title: Combined administration of anisodamine and neostigmine rescued acute lethal crush syndrome through α7nAChR-dependent JAK2-STAT3 signaling.
abstract: Previously we showed that Ani (anisodamine)/Neo (neostigmine) combination produced anti-shock effect via activating α7 nicotinic acetylcholine receptor (α7nAChR). In this study, we aim to investigate the therapeutic effect and underlying mechanisms of Ani/Neo combination in acute lethal crush syndrome (CS). In rat and rabbit CS models, Ani/Neo combination increased the 24 h survival rates, improved hemodynamics and decreased the levels of creatine kinase, MB isoenzyme of creatine kinase, blood urea nitrogen, creatinine, K+in serum. It also decreased the levels of H2O2, myeloperoxidase (MPO) and nitric oxide (NO) in serum and compressed muscle in rat CS model. In wild-type (WT) mice with CS, Ani/Neo combination increased 24 h survival rate and decreased the levels of H2O2, MPO, NO, TNFα, IL-6 and IL-10 in compressed muscle. These effects were attenuated by α7nAChR knockout (KO). Moreover, Ani/Neo combination prevented the decrease of phosphorylation of Janus kinase 2 (JAK2) and phosphorylation of signal transducer and activator of transcription 3 (STAT3) induced by CS. These effects of Ani/Neo in CS mice were cancelled by methyllycaconitine (α7nAChR antagonist) and α7nAChR KO. Collectively, our results demonstrate that Ani/Neo combination could produce therapeutic effects in CS. The underlying mechanism involves the activation of α7nAChR-dependent JAK2-STAT3 signaling pathway.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, China.
authors.forename: Zhe-Qi
authors.initials: ZQ
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, China.
authors.forename: Bo-Zong
authors.initials: BZ
authors.lastname: Shao
authors.affiliation: Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Ke
authors.affiliation: Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, China.
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, China.
authors.forename: Guo-Ku
authors.initials: GK
authors.lastname: Liu
authors.affiliation: Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Xiong-Wen
authors.initials: XW
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, China.
authors.forename: Ding-Feng
authors.initials: DF
authors.lastname: Su
authors.affiliation: Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, China.
authors.forename: Chong
authors.initials: C
authors.lastname: Liu
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001806:Blood Urea Nitrogen; D003402:Creatine Kinase / Q000097:blood; D003404:Creatinine / Q000097:blood; D003444:Crush Syndrome / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004573:Electrolytes / Q000097:blood; D006339:Heart Rate / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000097:blood; D053614:Janus Kinase 2 / Q000378:metabolism*; D018345:Mice, Knockout; D009132:Muscles / Q000378:metabolism; D009388:Neostigmine / Q000008:administration & dosage* / Q000627:therapeutic use*; D009569:Nitric Oxide / Q000097:blood; D009195:Peroxidase / Q000097:blood; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use; D011817:Rabbits; D051381:Rats; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D012991:Solanaceous Alkaloids / Q000008:administration & dosage* / Q000627:therapeutic use*; D016019:Survival Analysis; D013599:Systole / Q000187:drug effects; D013997:Time Factors; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism*
chemical_list: D016207:Cytokines; D004573:Electrolytes; D020011:Protective Agents; D050796:STAT3 Transcription Factor; D012991:Solanaceous Alkaloids; D064569:alpha7 Nicotinic Acetylcholine Receptor; C003922:anisodamine; D009569:Nitric Oxide; D009388:Neostigmine; D003404:Creatinine; D006861:Hydrogen Peroxide; D009195:Peroxidase; D053614:Janus Kinase 2; D003402:Creatine Kinase