p38 MAPKはα7ニコチン受容体PAMであるPNU-120596によって阻害される

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  • p38 MAPK is directly inhibited by PNU-120596, a positive allosteric modulator of α7 nicotinic acetylcholine receptor

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<p>PNU-120596 is a typical α7 nAChR PAM and widely used to study the role of α7 nAChR in neurological disorders and inflammation-associated diseases. In this study, we revealed that PNU-120596 can directly inhibit p38 MAPK independent of α7 nAChR by cell-based assay, in vitro kinase assay, binding assay and docking simulation.</p><p>p38 MAPK phosphorylation by several factors (oxidative stress, osmotic stress, TNF-α, or muscarinic stimulation) was inhibited by PNU-120596 as well as p38 MAPK inhibitor BIRB-796. Inhibition of p38 MAPK phosphorylation by PNU-120596 was not affected by α7 nAChR antagonist, methyllycaconitine (MLA). In vitro kinase assay revealed that PNU-120596 directly inhibits p38α MAPK-induced ATF2 phosphorylation. MKK6-induced phosphorylation of p38α MAPK was also inhibited by PNU-120596. Real-time monitoring of binding to p38α MAPK using fluoroprobe SKF-86002 showed quite rapid binding of PNU-120596 compared to BIRB-796. Docking simulation indicated that the diaryl urea scaffold of PNU-120596 is important to form hydrogen bonds with p38α MAPK. Finally, we showed that PNU-120596 suppressed LPS-induced phosphorylation of p38 MAPK and expression of inflammatory factors including TNF-α, IL-6 and COX-2, independent of α7 nAChR activity in microglial cell BV-2. These results indicate that PNU-120596 might exert an anti-inflammatory effect through not only α7 nAChR potentiation but also direct inhibition of p38 MAPK.</p>

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