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.

中文翻译：

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α7 烟碱乙酰胆碱受体的沉默激动剂在体外调节炎症并减轻 EAE

众所周知，烟碱乙酰胆碱受体 (nAChR) 在神经系统中作为配体门控离子通道发挥作用。然而，最近的证据表明，尼古丁通过使非神经元 nAChR 脱敏而不是通过诱导通道开放来调节炎症。沉默激动剂是选择性诱导 nAChRs 脱敏状态同时很少或不产生通道开放的分子。α7 nAChRs 的一种沉默激动剂最近被证明可以减轻炎症性疼痛动物模型中的炎症。本研究的目的是确定 α7 nAChRs 的沉默激动剂是否也能有效调节多发性硬化症动物模型中的炎症和疾病表现。我们首先评估了各种 nAChR 配体和 α7 nAChR 选择性沉默激动剂的作用，1-乙基-4-（3-（溴）苯基）哌嗪（间溴PEP），对小鼠骨髓来源的单核细胞/巨噬细胞（BMDM）数量、表型和细胞因子产生的调节。非竞争性拮抗剂美加明和沉默激动剂间溴 PEP 通过影响它们的活力和增殖来减少促炎性 BMDM 数量。这两种分子还显着减少了小鼠 BMDM 产生的细胞因子，并显着改善了实验性自身免疫性脑脊髓炎的疾病。最后，间溴 PEP 还减轻了小鼠的慢性炎症性疼痛。总之，我们的结果进一步支持了 nAChR 可能通过受体脱敏而不是通道开放来调节炎症的假设。