the activation of the cholinergic anti-inflammatory pathway [ 14 ]. Anisodamine has been widely used in China since 1965 for the treatment of circulatory disorders such as septic shock and disseminated intravascular coagulation (DIC).…”

Repurposing Donepezil to Treat COVID-19: A Call for Retrospective Analysis of Existing Patient Datasets

“…The preceding section outlined our reasoning supporting donepezil as a potential therapy for those in high-risk groups associated with increased inflammation. Previous reports have also discussed manipulating cholinergic signal transmission as a COVID-19 therapeutic strategy [73,[101][102][103][104][105]. There are four clinical trials currently underway examining manipulation of the CAP to treat COVID-19.…”

The Cholinergic and ACE-2-Dependent Anti-Inflammatory Systems in the Lung: New Scenarios Emerging From COVID-19

“…However, it is likely that nicotine by itself may exert a role in this process considering that it induces ACE2 upregulation in cultured human bronchial epithelial cells and this effect is blunted by the selective nAChR blocker, α-bungarotoxin, and by anti-α7 siRNAs ( Russo et al, 2020 ). Nicotine contained in smoke could be, therefore, acting as an activator of the cholinergic anti-inflammatory system in the lung, which could be beneficial in COVID-19 ( Tizabi et al, 2020 ; Qin et al, 2021 ). Indeed, although cholinergic stimulation is expected to increase the density of the SARS-CoV2 receptor ACE2, the higher activity of this enzyme could reduce Ang II-induced proinflammatory status mainly by enhancing the levels of its functional antagonist Ang-(1-7) ( Magalhaes et al, 2020 ).…”