Long COVID - a critical disruption of cholinergic neurotransmission?

Abstract

Background: Following the COVID-19 pandemic, there are many chronically ill Long COVID (LC) patients with different symptoms of varying degrees of severity. The pathological pathways of LC remain unclear until recently and make identification of path mechanisms and exploration of therapeutic options an urgent challenge. There is an apparent relationship between LC symptoms and impaired cholinergic neurotransmission.

Methods: This paper reviews the current literature on the effects of blocked nicotinic acetylcholine receptors (nAChRs) on the main affected organ and cell systems and contrasts this with the unblocking effects of the alkaloid nicotine. In addition, mechanisms are presented that could explain the previously unexplained phenomenon of post-vaccination syndrome (PVS). The fact that not only SARS-CoV-2 but numerous other viruses can bind to nAChRs is discussed under the assumption that numerous other post-viral diseases and autoimmune diseases (ADs) may also be due to impaired cholinergic transmission. We also present a case report that demonstrates changes in cholinergic transmission, specifically, the availability of α4β2 nAChRs by using (-)-[¹⁸F]Flubatine whole-body positron emission tomography (PET) imaging of cholinergic dysfunction in a LC patient along with a significant neurological improvement before and after low-dose transcutaneous nicotine (LDTN) administration. Lastly, a descriptive analysis and evaluation were conducted on the results of a survey involving 231 users of LDTN.

Results: A substantial body of research has emerged that offers a compelling explanation for the phenomenon of LC, suggesting that it can be plausibly explained because of impaired nAChR function in the human body. Following a ten-day course of transcutaneous nicotine administration, no enduring neuropathological manifestations were observed in the patient. This observation was accompanied by a significant increase in the number of free ligand binding sites (LBS) of nAChRs, as determined by (-)-[¹⁸F]Flubatine PET imaging. The analysis of the survey shows that the majority of patients (73.5%) report a significant improvement in the symptoms of their LC/MEF/CFS disease as a result of LDTN.

Conclusions: In conclusion, based on current knowledge, LDTN appears to be a promising and safe procedure to relieve LC symptoms with no expected long-term harm.

Keywords: Cholinergic neurotransmission; Flubatine; Long COVID; Low dose transdermal nicotine; Nicotinic acetylcholine receptors; Spike glycoprotein.

Fig. 1

The consequences of spike glycoprotein (SGP)-related blockade of nicotinic acetylcholine receptors (nAChRs) are shown based on the individual organ systems affected, with receptor blockade and its consequences shown in the left semicircle and normal cholinergic receptor function after SGP displacement by nicotine shown in the right semicircle. a impaired cholinergic neuromodulation with reduced nitric oxide (NO) and impaired neuronal excitability; b impaired mitochondrial acetylcholine action with reduced adenosine triphosphate (ATP) synthesis capacity and reduced reactive oxygen species (ROS) and Ca⁺⁺ clearance; c impaired b-lymphocytic cholinergic innervation with natural autoantibodies (nAA) to pathological autoantibodies (pAA) shift; d impaired mastocytic cholinergic innervation with reduced inducible NO synthetase (iNOS) and inadequate mast cell degranulation; e impaired acetylcholine action on erythrocytes with decreased erythrocyte elasticity and oxygen uptake with increased pH/P50_O2 and rightward shift of oxygen dissociation curve (ODC); f impaired thrombocyte cholinergic innervation with increased P-selectin expression and increased aggregability g impaired endothelial cholinergic innervation with reduced endothelial NO synthetase (eNOS) synthesis, vasoconstriction, leukocyte adhesion and thrombogenesis; h SGP-induced blockade of neuromuscular junctions leads to reduced strength and painful overloading of unblocked muscle fibrils

Fig. 2

A Coronal slices of whole-body (-)-[¹⁸F]Flubatine PET and B axial slices the brain fused with T1-MR images of the same patient before (top row) and after treatment (middle row) with nicotine patches. Parametric images of total distribution volume (obtained by Logan graphical analysis) depict the distribution of α4β2* nAChRs in the body. The higher V_T signal observed post-treatment reflects increased receptor availability for the tracer. Bottom row illustrates the absolute V_T differences between both scanning sessions with red indicating an increase and blue color a decrease after treatment