Activation of α7 Nicotinic Acetylcholine Receptor Decreases On-site Mortality in Crush Syndrome through Insulin Signaling-Na/K-ATPase Pathway

Abstract

On-site mortality in crush syndrome remains high due to lack of effective drugs based on definite diagnosis. Anisodamine (Ani) is widely used in China for treatment of shock, and activation of α7 nicotinic acetylcholine receptor (α7nAChR) mediates such antishock effect. The present work was designed to test whether activation of α7nAChR with Ani decreased mortality in crush syndrome shortly after decompression. Sprague-Dawley rats and C57BL/6 mice with crush syndrome were injected with Ani (20 mg/kg and 28 mg/kg respectively, i.p.) 30 min before decompression. Survival time, serum potassium, insulin, and glucose levels were observed shortly after decompression. Involvement of α7nAChR was verified with methyllycaconitine (selective α7nAChR antagonist) and PNU282987 (selective α7nAChR agonist), or in α7nAChR knockout mice. Effect of Ani was also appraised in C2C12 myotubes. Ani reduced mortality and serum potassium and enhanced insulin sensitivity shortly after decompression in animals with crush syndrome, and PNU282987 exerted similar effects. Such effects were counteracted by methyllycaconitine or in α7nAChR knockout mice. Mortality and serum potassium in rats with hyperkalemia were also reduced by Ani. Phosphorylation of Na/K-ATPase was enhanced by Ani in C2C12 myotubes. Inhibition of tyrosine kinase on insulin receptor, phosphoinositide 3-kinase, mammalian target of rapamycin, signal transducer and activator of transcription 3, and Na/K-ATPase counteracted the effect of Ani on extracellular potassium. These findings demonstrated that activation of α7nAChR could decrease on-site mortality in crush syndrome, at least in part based on the decline of serum potassium through insulin signaling-Na/K-ATPase pathway.

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

“…Recent study by Fan et al . reported that administration of Ani contributed to the alleviation of CS in on-site mortality through the α7nAChR-mediated enhancement of insulin sensitivity and the increased phosphorylation of Na/K-ATPase in C2C12 myotubes, which led to the decrease of serum potassium28. We think this could be a mechanism for our observed beneficial effect of Ani/Neo combination on CS in this study.…”

Acute lung injury is reduced by the α7nAChR agonist PNU‐282987 through changes in the macrophage profile

“…PNU‐282987, a potent and selective agonist of α7nAChR (25, 55, 56), has been used to evaluate the effect of these receptors in different models of inflammation (57–61). Our results show that PNU‐282987 is efficient for the treatment and prevention of lung inflammation in LPS‐induced ALI in mice, further stressing the importance of the cholinergic anti‐inflammatory pathway and the manipulation of α7nAChR as a pharmacological tool to treat inflammatory diseases (13).…”

A Role for the Insulin Receptor in the Suppression of Dengue Virus and Zika Virus in Wolbachia-Infected Mosquito Cells

“…The effect of downregulation of the IR by siRNA on virus production was not as strong as that observed upon Wolbachia infection (Figures 2E and 2F). We then used a selective chemical kinase inhibitor of the IR, hydroxy-2-naphthalenyl-methyl phosphonic acid trisacetoxymethylester (HNMPA(AM)-3) (Fan et al, 2016), to determine whether IR kinase activity is required for ZIKV and DENV replication. Cell toxicity assays revealed that concentrations % 25 mM of the inhibitor are non-toxic for Wolbachia-infected (Aag2wMel) and non-infected (Aag2wMel.tet) cells ( Figure 3A).…”