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α7 Nicotinic Acetylcholine Receptor Agonists: Therapeutic Potential in a Murine Model of Rheumatoid Arthritis

Therapeutic Potential of alpha7 Nicotinic Acetylcholine Receptor Agonists
α7 Nicotinic Acetylcholine Receptor Agonists: Therapeutic Potential

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.

Thus, there is still a need for the identification of new pathways involved in the modulation of inflammation, which could help to increase the efficacy of the RA treatment.

Previous research revealed that the efferent vagus nerve may decrease peripheral inflammation via inhibition of the release of inflammatory cytokines.

The vagus/cholinergic anti-inflammatory effect was documented in animal disease models such as carrageenan-induced inflammation and collagen-induced arthritis (L. Borovikova et al., 2000; Y. Levine et al., 2014), where the intraperitoneal administration of α7 nAChR agonists was also proven to be effective (M. van Maanen et al., 2009).

Thus, the identification and use of specific α7 agonists that are able to inhibit inflammation stimulated the development of selective compounds aimed to the modulation of α7 nAChR.

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).

This receptor is not only expressed by neuronal cells but also by macrophages and other cells involved in the inflammatory response.This effect is dependent on the activation of nicotinic acetylcholine receptors (nACh), mainly the α7 subunit, expressed on macrophages that respond to acetylcholine (ACh), the main cholinergic neurotransmitter released by the efferent vagus nerve.

The cholinergic anti-inflammatory pathway may also be relevant in arthritis. Pharmacological or electrical stimulation of the vagus nerve decreases carrageenan-induced inflammation in the rat paw. Moreover, we have shown that unilateral cervical vagotomy exacerbates collagen-induced arthritis (CIA), whereas treatment with AR-R17779, an α7 nAChR agonist, ameliorates arthritis activity.

In addition, α7-deficient mice showed a marked increase in synovial inflammation compared with wild-type littermates. Underscoring the potential importance of α7 nAChR in humans, it has been shown that leukocytes and fibroblast-like synoviocytes (FLS) in the RA synovium express α7 nAChR and α7 nAChR-specific agonists can, in vitro, modulate the inflammatory response of RA FLS

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,