According to van Maanen et al., and their recent publication in PLoS One, two new experimental compounds affecting the acetylcholine-receptor system are able to delay collagen-induced arthritis (CIA) in mice, showing the therapeutic potential of chemicals targeting the α7 subunit of nicotinic acetylcholine receptors (α7nAChR).
Rheumatoid arthritis (RA) is a chronic, immune-mediated inflammatory disease of unknown etiology, characterized by nonspecific, often symmetric, inflammation of the peripheral joints. Although the introduction of anti-tumor necrosis factor (TNF) therapy and other new biologicals has played a major role in improving patient outcomes, RA is still associated with long-term morbidity and early mortality.
The key mediator of the cholinergic anti-inflammatory pathway, acetylcholine (ACh), may inhibit pro-inflammatory cytokine release via interaction with members of the nicotinic acetylcholine receptor family (nAChR), and in particular with the α7 subunit (α7 nAChR).
In the PLoS ONE study, Marjolein van Maanen et al., used two novel α7nAChR selective agonists, PMP-311 and PMP-072, studied their effects and tested their therapeutic potential in the collagen-induced arthritis model in mice. In this study, the authors found that these compounds were effective in reducing arthritis incidence, preventing onset of disease, and protecting against synovial inflammation and joint destruction.
The report also showed that α7nAChR agonists may exert anti-inflammatory effects independently of ion channel activation. This clearly shows a therapeutic potential of these agonists.
This study extends previous work showing that α7nAChR ligands may reduce disease activity in animal models of rheumatoid arthritis. This research may also suggest and stimulate the development of new therapeutic strategies or targets in patients with rheumatoid arthritis.
Source: PLoS One, 2015, 10(1):e0116227. DOI:10.1371/journal.pone.0116227
Read More: PLoS One
Cover Image: Relationship of alpha7 nicotinic receptors and anti-inflammatory pathways. Schematic showing alpha7 nicotinic receptor-mediated activation of JAK2 and cross-talk mechanisms between alpha7 receptors and β-amyloid-activated pathways.
Alpha7-mediated neuroprotection via the JAK2 pathway intersects with the anti-inflammatory pathway mediated through STAT3/NF-κB.
ACh Acetylcholine, Akt protein kinase B, Bcl-2 B cell lymphoma 2 protein, GSK-3β glycogen synthase kinase 3 beta, IκB inhibitor kappa B, JAK2 Janus kinase 2, mTOR mammalian target of rapamycin, NF-κB nuclear factor kappa B and transcription factor complex, STAT signal transducer and activator of transcription, PARP poly (ADP-ribose) polymerase, Thy thymocyte.
From: Alpha7 nicotinic receptors as novel therapeutic targets for inflammation-based diseases; 2010, Cellular and Molecular Life Sciences 68(6):931-49, by Merouane Bencherif, Patrick M. Lippiello, Rudolf Lucas, and Mario B. Marrero, https://pubmed.ncbi.nlm.nih.gov/20953658/