K受体激动剂通过MAPK-ERK 1/2通路对术后认知功能保护作用研究
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摘要
目的探讨K受体激动剂对体外循环(CPB)后大鼠认知功能的保护作用。方法选取健康成年清洁级雄性SD大鼠48只,按完全随机数字表法将其分为CPB手术组(C组)、CPB+K阿片受体激动剂(U50488H)组(K组)、CPB+U50488H+K阿片受体拮抗剂(Nor-BN)组(NK组)及CPB+U50488H+MAPK-ERK1/2通路特异阻断剂(U0126)组(UK组),每组各12只。应用Western-blot法观察各组大鼠海马组织NF-κB-p65、α7烟碱型胆碱能受体(α7nAChR)、p-erk蛋白水平的表达情况。结果 C组NF-KB-p65蛋白表达水平显著高于K组、NK组及UK组,且K组最低,组间比较,差异均有统计学意义(P <0. 05)。K组、NK组及UK组海马组织中α7nAChR蛋白表达水平均高于C组; NK组及UK组α7nAChR表达水平均低于K组; NK组大鼠α7nAChR表达水平低于UK组;组间比较,差异均有统计学意义(P <0. 05)。K组p-erk蛋白表达水平高于C组、NK组及UK组,组间比较,差异有统计学意义(P <0. 05)。结论 K阿片受体激动剂对认知功能的保护与MAPK-erk1/2通路上调α7n AChR激活胆碱能抗炎通路有关,可激活α7n AChR,抑制核转录因子-κB蛋白表达,减少炎症反应,从而降低CPB所致术后认知功能障碍的发生率。
Objective To investigate the protective effect of K receptor agonists on cognitive function in rats after cardiopulmonary bypass( CPB). Methods A total of 48 healthy adult clean grade male SD rats were selected and divided into CPB surgery group( C group),CPB + U50488 H + K opioid receptor agonist( U50488 H) group( K group),CPB + U50488 H + K opioid receptor antagonist( Nor-BN) group( NK group) and CPB + U50488 H + mapk-erk1/2 pathway specific blocker( U0126) group( UK group) by complete random number table method,with 12 rats in each group. The expression levels of NF-κB-p65,α7 nicotinic cholinergic receptor( α7 nAChR) and p-erk protein in hippocampal tissues were observed by Western-blot. Results The expression level of NF-KB-p65 protein in group C was significantly higher than that in group K,NK and UK,with the lowest expression level in group K( P < 0. 05).The hippocampal protein expression levels of group K,NK and UK were higher than those of group C. The expression levels of group NK and group UK were lower than group K. The expression level of α7 nAChR in NK group was lower than that in UK group( P <0. 05). The expression level of p-erk protein in group K was higher than that in group C,NK and UK( P < 0. 05). Conclusion The protective effect of K opioid receptor agonists on cognitive function is related to the mapk-erk1/2 pathway up-regulating α7 nAChR to activate the cholinergic anti-inflammatory pathway,which can activate α7 nAChR,inhibit the expression of NF-κB protein and reduce the inflammatory response,thus reducing the incidence of postoperative cognitive dysfunction caused by CPB.
Objective To investigate the protective effect of K receptor agonists on cognitive function in rats after cardiopulmonary bypass( CPB). Methods A total of 48 healthy adult clean grade male SD rats were selected and divided into CPB surgery group( C group),CPB + U50488 H + K opioid receptor agonist( U50488 H) group( K group),CPB + U50488 H + K opioid receptor antagonist( Nor-BN) group( NK group) and CPB + U50488 H + mapk-erk1/2 pathway specific blocker( U0126) group( UK group) by complete random number table method,with 12 rats in each group. The expression levels of NF-κB-p65,α7 nicotinic cholinergic receptor( α7 nAChR) and p-erk protein in hippocampal tissues were observed by Western-blot. Results The expression level of NF-KB-p65 protein in group C was significantly higher than that in group K,NK and UK,with the lowest expression level in group K( P < 0. 05).The hippocampal protein expression levels of group K,NK and UK were higher than those of group C. The expression levels of group NK and group UK were lower than group K. The expression level of α7 nAChR in NK group was lower than that in UK group( P <0. 05). The expression level of p-erk protein in group K was higher than that in group C,NK and UK( P < 0. 05). Conclusion The protective effect of K opioid receptor agonists on cognitive function is related to the mapk-erk1/2 pathway up-regulating α7 nAChR to activate the cholinergic anti-inflammatory pathway,which can activate α7 nAChR,inhibit the expression of NF-κB protein and reduce the inflammatory response,thus reducing the incidence of postoperative cognitive dysfunction caused by CPB.
引文
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[2]Broad J,Maurel D,Kung VW,et al.Human native kappa opioid receptor functions not predicted by recombinant receptors:implications for drug design[J].Sci Rep,2016,6:30797.
[3]Mori T,Yoshizawa K,Ueno T,et al.Involvement of dopamine D2receptor signal transduction in the discriminative stimulus effects of theκ-opioid receptor agonist U-50,488H in rats[J].Behav Pharmacol,2013,24(4):275-281.
[4]段铭杰,孙莹杰,郑翔,等.改良穿刺法建立大鼠无血预充非停跳体外循环后认知功能障碍模型[J].中国体外循环杂志,2017,15(3):179-184.
[5]Reed JC.Proapoptotic multidomain Bcl-2/Bax-family proteins:mechanisms,physiological roles,and therapeutic opportunities[J].Cell Death Differ,2006,13(8):1378-1386.
[6]Dingeldein APG,Pokorna S,Lidman M,et al.Apoptotic bax at oxidatively stressed mitochondrial membranes:lipid dynamics and permeabilization[J].Biophys J,2017,112(10):2147-2158.
[7]Bonaz B,Sinniger V,Pellissier S.Anti-inflammatory properties of the vagus nerve:potential therapeutic implications of vagus nerve stimulation[J].J Physiol,2016,594(20):5781-5790.
[8]Samuels IS,Karlo JC,Faruzzi AN,et al.Deletion of ERK2 mitogen-activated protein kinase identifies its key roles in cortical neurogenesis and cognitive function[J].J Neurosci,2008,28(27):6983-6995.
[9]Tajik A,Rezayof A,Ghasemzadeh Z,et al.Activation of the dorsal hippocampal nicotinic acetylcholine receptors improves tamoxifeninduced memory retrieval impairment in adult female rats[J].Neuroscience,2016,327:1-9.
[10]Hamano R,Takahashi HK,Iwagaki H,et al.Stimulation of alpha7 nicotinic acetylcholine receptor inhibits CD14 and the tolllike receptor 4 expression in human monocytes[J].Shock,2006,26(4):358-364.
[11]Yoshikawa H,Kurokawa M,Ozaki N,et al.Nicotine inhibits the production of proinflammatory mediators in human monocytes by suppression of I-kappaB phosphorylation and nuclear factor-kappaB transcriptional activity through nicotinic acetylcholine receptor alpha7[J].Clin Exp Immunol,2006,146(1):116-123.
[12]Takahashi K,Nakagawasai O,Sugawara M,et al.Kappa opioid receptor agonist administration in olfactory bulbectomized mice restores cognitive impairment through cholinergic neuron activation[J].Biol Pharm Bull,2018,41(6):957-960.