α7烟碱型乙酰胆碱受体在右美托咪定及褪黑素协同防治大鼠谵妄中的作用
|
摘要
目的探讨右美托咪定及褪黑素协同防治大鼠谵妄的作用及右美托咪定及褪黑素对α7烟碱型乙酰胆碱受体(α7AchR)的调节作用。方法雄性SD大鼠30只,6～8周龄,随机分为六组:对照组(C组)、东莨菪碱诱导谵妄模型组(S组)、右美托咪定组(D组)、褪黑素组(M组)、α-银环蛇毒素(α-BGT)拮抗组(BM组)和右美托咪定+褪黑素组(DM组),每组5只。S组腹腔注射0.5%东莨菪碱1.8mg/kg建立谵妄大鼠模型;C组用等容量生理盐水代替建模药物;D组及DM组于建模前15min腹腔注射右美托咪定40μg/kg;BM组于建模前15min腹腔注射α-BGT 1μg/kg;M组、BM组及DM组建模后立即在对侧腹腔注射褪黑素5 mg/kg。分别于造模前15 min及造模后10min进行旷场实验。实验结束后处死大鼠,经内眦取血,采用ELISA法检测大鼠血清α7nAchR浓度。结果与C组比较,S组周围格路程、旷场总路程明显延长,周围格速度、旷场总速度明显加快(P<0.05);与S组比较,D组、M组、DM组周围格路程、旷场总路程明显缩短,周围格速度、旷场总速度明显减慢(P<0.01)。与D组比较,DM组周围格路程、旷场总路程明显缩短(P<0.05)。与C组比较,S组α7nAChR浓度明显降低(P<0.05);与S组比较,D组α7nAChR浓度明显升高(P<0.01)。结论右美托咪定可改善谵妄症状,可能是通过提高α7nAChR表达。而褪黑素可能增强右美托咪定的谵妄防治效果。
Objective To observe dexmedetomidine coordinate with mlelatonin attenuate the scopolamine-induced delirium in rats and its mechanism.Methods Thirty male adult SD rats aged 6-8 weeks were randomly divided into six groups:normal saline control group(group C),scopolamineinduced delirious model group(group S),dexmedetomidine group(group D),mlelaton group(group M),α-bungarotoxin antagonism group(group BM),joint protection group(group DM).A model of delirium was reproduced by intraperitoneal injection of scopolamine 1.8 mg/kg.The rats in group C was given equal sterile normal saline instead,the rats in group D was intraperitoneal injected of dexmedetomidine 40μg/kg 15 minutes before scopolamine injection,the rats in group M was intraperitoneal injected of mlelaton 5 mg/kg in the contralateral abdominal at the same time with scopolamine injection,the rats in group BM was intraperitoneal injected ofα-BGT 1μg/kg 15 minutes before scopolamine injection and mlelaton 5 mg/kg in the contralateral abdominal at the same time with scopolamine injection,the rats in group DM was intraperitoneal injected of dexmedetomidine 40μg/kg 15 minutes before scopolamine injection and mlelaton 5 mg/kg in the contralateral abdominal at the same time with scopolamine injection.The rats were assigned for open field test 15 minutes before and 10 minutes after model reproduction for 15 minutes.The level of α7nAchR in serum was determined by enzyme linked immunosorbent assay.Results When compared with group C,rats in group S ran significant longer total distance and space distance,had faster total speed and space speed(P<0.05).When compared with group S,rats in group D,group M,group DM ran significant shorter total distance and space distance,had significant slower total speed and space speed(P <0.01);when compared with group D,rats in group DM ran significant shorter total distance and space distance(P<0.05),had slower total speed and space speed,however without significant statistical difference.When compared with that in group C,the level of α7nAChR in serum were significantly decreased in group S(P<0.05).When compared with group S,the level of α7nAChR were significantly increased in group D(P<0.01).There were no significant difference between group M and group S(P=0.96).When compared with group D,the level of α7nAChR had an elevated trend in group DM.Conclusion Dexmedetomidine can improve the symptoms of delirium,possibly by increasing the activity of alph a 7nAChR.Melatonin may improve the effect of dextromidine on delirium.
Objective To observe dexmedetomidine coordinate with mlelatonin attenuate the scopolamine-induced delirium in rats and its mechanism.Methods Thirty male adult SD rats aged 6-8 weeks were randomly divided into six groups:normal saline control group(group C),scopolamineinduced delirious model group(group S),dexmedetomidine group(group D),mlelaton group(group M),α-bungarotoxin antagonism group(group BM),joint protection group(group DM).A model of delirium was reproduced by intraperitoneal injection of scopolamine 1.8 mg/kg.The rats in group C was given equal sterile normal saline instead,the rats in group D was intraperitoneal injected of dexmedetomidine 40μg/kg 15 minutes before scopolamine injection,the rats in group M was intraperitoneal injected of mlelaton 5 mg/kg in the contralateral abdominal at the same time with scopolamine injection,the rats in group BM was intraperitoneal injected ofα-BGT 1μg/kg 15 minutes before scopolamine injection and mlelaton 5 mg/kg in the contralateral abdominal at the same time with scopolamine injection,the rats in group DM was intraperitoneal injected of dexmedetomidine 40μg/kg 15 minutes before scopolamine injection and mlelaton 5 mg/kg in the contralateral abdominal at the same time with scopolamine injection.The rats were assigned for open field test 15 minutes before and 10 minutes after model reproduction for 15 minutes.The level of α7nAchR in serum was determined by enzyme linked immunosorbent assay.Results When compared with group C,rats in group S ran significant longer total distance and space distance,had faster total speed and space speed(P<0.05).When compared with group S,rats in group D,group M,group DM ran significant shorter total distance and space distance,had significant slower total speed and space speed(P <0.01);when compared with group D,rats in group DM ran significant shorter total distance and space distance(P<0.05),had slower total speed and space speed,however without significant statistical difference.When compared with that in group C,the level of α7nAChR in serum were significantly decreased in group S(P<0.05).When compared with group S,the level of α7nAChR were significantly increased in group D(P<0.01).There were no significant difference between group M and group S(P=0.96).When compared with group D,the level of α7nAChR had an elevated trend in group DM.Conclusion Dexmedetomidine can improve the symptoms of delirium,possibly by increasing the activity of alph a 7nAChR.Melatonin may improve the effect of dextromidine on delirium.
引文
[1]Jackson P,Khan A.Deliriumin critically ill patients.Crit Care Clin,2015,31(3):589-603.
[2]Hollinger A,Siegemund M,Goettel N,et al.Postoperative delirium in cardiac surgery:an unavoidable menace?Journal of Cardiothoracic And Vascular Anesthesia,2015,29(6):1677-1687.
[3]Crocker E,Beggs T,Hassan A,et al.Long-term effects ofpostoperative delirium in patients undergoing cardiac operation:asystematic review.Ann Thorac Surg,2016,102(4):1391-1399.
[4]Zhu YJ,Peng K,Meng XW,et al.Attenuation of neuroinflammation by dexmedetomidine is associated with activation of a cholinergic anti-inflammatory pathway in a rat tibial fracture model.Brain Research,2016,1644:1-8.
[5]张雪艳,李志峰,孙晓晨,等.α7亚基烟碱乙酰胆碱受体在右美托咪定防治内毒素血症小鼠谵妄中的作用.中华危重病急救医学,2016,26(2):127-133.
[6]Riker RR,Shehabi Y,Bokesch PM,et al.Dexmedetomidine vs midazolam for sedation of criticallyill patients:a randomized trial.JAMA,2009,301:489-499.
[7]Pandharipande PP,Pun BT,Herr DL,et al.Effect ofsedation with dexmedetomidine vs lorazepam on acutebrain dysfunction in mechanically ventilated patients:the MENDS randomized controlled trial.JAMA,2007,298:2644-2653.
[8]Markus RP,Santos JM,Zago W,et al.Melatonin nocturnal surgemodulates nicotinic receptors and nicotine-induced[3H]glutamate release in rat cerebellum slices.J Pharmacol Exp Ther,2003,305(2):525-530.
[9]Jeong JK,Park SY.Melatonin regulates the autophagic flux via activation of alpha-7nicotinic acetylcholine receptors.J Pineal Res,2015,59(1):24-37.
[10]Hatta K,Kishi Y,Wade K,et al.Preventive effects of ramelteon on delirium arandomized placebo-controlled trial.JAMA Psychiatry,2014,71(4):397-403.
[11]Artemiou P,Bily B,Bilecova-Rabajdova M,et al.Melatonin treatment in the prevention of postoperativedelirium in cardiac surgery patients.Kardiochirurgia i Torakochirurgia Polska,2015,12(2):126-133.
[12]Nakamura K,Kurasawa M,Tanaka Y.Scopolamine model of delirium in rats and reversal of the performance impairment by aniracetam.Drug Dev Res.1998,43(2):85-97.
[13]裘毅敏,李士通,江继宏,等.腹腔注射东莨菪碱诱发大鼠谵妄模型.第二军医大学学报,2010,31:694-695.
[14]Katz RJ,Roth KA,Carroll BJ.Acuteand chronic stresseffects on open field activity in the rat:implications for a modelof depression.Neurosci Biobehav Rev,1981,5:247-251.
[15]车鹏,田建英.a7烟碱型乙酰胆碱受体相关疾病及其研究进展.宁夏医科大学学报,2010,32(2):308-311.
[16]Miller PS,Richardson JS,Jyu CA,et al.Association of low serum anticholinergic levels and cognitive impairment in elderly presurgical patients.Am J Psychiatry,1988,145:342-345.
[17]Plaschke K,Thomas C,Engelhardt R,et al.Significant correlation between plasma and CSF anticholinergic activity in presurgical patients.Neuroscience Letters,2007,417:16-20.
[18]Matsuda A,Jacob A,Wu RQ,et al.Novel therapeutic targets for sepsis:regulation of exaggerated inflammatory responses.J Nippon Med Sch,2012,79(1):4-18.
[19]Cerejeira J,Firmino H,Vaz-Serra A,et al.The neuroinflammatory hypothesis of delirium.Acta Neuropathol,2010,119:737-754.
[20]盛孝敏,甘秀妮,张传来,等.夜间使用眼罩耳塞对ICU患者谵妄及睡眠障碍的疗效观察.中国医科大学学报,2013,42(5):463-465.
[21]Carrasco G,Baeza N,CabréL,et al.Dexmedetomidine for the Treatment of Hyperactive Delirium Refractory to Haloperidol in Nonintubated ICU Patients:A Nonrandomized Controlled Trial.Crit Care Med,2016,44:1295-1306.
[22]刘作易,粱宗琦.褪黑激素的研究开发现状.生命化学,2001,21(1):69-70.
[23]Niranjan R,Nath C,Shukla R.Melatonin attenuated mediators of neuroinflammation and alpha-7nicotinic acetylcholine receptor mRNA expression in lipopolysaccharide(LPS)stimulated rat astrocytoma cells,C6.Free Radical Research,2012,46(9):1167-1177.
[24]Parada E,Buendia I,Leon R,et al.Neuroprotective effect of melatonin against ischemia is partiallymediated by alpha-7nicotinic receptor modulation and HO-1overexpression.J Pineal Res,2014,56:204-212.
[2]Hollinger A,Siegemund M,Goettel N,et al.Postoperative delirium in cardiac surgery:an unavoidable menace?Journal of Cardiothoracic And Vascular Anesthesia,2015,29(6):1677-1687.
[3]Crocker E,Beggs T,Hassan A,et al.Long-term effects ofpostoperative delirium in patients undergoing cardiac operation:asystematic review.Ann Thorac Surg,2016,102(4):1391-1399.
[4]Zhu YJ,Peng K,Meng XW,et al.Attenuation of neuroinflammation by dexmedetomidine is associated with activation of a cholinergic anti-inflammatory pathway in a rat tibial fracture model.Brain Research,2016,1644:1-8.
[5]张雪艳,李志峰,孙晓晨,等.α7亚基烟碱乙酰胆碱受体在右美托咪定防治内毒素血症小鼠谵妄中的作用.中华危重病急救医学,2016,26(2):127-133.
[6]Riker RR,Shehabi Y,Bokesch PM,et al.Dexmedetomidine vs midazolam for sedation of criticallyill patients:a randomized trial.JAMA,2009,301:489-499.
[7]Pandharipande PP,Pun BT,Herr DL,et al.Effect ofsedation with dexmedetomidine vs lorazepam on acutebrain dysfunction in mechanically ventilated patients:the MENDS randomized controlled trial.JAMA,2007,298:2644-2653.
[8]Markus RP,Santos JM,Zago W,et al.Melatonin nocturnal surgemodulates nicotinic receptors and nicotine-induced[3H]glutamate release in rat cerebellum slices.J Pharmacol Exp Ther,2003,305(2):525-530.
[9]Jeong JK,Park SY.Melatonin regulates the autophagic flux via activation of alpha-7nicotinic acetylcholine receptors.J Pineal Res,2015,59(1):24-37.
[10]Hatta K,Kishi Y,Wade K,et al.Preventive effects of ramelteon on delirium arandomized placebo-controlled trial.JAMA Psychiatry,2014,71(4):397-403.
[11]Artemiou P,Bily B,Bilecova-Rabajdova M,et al.Melatonin treatment in the prevention of postoperativedelirium in cardiac surgery patients.Kardiochirurgia i Torakochirurgia Polska,2015,12(2):126-133.
[12]Nakamura K,Kurasawa M,Tanaka Y.Scopolamine model of delirium in rats and reversal of the performance impairment by aniracetam.Drug Dev Res.1998,43(2):85-97.
[13]裘毅敏,李士通,江继宏,等.腹腔注射东莨菪碱诱发大鼠谵妄模型.第二军医大学学报,2010,31:694-695.
[14]Katz RJ,Roth KA,Carroll BJ.Acuteand chronic stresseffects on open field activity in the rat:implications for a modelof depression.Neurosci Biobehav Rev,1981,5:247-251.
[15]车鹏,田建英.a7烟碱型乙酰胆碱受体相关疾病及其研究进展.宁夏医科大学学报,2010,32(2):308-311.
[16]Miller PS,Richardson JS,Jyu CA,et al.Association of low serum anticholinergic levels and cognitive impairment in elderly presurgical patients.Am J Psychiatry,1988,145:342-345.
[17]Plaschke K,Thomas C,Engelhardt R,et al.Significant correlation between plasma and CSF anticholinergic activity in presurgical patients.Neuroscience Letters,2007,417:16-20.
[18]Matsuda A,Jacob A,Wu RQ,et al.Novel therapeutic targets for sepsis:regulation of exaggerated inflammatory responses.J Nippon Med Sch,2012,79(1):4-18.
[19]Cerejeira J,Firmino H,Vaz-Serra A,et al.The neuroinflammatory hypothesis of delirium.Acta Neuropathol,2010,119:737-754.
[20]盛孝敏,甘秀妮,张传来,等.夜间使用眼罩耳塞对ICU患者谵妄及睡眠障碍的疗效观察.中国医科大学学报,2013,42(5):463-465.
[21]Carrasco G,Baeza N,CabréL,et al.Dexmedetomidine for the Treatment of Hyperactive Delirium Refractory to Haloperidol in Nonintubated ICU Patients:A Nonrandomized Controlled Trial.Crit Care Med,2016,44:1295-1306.
[22]刘作易,粱宗琦.褪黑激素的研究开发现状.生命化学,2001,21(1):69-70.
[23]Niranjan R,Nath C,Shukla R.Melatonin attenuated mediators of neuroinflammation and alpha-7nicotinic acetylcholine receptor mRNA expression in lipopolysaccharide(LPS)stimulated rat astrocytoma cells,C6.Free Radical Research,2012,46(9):1167-1177.
[24]Parada E,Buendia I,Leon R,et al.Neuroprotective effect of melatonin against ischemia is partiallymediated by alpha-7nicotinic receptor modulation and HO-1overexpression.J Pineal Res,2014,56:204-212.