Cargando…

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

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Fan, Bo-Shi, Zhang, En-Hui, Wu, Miao, Guo, Jin-Min, Su, Ding-Feng, Liu, Xia, Yu, Jian-Guang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4810156/
https://www.ncbi.nlm.nih.gov/pubmed/27065867
http://dx.doi.org/10.3389/fphar.2016.00079
_version_ 1782423741006872576
author Fan, Bo-Shi
Zhang, En-Hui
Wu, Miao
Guo, Jin-Min
Su, Ding-Feng
Liu, Xia
Yu, Jian-Guang
author_facet Fan, Bo-Shi
Zhang, En-Hui
Wu, Miao
Guo, Jin-Min
Su, Ding-Feng
Liu, Xia
Yu, Jian-Guang
author_sort Fan, Bo-Shi
collection PubMed
description 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.
format Online
Article
Text
id pubmed-4810156
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-48101562016-04-08 Activation of α7 Nicotinic Acetylcholine Receptor Decreases On-site Mortality in Crush Syndrome through Insulin Signaling-Na/K-ATPase Pathway Fan, Bo-Shi Zhang, En-Hui Wu, Miao Guo, Jin-Min Su, Ding-Feng Liu, Xia Yu, Jian-Guang Front Pharmacol Pharmacology 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. Frontiers Media S.A. 2016-03-29 /pmc/articles/PMC4810156/ /pubmed/27065867 http://dx.doi.org/10.3389/fphar.2016.00079 Text en Copyright © 2016 Fan, Zhang, Wu, Guo, Su, Liu and Yu. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Fan, Bo-Shi
Zhang, En-Hui
Wu, Miao
Guo, Jin-Min
Su, Ding-Feng
Liu, Xia
Yu, Jian-Guang
Activation of α7 Nicotinic Acetylcholine Receptor Decreases On-site Mortality in Crush Syndrome through Insulin Signaling-Na/K-ATPase Pathway
title Activation of α7 Nicotinic Acetylcholine Receptor Decreases On-site Mortality in Crush Syndrome through Insulin Signaling-Na/K-ATPase Pathway
title_full Activation of α7 Nicotinic Acetylcholine Receptor Decreases On-site Mortality in Crush Syndrome through Insulin Signaling-Na/K-ATPase Pathway
title_fullStr Activation of α7 Nicotinic Acetylcholine Receptor Decreases On-site Mortality in Crush Syndrome through Insulin Signaling-Na/K-ATPase Pathway
title_full_unstemmed Activation of α7 Nicotinic Acetylcholine Receptor Decreases On-site Mortality in Crush Syndrome through Insulin Signaling-Na/K-ATPase Pathway
title_short Activation of α7 Nicotinic Acetylcholine Receptor Decreases On-site Mortality in Crush Syndrome through Insulin Signaling-Na/K-ATPase Pathway
title_sort activation of α7 nicotinic acetylcholine receptor decreases on-site mortality in crush syndrome through insulin signaling-na/k-atpase pathway
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4810156/
https://www.ncbi.nlm.nih.gov/pubmed/27065867
http://dx.doi.org/10.3389/fphar.2016.00079
work_keys_str_mv AT fanboshi activationofa7nicotinicacetylcholinereceptordecreasesonsitemortalityincrushsyndromethroughinsulinsignalingnakatpasepathway
AT zhangenhui activationofa7nicotinicacetylcholinereceptordecreasesonsitemortalityincrushsyndromethroughinsulinsignalingnakatpasepathway
AT wumiao activationofa7nicotinicacetylcholinereceptordecreasesonsitemortalityincrushsyndromethroughinsulinsignalingnakatpasepathway
AT guojinmin activationofa7nicotinicacetylcholinereceptordecreasesonsitemortalityincrushsyndromethroughinsulinsignalingnakatpasepathway
AT sudingfeng activationofa7nicotinicacetylcholinereceptordecreasesonsitemortalityincrushsyndromethroughinsulinsignalingnakatpasepathway
AT liuxia activationofa7nicotinicacetylcholinereceptordecreasesonsitemortalityincrushsyndromethroughinsulinsignalingnakatpasepathway
AT yujianguang activationofa7nicotinicacetylcholinereceptordecreasesonsitemortalityincrushsyndromethroughinsulinsignalingnakatpasepathway