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: Zhe-Qi Xu, Bo-Zong Shao, Ping Ke, Jian-Guo Liu, Guo-Ku Liu, Xiong-Wen Chen, Ding-Feng Su, Chong Liu
• Journal: Scientific reports (Sci Rep) Vol. 6 Pg. 37709 (11 22 2016) ISSN: 2045-2322 [Electronic] England
• PMID: 27874086 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Electrolytes
• Protective Agents
• STAT3 Transcription Factor
• Solanaceous Alkaloids
• alpha7 Nicotinic Acetylcholine Receptor
• anisodamine
• Nitric Oxide
• Neostigmine
• Creatinine
• Hydrogen Peroxide
• Peroxidase
• Janus Kinase 2
• Creatine Kinase

Topics

• Animals
• Blood Pressure (drug effects)
• Blood Urea Nitrogen
• Creatine Kinase (blood)
• Creatinine (blood)
• Crush Syndrome (blood, drug therapy, physiopathology)
• Cytokines (metabolism)
• Disease Models, Animal
• Electrolytes (blood)
• Heart Rate (drug effects)
• Hydrogen Peroxide (blood)
• Janus Kinase 2 (metabolism)
• Mice, Knockout
• Muscles (metabolism)
• Neostigmine (administration & dosage, therapeutic use)
• Nitric Oxide (blood)
• Peroxidase (blood)
• Protective Agents (pharmacology, therapeutic use)
• Rabbits
• Rats
• STAT3 Transcription Factor (metabolism)
• Signal Transduction
• Solanaceous Alkaloids (administration & dosage, therapeutic use)
• Survival Analysis
• Systole (drug effects)
• Time Factors
• alpha7 Nicotinic Acetylcholine Receptor (metabolism)