阿立哌唑抑制Sirt1/FoxO3信号转导通路改善MK-801诱导精神分裂症小鼠的机制研究
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摘要
目的分析地佐环平(MK-801)诱导的精神分裂症小鼠发病的Sirt1/Fox O3信号转导通路机制及阿立哌唑的改善作用。方法清洁级昆明小鼠36只随机分为对照组、精神分裂症组、烟酰胺组(Nicotinamide组)和阿立哌唑组,每组9只。腹腔注射N-甲基-D-天冬氨酸受体(N-methyl-D-aspartic acid receptor,NMDA受体)拮抗剂MK-801(0. 25 mg/kg)建立谷氨酸低下精神分裂症模型。对照组和精神分裂症小鼠给予0. 9%氯化钠溶液灌胃治疗,Nicotinamide组(20 mg/kg,口服)和阿立哌唑组(50 mg/kg,口服)小鼠给予对应剂量的药物治疗。分析4组小鼠的自发活动情况,免疫印迹法和免疫荧光法检测小鼠海马组织中沉默信息调节因子1(silent information regulator 1,Sirt1)和叉形头转录因子的O亚型(Forkhead box O3,Fox O3)蛋白的表达水平。结果精神分裂症组小鼠活动总距离和中心区活动距离较对照组、Nicotinamide组、阿立哌唑组显著增加(P <0. 01),Sirt蛋白和Fox O3蛋白表达对照组、Nicotinamide组、阿立哌唑组明显增强(P <0. 01),而Nicotinamide组和阿立哌唑组小鼠的上述异常部分恢复,且与精神分裂症组相比差异有统计学意义(P <0. 01)。结论阿立哌唑可能通过抑制激活的Sirt1/Fox O3信号转导通路改善MK-801诱导的精神分裂症小鼠异常。
Objective To investigate the mechanism of Sirt1/Fox O3 signal transduction pathway and the improvement effects of aripiprazole on MK-801 induced schizophrenia in mice. Methods A total of 36 clean grade Kunming mice were randomly divided into four groups: control group,schizophrenia group,nicotinamide group and aripiprazole group,with 9 mice in each group. The animal models were established by intraperitoneal injection of NMDA receptor antagonist MK-801( 0. 25mg/kg). The mice in control group schizophrenia group were given 0. 9% sodium chloride solution by gavage,however,the mice in nicotinamide group and aripiprazole group were treated by nicotinamide( 20mg/kg,PO) and aripiprazole( 50mg/kg,PO),respectively. The spontaneous activity of mice in each group was analyzed,moreover,the expression levels of Sirt1 and Fox O3 protein in the hippocampus of mice were detected by Western Blot and immunofluorescence. Results The total activity distance and central activity distance in schizophrenia group were significantly increased,as compared with those in control group,nicotinamide group and aripiprazole group( P < 0. 01),and the expression levels of Sirt1 and Fox O3 protein in schizophrenia group were significantly increased,as compared with those in control group, nicotinamide group and aripiprazole group( P < 0. 01). However the above abnormalities in nicotinamide group and aripiprazole group were recovered partly,there were significant differences between the two medication groups and schizophrenia group( P < 0. 01). Conclusion Aripiprazole may improve the abnormality of MK-801 induced schizophrenia in mice by inhibiting the activation of Sirt1/Fox O3 signal transduction pathway.
Objective To investigate the mechanism of Sirt1/Fox O3 signal transduction pathway and the improvement effects of aripiprazole on MK-801 induced schizophrenia in mice. Methods A total of 36 clean grade Kunming mice were randomly divided into four groups: control group,schizophrenia group,nicotinamide group and aripiprazole group,with 9 mice in each group. The animal models were established by intraperitoneal injection of NMDA receptor antagonist MK-801( 0. 25mg/kg). The mice in control group schizophrenia group were given 0. 9% sodium chloride solution by gavage,however,the mice in nicotinamide group and aripiprazole group were treated by nicotinamide( 20mg/kg,PO) and aripiprazole( 50mg/kg,PO),respectively. The spontaneous activity of mice in each group was analyzed,moreover,the expression levels of Sirt1 and Fox O3 protein in the hippocampus of mice were detected by Western Blot and immunofluorescence. Results The total activity distance and central activity distance in schizophrenia group were significantly increased,as compared with those in control group,nicotinamide group and aripiprazole group( P < 0. 01),and the expression levels of Sirt1 and Fox O3 protein in schizophrenia group were significantly increased,as compared with those in control group, nicotinamide group and aripiprazole group( P < 0. 01). However the above abnormalities in nicotinamide group and aripiprazole group were recovered partly,there were significant differences between the two medication groups and schizophrenia group( P < 0. 01). Conclusion Aripiprazole may improve the abnormality of MK-801 induced schizophrenia in mice by inhibiting the activation of Sirt1/Fox O3 signal transduction pathway.
引文
1万星,许瑞环.精神分裂症风险基因多态性的研究进展.医学综述,2016,22:4609-4613.
2宋丽华,李素水,孙志刚,等.精神分裂症认知障碍和功能预后关系的纵向研究进展.国际精神病学杂志,2015,42:47-51.
3魏江平,付文君,陈欢,等.通络醒脑泡腾片经Nampt/SIRT1/FOXO3途径改善SAMP8小鼠的学习记忆.中成药,2017,39:684-689.
4邓丽丽,万静枝,袁丁,等.竹节参总皂苷通过线粒体途径保护H2O2诱导的SH-SY5Y神经细胞损伤.中药材,2015,38:1690-1693.
5陈海莹,乔颖,蔡亦蕴,等.阿立哌唑联合多奈哌齐改善精神分裂症患者认知功能障碍的效果及对患者血清中炎症反应的影响研究.安徽医药,2015,19:2408-2410.
6赵永厚,赵玉萍,高潇,等.愈癫汤对MK-801致精神分裂症模型大鼠NO信号通路的影响.中华中医药杂志,2017,32:5081-5083.
7刘艳艳,赵鹏,李萌.帕利哌酮对抗青春期亚急性给予MK-801所致小鼠空间工作记忆的破坏作用.医学理论与实践,2016,29:3155-3157.
8魏毅君,翟蒙恩,王晓武,等.姜黄素后处理通过SIRT1/FOXO1信号通路拮抗小鼠脑缺血再灌注损伤.现代生物医学进展,2017,17:3216-3219.
9李德渊,伍金林,罗黎力,等.c-Jun氨基末端激酶介导的FOXO3a核转位在缺氧缺血性脑损伤新生大鼠神经元凋亡中的作用.中国当代儿科杂志,2017,19:458-462.
10李德渊,屈艺,李晋辉,等.核转录因子FOXO3a在新生大鼠缺氧缺血性脑损伤神经元凋亡中的作用.中国当代儿科杂志,2013,15:1023-1027.
11陶斯恒.Fox O3α在阿尔兹海默模型大鼠脑中的分布.安徽师范大学,2013.
12陈永平,谢运兰,王衡,等.SIRT1在癫痫患者及大鼠脑组织中的表达与活性.南方医科大学学报,2013,33:528-532.
13马毓,巩莉,党辉,等.脑缺血再灌注后大鼠缺血侧脑组织中SIRT1的表达.贵州医科大学学报,2017,42:1028-1032.
14张杰,张晓岩,张先钧,等.西红花苷干预对急性低氧条件大鼠脑海马FOXO3α表达的影响.时珍国医国药,2017,28:2844-2846.
15慕雅婷,李艳,郭琼,等.远端同源异型盒2和叉头盒O3a在大鼠脑皮质发育过程中的分布与表达.解剖学报,2017,48:658-662.
16庞博,孙雪峰.白藜芦醇对丙泊酚所致大鼠神经元损伤的保护作用研究.海南医学院学报,2018,3:1-10.
17李传文,张嵘,侯亮,等.SIRT1/NF-κB通路参与白藜芦醇改善大鼠脑缺血再灌注损伤炎性反应.安徽医科大学学报,2018,53:6-9.
18 Castro V,Bertrand L,Luethen M,et al.Occludin controls hiv transcription in brain pericytes via regulation of sirt-1 activation.FASEB J,2016,30:1234-1246.
19刘俊宁,王庆莲,张燕,等.补气活血通络法对神经吻合术后大鼠神经及腓肠肌蛋白表达的影响.潍坊医学院学报,2017,39:251-254.
20 Yang F,Zhou L,Wang D,et al.Minocycline ameliorates hypoxiainduced blood-brain barrier damage by inhibition of hif-1alpha through sirt-3/phd-2 degradation pathway.Neuroscience,2015,30:250-259.
2宋丽华,李素水,孙志刚,等.精神分裂症认知障碍和功能预后关系的纵向研究进展.国际精神病学杂志,2015,42:47-51.
3魏江平,付文君,陈欢,等.通络醒脑泡腾片经Nampt/SIRT1/FOXO3途径改善SAMP8小鼠的学习记忆.中成药,2017,39:684-689.
4邓丽丽,万静枝,袁丁,等.竹节参总皂苷通过线粒体途径保护H2O2诱导的SH-SY5Y神经细胞损伤.中药材,2015,38:1690-1693.
5陈海莹,乔颖,蔡亦蕴,等.阿立哌唑联合多奈哌齐改善精神分裂症患者认知功能障碍的效果及对患者血清中炎症反应的影响研究.安徽医药,2015,19:2408-2410.
6赵永厚,赵玉萍,高潇,等.愈癫汤对MK-801致精神分裂症模型大鼠NO信号通路的影响.中华中医药杂志,2017,32:5081-5083.
7刘艳艳,赵鹏,李萌.帕利哌酮对抗青春期亚急性给予MK-801所致小鼠空间工作记忆的破坏作用.医学理论与实践,2016,29:3155-3157.
8魏毅君,翟蒙恩,王晓武,等.姜黄素后处理通过SIRT1/FOXO1信号通路拮抗小鼠脑缺血再灌注损伤.现代生物医学进展,2017,17:3216-3219.
9李德渊,伍金林,罗黎力,等.c-Jun氨基末端激酶介导的FOXO3a核转位在缺氧缺血性脑损伤新生大鼠神经元凋亡中的作用.中国当代儿科杂志,2017,19:458-462.
10李德渊,屈艺,李晋辉,等.核转录因子FOXO3a在新生大鼠缺氧缺血性脑损伤神经元凋亡中的作用.中国当代儿科杂志,2013,15:1023-1027.
11陶斯恒.Fox O3α在阿尔兹海默模型大鼠脑中的分布.安徽师范大学,2013.
12陈永平,谢运兰,王衡,等.SIRT1在癫痫患者及大鼠脑组织中的表达与活性.南方医科大学学报,2013,33:528-532.
13马毓,巩莉,党辉,等.脑缺血再灌注后大鼠缺血侧脑组织中SIRT1的表达.贵州医科大学学报,2017,42:1028-1032.
14张杰,张晓岩,张先钧,等.西红花苷干预对急性低氧条件大鼠脑海马FOXO3α表达的影响.时珍国医国药,2017,28:2844-2846.
15慕雅婷,李艳,郭琼,等.远端同源异型盒2和叉头盒O3a在大鼠脑皮质发育过程中的分布与表达.解剖学报,2017,48:658-662.
16庞博,孙雪峰.白藜芦醇对丙泊酚所致大鼠神经元损伤的保护作用研究.海南医学院学报,2018,3:1-10.
17李传文,张嵘,侯亮,等.SIRT1/NF-κB通路参与白藜芦醇改善大鼠脑缺血再灌注损伤炎性反应.安徽医科大学学报,2018,53:6-9.
18 Castro V,Bertrand L,Luethen M,et al.Occludin controls hiv transcription in brain pericytes via regulation of sirt-1 activation.FASEB J,2016,30:1234-1246.
19刘俊宁,王庆莲,张燕,等.补气活血通络法对神经吻合术后大鼠神经及腓肠肌蛋白表达的影响.潍坊医学院学报,2017,39:251-254.
20 Yang F,Zhou L,Wang D,et al.Minocycline ameliorates hypoxiainduced blood-brain barrier damage by inhibition of hif-1alpha through sirt-3/phd-2 degradation pathway.Neuroscience,2015,30:250-259.