Omicron SARS-CoV-2 Spike-1 Protein's Decreased Binding Affinity to α7nAChr: Implications for Autonomic Dysregulation of the Parasympathetic Nervous System and the Cholinergic Anti-Inflammatory Pathway—An In Silico Analysis

Omicron is the dominant strain of COVID-19 in the United States and worldwide. Although this variant is highly transmissible and may evade natural immunity, vaccines, and therapeutic antibodies, preclinical results in animal models and clinical data in humans suggest omicron causes a less severe form of infection. The molecular basis for the attenuation of virulence when compared to previous variants is currently not well understood. Using protein–ligand docking simulations to evaluate and compare the capacity of SARS-CoV-2 spike-1 proteins with the different COVID-19 variants to bind to the human α7nAChr (i.e., the core receptor under the control of the vagus nerve regulating the parasympathetic nervous system and the cholinergic anti-inflammatory pathway), we found that 10 out of the 14 mutated residues on the RBD of the B.1.1.529 (Omicron) spike, compared to between 0 and 2 in all previous variants, were present at the interaction interface of the α7nAChr. We also demonstrated, through protein–protein docking simulations, that these genetic alterations cause a dramatic decrease in the ability of the Omicron SARS-CoV-2 spike-1 protein to bind to the α7nAChr. These results suggest, for the first time, that the attenuated nature of Omicron infection in humans and animals compared to previous variants may be attributable to a particular set of genetic alterations, specifically affecting the binding site of the SARS-CoV-2 spike-1 protein to the α7nAChr. [ FROM AUTHOR]

Donepezil Beyond Alzheimer’s Disease? A Narrative Review of Therapeutic Potentials of Donepezil in Different Diseases

Donepezil hydrochloride is an acetylcholine esterase inhibitor studied and approved to treat Alzheimer’s disease (AD). However, this drug can have positive therapeutic potential in treating different conditions, including various neurodegenerative disorders such as other types of dementia, multiple sclerosis, Parkinson’s disease, psychiatric and mood disorders, and even infectious diseases. Hence, this study reviewed the therapeutic potential of this drug in treating Alzheimer’s and other diseases by reviewing the articles from databases including Web of Science, Scopus, PubMed, Cochrane, and Science Direct. It was shown that donepezil could affect the pathophysiology of these diseases via mechanisms such as increasing the concentration of acetylcholine, modulating local and systemic inflammatory processes, affecting acetylcholine receptors like nicotinic and muscarinic receptors, and activating various cellular signaling via receptors like sigma-1 receptors. Despite many therapeutic potentials, this drug has not yet been approved for treating non-Alzheimer’s diseases, and more comprehensive studies are needed.

A Functional Interaction Between Y674-R685 Region of the SARS-CoV-2 Spike Protein and the Human α7 Nicotinic Receptor.

The α7 nicotinic acetylcholine receptor (nAChR) is present in neuronal and non-neuronal cells and has anti-inflammatory actions. Molecular dynamics simulations suggested that α7 nAChR interacts with a region of the SARS-CoV-2 spike protein (S), and a potential contribution of nAChRs to COVID-19 pathophysiology has been proposed. We applied whole-cell and single-channel recordings to determine whether a peptide corresponding to the Y674-R685 region of the S protein can directly affect α7 nAChR function. The S fragment exerts a dual effect on α7. It activates α7 nAChRs in the presence of positive allosteric modulators, in line with our previous molecular dynamics simulations showing favourable binding of this accessible region of the S protein to the nAChR agonist binding site. The S fragment also exerts a negative modulation of α7, which is evidenced by a profound concentration-dependent decrease in the durations of openings and activation episodes of potentiated channels and in the amplitude of macroscopic responses elicited by ACh. Our study identifies a potential functional interaction between α7 nAChR and a region of the S protein, thus providing molecular foundations for further exploring the involvement of nAChRs in COVID-19 pathophysiology.

Nicotine patches in patients on mechanical ventilation for severe COVID-19: a randomized, double-blind, placebo-controlled, multicentre trial.

PURPOSE: Epidemiologic studies have documented lower rates of active smokers compared to former or non-smokers in symptomatic patients affected by coronavirus disease 2019 (COVID-19). We assessed the efficacy and safety of nicotine administered by a transdermal patch in critically ill patients with COVID-19 pneumonia. METHODS: In this multicentre, double-blind, placebo-controlled trial conducted in 18 intensive care units in France, we randomly assigned adult patients (non-smokers, non-vapers or who had quit smoking/vaping for at least 12 months) with proven COVID-19 pneumonia receiving invasive mechanical ventilation for up to 72 h to receive transdermal patches containing either nicotine at a daily dose of 14 mg or placebo until 48 h following successful weaning from mechanical ventilation or for a maximum of 30 days, followed by 3-week dose tapering by 3.5 mg per week. Randomization was stratified by centre, non- or former smoker status and Sequential Organ Function Assessment score (< or ≥ 7). The primary outcome was day-28 mortality. Main prespecified secondary outcomes included 60-day mortality, time to successful extubation, days alive and free from mechanical ventilation, renal replacement therapy, vasopressor support or organ failure at day 28. RESULTS: Between November 6th 2020, and April 2nd 2021, 220 patients were randomized from 18 active recruiting centers. After excluding 2 patients who withdrew consent, 218 patients (152 [70%] men) were included in the analysis: 106 patients to the nicotine group and 112 to the placebo group. Day-28 mortality did not differ between the two groups (30 [28%] of 106 patients in the nicotine group vs 31 [28%] of 112 patients in the placebo group; odds ratio 1.03 [95% confidence interval, CI 0.57-1.87]; p = 0.46). The median number of day-28 ventilator-free days was 0 (IQR 0-14) in the nicotine group and 0 (0-13) in the placebo group (with a difference estimate between the medians of 0 [95% CI -3-7]). Adverse events likely related to nicotine were rare (3%) and similar between the two groups. CONCLUSION: In patients having developed severe COVID-19 pneumonia requiring invasive mechanical ventilation, transdermal nicotine did not significantly reduce day-28 mortality. There is no indication to use nicotine in this situation.

Acute Interstitial Pneumonia and Acute Respiratory Distress Syndrome (ARDS) from a Forgotten Plant

Introduction: Conium maculatum, poison hemlock, is native to Europe, North Africa and Western Asia. Over the last 50 years, it has become more prevalent as an invasive species in the United States. Notorious for its role in Socrates' suicide in 399 BC and frequently referenced by Shakespeare, the plant has a rich history of toxicity in man. We present a case of an accidental hemlock exposure leading to acute interstitial pneumonia and acute respiratory distress syndrome. Case Presentation: A 58 year old male presented with acute dyspnea and cough with hemoptysis the morning after clearing wooded brush in his backyard. Other symptoms included tachycardia, diaphoresis, nausea, and diarrhea. His condition rapidly progressed to acute respiratory failure with imaging suggestive of ARDS. Thorough investigation for infectious and inflammatory etiology was unremarkable. Open lung biopsy was consistent with diffuse alveolar damage. Further history from the wife revealed the presence of significant amounts of poison hemlock identified in photos from the yard. Initial treatment included prednisone with prolonged taper with eventual transition to mycophenolate mofetil. After a prolonged hospital course, he was discharged with tracheostomy and continued ventilatory support. Discussion: Hemlock produces piperidine alkaloids akin to nicotine including coniine and γ-coniceine. These inhibit the nicotinic acetylcholine receptors of the central nervous system causing an array of symptoms that without intervention lead to respiratory depression and death. Diagnosis is based on history. Treatment is supportive, in many instances requiring mechanical ventilation. Conclusions: Even in the Covid era, ARDS differential diagnosis is dependent on thorough history taking, including obscure environmental exposures.

In Silico Analysis of the Multi-Targeted Mode of Action of Ivermectin and Related Compounds

Some clinical studies have indicated activity of ivermectin, a macrocyclic lactone, against COVID-19, but a biological mechanism initially proposed for this anti-viral effect is not applicable at physiological concentrations. This in silico investigation explores potential modes of action of ivermectin and 14 related compounds, by which the infectivity and morbidity of the SARS-CoV-2 virus may be limited. Binding affinity computations were performed for these agents on several docking sites each for models of (1) the spike glycoprotein of the virus, (2) the CD147 receptor, which has been identified as a secondary attachment point for the virus, and (3) the alpha-7 nicotinic acetylcholine receptor (alpha 7nAChr), an indicated point of viral penetration of neuronal tissue as well as an activation site for the cholinergic anti-inflammatory pathway controlled by the vagus nerve. Binding affinities were calculated for these multiple docking sites and binding modes of each compound. Our results indicate the high affinity of ivermectin, and even higher affinities for some of the other compounds evaluated, for all three of these molecular targets. These results suggest biological mechanisms by which ivermectin may limit the infectivity and morbidity of the SARS-CoV-2 virus and stimulate an alpha 7nAChr-mediated anti-inflammatory pathway that could limit cytokine production by immune cells.