2012
DOI: 10.1016/j.jneuroim.2012.07.006
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The α7 nicotinic acetylcholine receptor ligands methyllycaconitine, NS6740 and GTS-21 reduce lipopolysaccharide-induced TNF-α release from microglia

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Cited by 118 publications
(109 citation statements)
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“…Although there have been some doubts concerning targeting a7 nAChRs in the treatment of colitis [e.g., it has been suggested that a7 nAChRs agonists worsen the disease (Snoek et al, 2010)], we suggest that alteration of the frequencies of FoxP3 1 -and/or IL-17A 1 -expressing T cells may underlie the beneficial effects of encenicline on intestinal inflammation. Furthermore we highlight the superiority of partial over full a7 nAChR agonists in the treatment of colitis, which is supported by recent reports showing on one hand that in vitro partial a7 nAChR agonists exhibit anti-inflammatory properties (Thomsen and Mikkelsen, 2012) and on the other indicating that full agonists do not affect colitis in vivo (Snoek et al, 2010).…”
Section: Encenicline In Colitissupporting
confidence: 83%
“…Although there have been some doubts concerning targeting a7 nAChRs in the treatment of colitis [e.g., it has been suggested that a7 nAChRs agonists worsen the disease (Snoek et al, 2010)], we suggest that alteration of the frequencies of FoxP3 1 -and/or IL-17A 1 -expressing T cells may underlie the beneficial effects of encenicline on intestinal inflammation. Furthermore we highlight the superiority of partial over full a7 nAChR agonists in the treatment of colitis, which is supported by recent reports showing on one hand that in vitro partial a7 nAChR agonists exhibit anti-inflammatory properties (Thomsen and Mikkelsen, 2012) and on the other indicating that full agonists do not affect colitis in vivo (Snoek et al, 2010).…”
Section: Encenicline In Colitissupporting
confidence: 83%
“…This discovery provided a compelling motivation to reconsider our view of a 7 and other nAChRs strictly as mediators of transmembrane signals relying on channel-mediated ion flux. The non-neuronal cells that mediate a 7 's control of inflammation have not been shown to generate a 7 -mediated currents; moreover, some a 7 -targeting ligands that can effectively control inflammation have little or no efficacy as ion channel activators (van Maanen et al, 2009;Thomsen and Mikkelsen, 2012;Clark et al, 2014).…”
Section: Discussionmentioning
confidence: 99%
“…One of the first such compounds to be identified was NS-6740 (Thomsen and Mikkelsen, 2012), and we have also characterized the compounds KC-1 (59-phenyl-3,4,5,6-tetrahydro-2,39-bipyridine) (Chojnacka et al, 2013), R-47 [(R)-N-(4-methoxyphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide] (Clark et al, 2014), also known as CTI-15072 (van Maanen et al, 2009), as silent agonists. These compounds are large and structurally diverse, so here we start with the smallest a 7 agonists to find the most rudimentary structure capable of silent agonism, which is that of TEA.…”
Section: Discussionmentioning
confidence: 99%
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“…Of course, even a partial agonist with low channel activation efficacy may still be quite effective at inducing structural changes associated with the desensitized conformations of the receptor (44), and this has led to the hypothesis that ␣7 function, especially in non-neuronal cells incapable of ion-channel signaling, may be due to the ability of orthosteric ligands to induce global changes in receptor structure that can be transmitted to the receptor's protein interactome (45,46) and accomplish metabotropic type signaling (47-49). The potential importance for signaling through non-conducting states is also supported by the identification of silent agonists (50) such as NS6740 (51,52), which has been shown to be a very effective analgesic in several models of inflammatory or neuropathic pain (53), although its primary effect on channel activity is desensitization.…”
Section: Discussionmentioning
confidence: 99%