The possible association between long-COVID and acetylcholine system dysfunction

In an in-depth review, the Russian research group from the Medical Institute, Maikop, discussed the possible association between long-COVID and acetylcholine system (AChS) dysfunction.

More than two years after the global COVID-19 pandemic, it is clear that infection with severe acute respiratory syndrome coronavirus type-2 (SARS-CoV-2) can lead to a new disease called post-acute COVID syndrome or long COVID. The most frequent, persistent and disabling symptoms of long COVID are neurological. These symptoms include headaches, visual and olfactory dysfunction, gait disturbances, paresthesia, muscular weakness, coordination problems, and cognitive impairment. Their presence results in a long-term impairment of functional ability.



About the study

A large number of acetylcholine (ACh) neurons are present in the brain, in particular in the forebrain and brainstem. These neurons send extensive projections to the cortex and subcortical structures. Numerous ACh synapses have been found in the hippocampus and prefrontal cortex, the brain regions responsible for memory and learning.

The authors analyzed the physiology and the mechanism of synaptic signal transmission through a chemical synapse as the main process by which the information is transmitted within the nervous system. They pointed out that the question of how SARS-CoV-2 infection affects the transmission of signal along nerve fibers, as well as the consequences of these influences, has not been practically studied.

The scientists then discussed the possible mechanisms by which SARS-CoV-2 can suppress AChS. Hyperproduction of nitric oxide (NO) and the formation of toxic compounds in synapses play a crucial role in AChS dysfunction. The occurrence of “cytokine storm” and the release of proinflammatory cytokines interleukin-1 (IL-1), IL-2, IL-6, and tumor necrosis factor-alpha (TNF-α) activates the synthesis of all forms of nitric oxide synthase (NOS), inducing the synthesis of a large amount of NO.

In a situation of increased production of cytokines, the anti-inflammatory function of the parasympathetic system is depleted.

A large amount of NO activates calcium channels, leading to increased ACh exocytosis. Additionally, a high concentration of NO in the synaptic cleft leads to the inhibition of acetylcholinesterase (AChE), which should rapidly degrade ACh after interaction with the ACh receptors. The inhibition of AChE decreases the rate of ACh destruction.

This is manifested by a longer activation of ACh receptors, opening of sodium and calcium channels and slowing down their inactivation. Consequently, increased production of ACh and decreased AChE activity lead to disruption of synaptic transmission in the central nervous system and neuromuscular synapses.

NO can be oxidized in a very aggressive, toxic and potent agent– peroxynitrite which causes changes in the protein and lipid components of the ACh receptors (AChRs), Ca2+, and Na+ channels. This even more disrupts the transmission of signals from the presynaptic to the postsynaptic membrane. It should be noted that the modification of the protein-lipid formations of AChR, Na+ and Ca2+channels by peroxynitrite is accompanied by an autoimmune response.

Clinically, these pathological processes are manifested by severe muscular fatigue in patients.

Furthermore, a number of studies conducted in patients with long COVID reported the presence of antibodies to AChRs. The severity of symptoms depends on the concentration of autoantibodies to AChRs.

Scientists referred to previous work by Alexandris et al., who conducted molecular modeling of the interaction between SARS-CoV-2 and the nicotinic acetylcholine receptors. Based on these results, the SARS-CoV-2 spike glycoprotein, which carries a “toxin-like” sequence in its receptor-binding domain, can bind to the α-subunits of the nicotinic acetylcholine receptors, inhibiting the activity of AChS. This mechanism was suggested as one of the causes of AChS dysfunction. (Alexandris N et al.Toxicol Rep 2021;8:73-83)

The authors concluded that disturbance of ACh synaptic transmission in the central and peripheral nervous systems could result in pathological findings in the acute period of SARS-CoV-2 infection and in the post-COVID period.

This article is published in Chinese Journal of Physiology.

Journal Reference:

Lysenkov SP, et al. Cholinergic deficiency in the cholinergic system as a pathogenetic link in the formation of various syndromes in COVID-19. Chin J Physiol 2023;66:1-13. (Open Access);year=2023;volume=66;issue=1;spage=1;epage=13;aulast=Lysenkov