COVID-19 and Neurocognitive Disorders

Elizabeta B. Mukaetova-Ladinska; Golo Kronenberg; Ruma Raha-Chowdhury


Curr Opin Psychiatry. 2021;34(2):149-156. 

In This Article

The Cholinergic Anti-inflammatory Pathway and the Vagus Nerve

The cholinergic system plays an important role in supressing excessive inflammation, as shown in experimental models of disease such as sepsis, ischaemia-reperfusion injury, haemorrhagic shock, abdominal surgery and infections (i.e. pancreatitis, colitis;[45]). The cytokine storm and the worsening of patients' health status can be dampened or even prevented by specifically targeting the vagal-driven cholinergic anti-inflammatory pathway (CAP).[46] The CAP is a concept that involves an anti-inflammatory effect of vagal efferents by the release of acetylcholine (ACh).[47] Nicotinic acetylcholine receptor alpha7 subunit (α7nAChRs) is required for ACh inhibition of macrophage-TNF release and cytokine modulation.[48] Apart from TNF, other pro-inflammatory cytokines such as IL-6, IL-1β were significantly decreased by vagus nerve stimulation (VNS) but not the anti-inflammatory cytokine IL-10.[46]

The vagus nerve, the longest nerve of the organism, innervates the lungs and the gastrointestinal tract, two organs which are targeted by SARS-CoV-2 (COVID-19). ACh released at the distal end of the vagus nerve acts on intrinsic neurons of the enteric nervous system, for example at the level of the gastrointestinal tract to inhibit the release of TNF by macrophages.[49] The intracellular signalling of α7nAChRs inhibits transactivational activity of the transcription factor NF-kB p65[48] and activates Jak2 and STAT3 signalling.[50] Consequently, α7nAChRs could be a candidate, as they are expressed on immune cells regulating antigen-specific antibody and pro-inflammatory cytokines production and likely regulate the intensity of immuneresponses.[51]