Anti-Inflammation of Spirocyclopiperazinium Salt Compound LXM-10 Targeting α7 nAChR and M4 mAChR and Inhibiting JAK2STAT3 Pathway in Rats.docVIP

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Anti-Inflammation of Spirocyclopiperazinium Salt Compound LXM-10 Targeting α7 nAChR and M4 mAChR and Inhibiting JAK2STAT3 Pathway in Rats.doc

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Anti-Inflammation of Spirocyclopiperazinium Salt Compound LXM-10 Targeting α7 nAChR and M4 mAChR and Inhibiting JAK2STAT3 Pathway in Rats

Anti-InflammationofSpirocyclopiperaziniumSalt CompoundLXM-10Targetinga7nAChRandM4mAChR andInhibitingJAK2/STAT3PathwayinRats WeiweiZhang1,2,QiSun3,XiaoliGao2,YiminJiang4,RuntaoLi1,3,JiaYe1,2 * 1State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China, 2Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University, Beijing, China, 3Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, China, 4MedicalandHealthyAnalysisCenter,PekingUniversity,Beijing,China Abstract ThepresentstudyaimstoinvestigatethetherapeuticeffectsofLXM-10byintragastricadministrationinbothacuteand chronic inflammatory models, and to explore the underlying molecular mechanisms. The results showed that LXM-10 producedsignificantanti-inflammatoryeffectsoncarrageenaninducedpawedemaandcompleteFreund’sadjuvant(CFA) inducedarthritis,inwhichLXM-10inhibitedpawswellinginadose-andtime-dependentmanner.ELISAanalysisshowed theproduction of pro-inflammatory cytokinesincluding TNF-aandIL-6 was decreasedby LXM-10. Westernblot analysis showedthatLXM-10significantlyreducedphosphorylationofJanuskinase2(JAK2)andfurtherbluntedphosphorylationof signal transducer and activator of transcription-3 (STAT3). The effects that LXM-10 had shown were attenuated by methyllycaconitine citrate (an a7 nicotinic acetylcholine receptor antagonist) or tropicamide (an M4 muscarinic acetylcholine receptor antagonist) in vivo. In conclusion, the studies showed that intragastric administration of LXM-10 exertedsignificantanti-inflammationeffectsinacuteandchronicmodels,whichmaybeattributetotheactivationofa7 nicotinic acetylcholine receptor and M4 muscarinic acetylcholine receptor, thereby inhibiting the JAK2/STAT3 signal pathway,andultimatelyreducingtheproductionofpro-inflammatorycytokinesofTNF-aandIL-6. Citation:ZhangW,SunQ,GaoX,JiangY,LiR,etal.(2013)Anti-InflammationofSpirocyclopiperaziniumSaltCompoundLXM-10Targetinga7nAChRan