κ阿片受体激动剂对心肺转流大鼠术后认知功能及α7nAChR表达的影响
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摘要
目的探讨κ阿片受体(kappa opioid receptors,KORs)激动剂U50488H对心肺转流(cardiopulmonary bypass,CPB)后大鼠认知功能及α7烟碱型乙酰胆碱能受体(α7nAChR)表达的影响。方法成年雄性SD大鼠32只,体重400～450g,随机分为四组:Sham组(S组)、CPB组(C组)、CPB+U50488H组(K组)、CPB+KORs拮抗剂Nor-BNI+U50488H组(N组),每组8只。四组大鼠于术前5d开始进行水迷宫训练,每天4次。S组不建模型,动静脉穿刺后进行机械通气60min,其余三组心肺转流60min。术后1d进行Morris水迷宫实验,随后处死大鼠,采集血清,取海马组织。采用ELISA法检测血清IL-1β、TNF-α、S100-β浓度、海马ACh含量及ChAT和AchE活性;采用Western blot法检测海马α7nAChR蛋白含量。结果与S组比较,C、K和N组逃避潜伏期明显延长,穿越平台次数明显减少,目标象限游泳距离和停留时间明显缩短(P<0.05);血清IL-1β、TNF-α和S100-β浓度明显升高,海马α7nAChR蛋白含量明显降低(P<0.05)。与C组比较,K组逃避潜伏期明显缩短,穿越平台次数明显增多,目标象限游泳距离和停留时间明显延长(P<0.05);血清IL-1β、TNF-α和S100-β浓度明显降低,海马α7nAChR蛋白含量明显升高(P<0.05)。与S组比较,C组、N组海马Ach含量及ChAT活性明显降低,AchE活性明显升高。与C组比较,K组海马Ach含量及ChAT活性明显升高,AchE活性明显降低(P<0.05)。结论 KORs激动剂激活胆碱能抗炎通路,上调α7nAChR的表达,减轻炎症反应,从而改善CPB后大鼠认知功能。
Objective To investigate the protective effect ofκ-opioid receptor(KORs)agonist U50488 Hon postoperative cognitive function in rats after cardiopulmonary bypass(CPB)and the relationship with the cholinergic anti-inflammatory pathway(CAP).Methods Thirty-two adult male SD rats,weighing 400-450 g,were randomly divided into 4 groups:sham group(group S),CPB group(group C),CPB+ U50488 H group(group K)and CPB+ KORs antagonists Nor-BNI+U50488 Hgroup(group N),8 rats in each group.The rats of the four groups were trained in water maze for five days,four times once a day before operation.In group S,the model was not established and mechanical ventilation was performed for 60 min after puncture.CPB was maintained for 60 min in the remaining three groups.The rats of each group were tested the cognitive function by the Morris water maze experiment one day after CPB,then the plasma samples and hippocampus were collected.The levels of plasma IL-1β,TNF-αand S100-β,hippocampus ACh levels and ChAT,AchE activitives were detected by ELISA;the levels of hippocampusα7 nAChR was detected by Western blot.Results Compared with group S,the average latency were significantly increased,the average number of cross platform were significantly decreased,the distance and time of rats swiming in the target quardrant were significantly shortened,the levels of plasma IL-1β,TNF-αand S100βwere increased,the levels of hippocampusα7 nAChR was decreased in groups C,K and N(P < 0.05).Compared with group C,the average latency were significantly decreased,the average number of cross platform were significantly increased,the distance and time of rats swiming in the target quardrant were significantly extended,the levels of plasma IL-1β,TNF-αand S100-βwere decreased,the levels of hippocampusα7 nAChR was increased in group K(P <0.05).Compared with group S,the levels of ACh and activities of ChAT were descended,AchE activity was enhanced in groups C and K(P < 0.05).Compared with group C,the levels of ACh and activities of ChAT were enhanced,AchE activity was descended in group K(P < 0.05).There was no significantly difference neither between groups K and S nor groups N and C.Conclusion KORs agonist activation CAP raises the expression ofα7 nAChR,relieves inflammation of the rats after CPB,then improves the postoperative cognitive function.
Objective To investigate the protective effect ofκ-opioid receptor(KORs)agonist U50488 Hon postoperative cognitive function in rats after cardiopulmonary bypass(CPB)and the relationship with the cholinergic anti-inflammatory pathway(CAP).Methods Thirty-two adult male SD rats,weighing 400-450 g,were randomly divided into 4 groups:sham group(group S),CPB group(group C),CPB+ U50488 H group(group K)and CPB+ KORs antagonists Nor-BNI+U50488 Hgroup(group N),8 rats in each group.The rats of the four groups were trained in water maze for five days,four times once a day before operation.In group S,the model was not established and mechanical ventilation was performed for 60 min after puncture.CPB was maintained for 60 min in the remaining three groups.The rats of each group were tested the cognitive function by the Morris water maze experiment one day after CPB,then the plasma samples and hippocampus were collected.The levels of plasma IL-1β,TNF-αand S100-β,hippocampus ACh levels and ChAT,AchE activitives were detected by ELISA;the levels of hippocampusα7 nAChR was detected by Western blot.Results Compared with group S,the average latency were significantly increased,the average number of cross platform were significantly decreased,the distance and time of rats swiming in the target quardrant were significantly shortened,the levels of plasma IL-1β,TNF-αand S100βwere increased,the levels of hippocampusα7 nAChR was decreased in groups C,K and N(P < 0.05).Compared with group C,the average latency were significantly decreased,the average number of cross platform were significantly increased,the distance and time of rats swiming in the target quardrant were significantly extended,the levels of plasma IL-1β,TNF-αand S100-βwere decreased,the levels of hippocampusα7 nAChR was increased in group K(P <0.05).Compared with group S,the levels of ACh and activities of ChAT were descended,AchE activity was enhanced in groups C and K(P < 0.05).Compared with group C,the levels of ACh and activities of ChAT were enhanced,AchE activity was descended in group K(P < 0.05).There was no significantly difference neither between groups K and S nor groups N and C.Conclusion KORs agonist activation CAP raises the expression ofα7 nAChR,relieves inflammation of the rats after CPB,then improves the postoperative cognitive function.
引文
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[11] Chen K,Sun Y,Diao Y,et al.α7nicotinic acetylcholine receptor agonist inhibits the damage of rat hippocampal neurons by TLR4/Myd88/NF-κB signaling pathway during cardiopulmonary bypass.Mol Med Rep,2017,16(4):4770-4776.
[2]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.中国体外循环杂志,2017,15(3):179-184.
[3]陈怡霏,段晓霞,张官鹏,等.体外循环术POCD患者血清GDNF、S100β和Aβ含量检测对病情评估的价值.临床和实验医学杂志,2017,16(1):47-49.
[4] Pgowska-Klimek I,S′wierzko AS,Michalski M,et al.Activation of the lectin pathway of complement by cardiopulmonary bypass contributes to the development of systemic inflammatory response syndrome after paediatric cardiac surgery.Clin Exp Immunol,2016,184(2):257-263.
[5] Kosour C,Dragosavac D,Antunes N,et al.Effect of ultrafiltration on pulmonary function and interleukins in patients undergoing cardiopulmonary bypass.J Cardiothorac Vasc Anesth,2016,30(4):884-890.
[6] Cheng Q,Yakel JL.Activation ofα7nicotinic acetylcholine receptors increases intracellular cAMP levels via activation of AC1in hippocampal neurons.Neuropharmacology,2015,95:405-414.
[7] Komal P,Estakhr J,Kamran M,et al.cAMP-dependent protein kinase inhibitsα7nicotinic receptor activity in layer 1cortical interneurons through activation of D1/D5dopamine receptors.J Physiol,2015,593(16):3513-3532.
[8]伊小婷,陈克研,周锦,等.肠神经胶质细胞与体外循环致肠损伤相关性的研究进展.现代生物医学进展,2017,17(16):3191-3194.
[9]王梅,孙莹杰,张铁铮.α7nAChR激动剂对体外循环致大鼠脑损伤的影响.中华麻醉学杂志,2016,36(8):930-933.
[10]计流,孙莹杰,张铁铮.α7烟碱型胆碱能受体激动剂对体外循环致大鼠脑损伤及核转录因子-κB-p65蛋白表达的影响.国际麻醉学与复苏杂志,2017,38(8):673-676,694.
[11] Chen K,Sun Y,Diao Y,et al.α7nicotinic acetylcholine receptor agonist inhibits the damage of rat hippocampal neurons by TLR4/Myd88/NF-κB signaling pathway during cardiopulmonary bypass.Mol Med Rep,2017,16(4):4770-4776.