GTS-21, an α7nAChR agonist, suppressed the production of key inflammatory mediators by PBMCs that are elevated in COPD patients and associated with impaired lung function

Abstract

Chronic obstructive pulmonary disease (COPD) is a lung inflammatory disease characterized by progressive airflow limitation, chronic respiratory symptoms and frequent exacerbations. There is an unmet need to identify novel therapeutic alternatives beside bronchodilators that prevent disease progression. Levels of both Nitric Oxide (NO) and IL-6 were significantly increased in the plasma of patients in the exacerbation phase (ECOPD, n = 13) when compared to patients in the stable phase (SCOPD, n = 38). Levels of both NO and IL-6 were also found to inversely correlate with impaired lung function (%FEV1 predicted). In addition, there was a strong positive correlation between levels of IL-6 and NO found in the plasma of patients and those spontaneously produced by their peripheral blood mononuclear cells (PBMCs), identifying these cells as a major source of these key inflammatory mediators in COPD. GTS-21, an agonist for the alpha 7 nicotinic receptors (α7nAChR), was found to exert immune-modulatory actions in PBMCs of COPD patients by suppressing the production of IL-6 and NO. This study provides the first evidence supporting the therapeutic potential of α7nAChR agonists in COPD due to their ability to suppress the production of key inflammatory markers associated with disease severity.

Nicotinic Receptor Subunits Atlas in the Adult Human Lung

“…Altogether, understanding the repartition and the possible assembly of nAChRs at the cancer cell surface may pave the way towards the design of effective anti-cancer drugs. (ii) nAChR SNPs were also associated with nicotine dependence and COPD [ 50 , 51 , 52 , 53 , 54 ]. CHRNA3/A5/B4 polymorphisms were heavily discussed in the dissection of the genetic origins of COPD, but no functional studies have been published so far [ 55 ].…”

“…CHRNA3/A5/B4 polymorphisms were heavily discussed in the dissection of the genetic origins of COPD, but no functional studies have been published so far [ 55 ]. In addition, α7 and its ligands received particular attention as potential inflammatory players in COPD patients [ 54 , 56 ]. Exploring the involvement of nAChRs in COPD pathogenesis and progression in light of their differential distribution in lung cell populations may help improve health care for this pathology lacking treatments.…”

Nicotinic receptors atlas in the adult human lung

“…(i) nAChRs single nucleotide polymorphisms (SNP) were associated to lung cancer cells [36,37] and nAChRs were shown to be involved in cancer cell proliferation and survival [38][39][40][41]. (ii) nAChRs SNPs were also associated with nicotine dependence and COPD [42][43][44][45][46]. (iii) Nicotine, the main ligand of nAChRs, and more generally smoking, have been shown in vitro and in vivo to modulate the expression of hACE2, the main receptor of SARS-CoV-2 spike S protein [47][48][49][50].…”

Possible Therapeutic Role of Cholinergic Agonists on COVID-19 related inflammatory response

“…Besides, procalcitonin, C-reactive protein (CRP) and IL-6 levels diminished with physostigmine treatment (17). Recent study revealed that GTS-21 improved lung function along with the reduction in plasma IL-6 level in patients with chronic obstructive pulmonary disease (46). Additionally, α7nAChR positive allosteric modulator and well-known antiparasitic drug ivermectin has been shown to reduce viral replication effectively in-vitro.…”