Combined administration of anisodamine and neostigmine rescued acute lethal crush syndrome through α7nAChR-dependent JAK2-STAT3 signaling.

Zhe-Qi Xu,Ping Ke,Xiong-Wen Chen,Bo-Zong Shao,Jian-Guo Liu,Chong Liu,Guo-Ku Liu,Ding-Feng Su

doi:10.1038/srep37709

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.

Highlights

Endogenous acetylcholine and blocks muscarinic receptors[9,10]
Our results demonstrated that the best ratio of Ani to Neo to improve animal survival after CS was about 500:1 and the best doses of combination was 20 mg/kg Ani and 40 μg/kg Neo in rat CS models
It is noted that current therapeutic strategy for CS is mainly to improve symptoms including fluid administration to prevent shock and diuresis to prevent crush-related acute kidney injury

Summary

Introduction

Endogenous acetylcholine and blocks muscarinic receptors[9,10]. Combining Ani with neostigmine (Neo), a cholinesterase inhibitor to increase endogenous acetylcholine, significantly augments the anti-shock effect in a dog hemorrhagic shock model and a murine endotoxic shock model through an α7 nAChR-dependent mechanism[9,11]. Based on these studies, we hypothesize that combined Ani and Neo may produce therapeutic benefits for CS via activation of α7nAChR. To test this hypothesis, performed a series of experiment with rat, rabbit, and mouse CS models

Objectives

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Results

Conclusion