AI Article Synopsis
- Nicotinic acetylcholine receptors (nAChRs), traditionally known for their role as ion channels in the nervous system, also appear to influence inflammation by promoting a desensitized state rather than channel activation.
- A study found that a silent agonist of α7 nAChRs, m-bromo PEP, effectively reduced inflammation and improved outcomes in an animal model of multiple sclerosis, impacting immune cell function and cytokine production.
- These findings suggest that α7 nAChR-selective silent agonists could serve as new anti-inflammatory treatments for various inflammatory disorders.
Article Abstract
Nicotinic acetylcholine receptors (nAChRs) are best known to function as ligand-gated ion channels in the nervous system. However, recent evidence suggests that nicotine modulates inflammation by desensitizing non-neuronal nAChRs, rather than by inducing channel opening. Silent agonists are molecules that selectively induce the desensitized state of nAChRs while producing little or no channel opening. A silent agonist of α7 nAChRs has recently been shown to reduce inflammation in an animal model of inflammatory pain. The objective of this study was to determine whether a silent agonist of α7 nAChRs can also effectively modulate inflammation and disease manifestation in an animal model of multiple sclerosis. We first evaluated the effects of various nAChR ligands and of an α7 nAChR-selective silent agonist, 1-ethyl-4-(3-(bromo)phenyl)piperazine (m-bromo PEP), on the modulation of mouse bone marrow-derived monocyte/macrophage (BMDM) numbers, phenotype and cytokine production. The non-competitive antagonist mecamylamine and the silent agonist m-bromo PEP reduced pro-inflammatory BMDM numbers by affecting their viability and proliferation. Both molecules also significantly reduced cytokine production by mouse BMDMs and significantly ameliorated disease in experimental autoimmune encephalomyelitis. Finally, m-bromo PEP also reduced chronic inflammatory pain in mice. Taken together, our results further support the hypothesis that nAChRs may modulate inflammation via receptor desensitization rather than channel opening. α7 nAChR-selective silent agonists may thus be a novel source of anti-inflammatory compounds that could be used for the treatment of inflammatory disorders.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604877 | PMC |
| http://dx.doi.org/10.1016/j.bbi.2019.12.014 | DOI Listing |
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