PDTC对慢性MPTP帕金森病小鼠模型黑质Bcl-xL表达的影响
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摘要
目的
(1)探讨慢性MPTP帕金森病模型小鼠黑质DA神经元减少与NF-κB通路依赖的凋亡蛋白Bcl-xL表达之间的关系。
(2)探索NF-κB通路抑制剂(PDTC)在PD预防中的作用。
方法
本研究采用慢性MPTP帕金森病小鼠(C57/BL)模型,随机将小鼠分成正常组,实验组,预防组,每组40只,均在同等条件下饲养。实验组用小鼠MPTP 25mg/kg腹腔注射,一周两次,持续5周;正常组腹腔注射与实验组等量的0.9%生理盐水;预防组先腹腔注射PDTC 40mg/kg,半小时后注射MPTP25mg/kg。注射完毕后,在不同时间点,观察各组小鼠的行为学、形态学情况;采用免疫组织化学法检测酪氨酸羟化酶和Bcl-xL的表达;采用逆转录聚合酶链式反应方法检测黑质Bcl-xL mRNA表达情况。分析:①神经毒素1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)诱导的慢性帕金森病(Parkinson's disease,PD)模型小鼠,黑质Bcl-xL表达及时间依赖性关系,了解NF-κB通路对DA神经元凋亡的调控作用;Bcl-xL表达与黑质DA神经元减少以及与小鼠行为学反应的一致性关系。②NF-κB(Nuclear factor-kappaB)通路抑制剂-二硫代氨基甲酸毗咯烷(pyrrolidine dithiocarbamate, PDTC)对Bcl-xL表达及黑质多巴胺神经元数目的影响。
结果
(1)行为学观察结果:与对照组比较,实验组小鼠出现震颤、竖毛、流涎、活动减少、动作缓慢等异常行为,爬杆时间明显延长(P<0.05),预防组出现部分症状,较实验组明显减轻。
(2)形态学改变:HE染色法染色后,与对照组相比,实验组黑质区多巴胺能神经元细胞数量明显减少(P<0.05),而预防组神经元减少没有实验组明显(P<0.05),但仍未达到对照组水平(P<0.05)。
(3)SABC免疫组化法结果:处理完毕后,在12h～24h时,实验组黑质区Bcl-xL蛋白较对照组表达增高,与其平均光密度(MOD)差别有统计学意义(P<0.05);1w～2w时,Bcl-xL表达较24h减少(P<0.05)。实验组较对照组TH阳性细胞减少(P<0.05) ,且在12h～24h时,TH阳性细胞较1w～2w增加(P<0.05)。预防组结果与实验组恰恰相反。
(4)RT-PCR结果:在12h时,实验组中脑黑质Bcl-xL mRNA表达较对照组增加(P<0.05),在24h时表达达到高峰,1w～2w时,其表达较对照组减少(P<0.05)。预防组与实验组出现相反结果。
结论
(1)实验结果显示:慢性MPTP帕金森病C57BL小鼠模型中,NF-κB通路介导的Bcl-xL表达参与了对DA神经元凋亡的调控。
(2)实验结果表明:NF-κB通路对Bcl-xL的调控表现为双向性,且这种作用具有时间依赖性,但最终导致DA神经元减少。
(3)NF-κB通路抑制剂(PDTC)在PD预防中有作用。
Objective
(1) To investigate the relationship of reduction of DA neurons in substantia nigra and Bcl-xL expression in a NF-κB pathway-dependent manner in the chronic Parkinson disease mouse model by MPTP.
(2) To explore the role of nuclear factor kappa-B inhibitor—pyrrolidine dithiocarbamate(PDTC) in the prevention of Parkinson disease..
Methods
This study adopted chronic parkinsonism C57BL/6J mice after the administration of MPTP,which were randomly divided into three groups:control group,test group,prevention group,40 mice in each group.All mice mice were bred at the same condition.MPTP was administered intraperitoneally to test group with the dose of 25mg/kg for 5 weeks,2 times per week, control group was injected with the same volume of saline.prevention group were given intraperitoneal injection of PDTC with the dose of 40mg/kg first,and next were given intraperitoneal injection of MPTP in half an hour;after treatment,The changes of ethology and Morphological were determined in mice of three groups at different time,The expression of Bcl-xL was determined by RT-PCR and immunohistochemistry.The expression of tyrosine hydroxylas (TH) were analyzed immunohistochemically.What was analyzed①The expression of Bcl-xL and the time-dependent correlation induced by MPTP injection;The consistent relationship between the expression of Bcl-xL and decrease in number of dopaminergic neurons and behavioral response in chronic mouse model of Parkinson disease induced by MPTP.②The effects of nuclear factor-kappa B (NF-κB) inhibitor-pyrrolidine dithiocarbamate(PDTC) on expression of Bcl-xL and the number of nigral neurona.
Results
(1)Behavior observation results:compared with control group,the test group manifested abnormal behaviors such as trembling,dribble at the mouth,pilo-erection,motor disorders,and the time of pole climbing in test group was are increasing significantly(p<0.05).Contrasting to the test group,but Symptom of the prevention group was not apparent.
(2)Morphologic examination change:after HE staining, compared with the control group,the number of TH positive neurons in SNc was decreasing significantly in the test group,and there was no difference between the prevention group and controls (p > 0.05).
(3)Results of the immunohistochemistry SABC:The integral optical density (IOD) of test group at 12h and 24h were more than that of the control,which indicates that the Bcl-xL expression of test group was increasing.1w～2w,the Bcl-xL expression of test group decreased.At the corresponding time after the last MPTP injection, as compared with the control group,the TH-positive cells of test group decreased (P <0.05).At the 12h~24h in the test group, TH-positive cells were more than these of 1w~2w (P <0.05). Prevention group results contrasted with the test group.
(4)The result of Bcl-xL mRNA by RT-PCR method:In comparison with the control group, The expression of Bcl-xL mRNA at 12h in the test group was obviously increasing(p<0.05),and its levels peaked at 24h;1w～2w,The expression of Bcl-xL mRNA was down-regulated(P<0.05),Prevention group received the opposite conclusion with the test group.
Conclusion
(1)These experiments suggested that expression of Bcl-xL played an important role in chronic mouse model of Parkinson disease induced by MPTP,which was regulated by NF-κB Signaling Pathway.
(2)The results of this experiment implied that there was dual effects of NF-κB pathway on that expression of Bcl-xL,and this effect was time-dependent, but in the end leading to DA neuronal loss.
(3) There was a significance in the prevention of Parkinson disease for nuclear factor kappa-B inhibitor—pyrrolidine dithiocarbamate(PDTC).
(1)探讨慢性MPTP帕金森病模型小鼠黑质DA神经元减少与NF-κB通路依赖的凋亡蛋白Bcl-xL表达之间的关系。
(2)探索NF-κB通路抑制剂(PDTC)在PD预防中的作用。
方法
本研究采用慢性MPTP帕金森病小鼠(C57/BL)模型,随机将小鼠分成正常组,实验组,预防组,每组40只,均在同等条件下饲养。实验组用小鼠MPTP 25mg/kg腹腔注射,一周两次,持续5周;正常组腹腔注射与实验组等量的0.9%生理盐水;预防组先腹腔注射PDTC 40mg/kg,半小时后注射MPTP25mg/kg。注射完毕后,在不同时间点,观察各组小鼠的行为学、形态学情况;采用免疫组织化学法检测酪氨酸羟化酶和Bcl-xL的表达;采用逆转录聚合酶链式反应方法检测黑质Bcl-xL mRNA表达情况。分析:①神经毒素1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)诱导的慢性帕金森病(Parkinson's disease,PD)模型小鼠,黑质Bcl-xL表达及时间依赖性关系,了解NF-κB通路对DA神经元凋亡的调控作用;Bcl-xL表达与黑质DA神经元减少以及与小鼠行为学反应的一致性关系。②NF-κB(Nuclear factor-kappaB)通路抑制剂-二硫代氨基甲酸毗咯烷(pyrrolidine dithiocarbamate, PDTC)对Bcl-xL表达及黑质多巴胺神经元数目的影响。
结果
(1)行为学观察结果:与对照组比较,实验组小鼠出现震颤、竖毛、流涎、活动减少、动作缓慢等异常行为,爬杆时间明显延长(P<0.05),预防组出现部分症状,较实验组明显减轻。
(2)形态学改变:HE染色法染色后,与对照组相比,实验组黑质区多巴胺能神经元细胞数量明显减少(P<0.05),而预防组神经元减少没有实验组明显(P<0.05),但仍未达到对照组水平(P<0.05)。
(3)SABC免疫组化法结果:处理完毕后,在12h～24h时,实验组黑质区Bcl-xL蛋白较对照组表达增高,与其平均光密度(MOD)差别有统计学意义(P<0.05);1w～2w时,Bcl-xL表达较24h减少(P<0.05)。实验组较对照组TH阳性细胞减少(P<0.05) ,且在12h～24h时,TH阳性细胞较1w～2w增加(P<0.05)。预防组结果与实验组恰恰相反。
(4)RT-PCR结果:在12h时,实验组中脑黑质Bcl-xL mRNA表达较对照组增加(P<0.05),在24h时表达达到高峰,1w～2w时,其表达较对照组减少(P<0.05)。预防组与实验组出现相反结果。
结论
(1)实验结果显示:慢性MPTP帕金森病C57BL小鼠模型中,NF-κB通路介导的Bcl-xL表达参与了对DA神经元凋亡的调控。
(2)实验结果表明:NF-κB通路对Bcl-xL的调控表现为双向性,且这种作用具有时间依赖性,但最终导致DA神经元减少。
(3)NF-κB通路抑制剂(PDTC)在PD预防中有作用。
Objective
(1) To investigate the relationship of reduction of DA neurons in substantia nigra and Bcl-xL expression in a NF-κB pathway-dependent manner in the chronic Parkinson disease mouse model by MPTP.
(2) To explore the role of nuclear factor kappa-B inhibitor—pyrrolidine dithiocarbamate(PDTC) in the prevention of Parkinson disease..
Methods
This study adopted chronic parkinsonism C57BL/6J mice after the administration of MPTP,which were randomly divided into three groups:control group,test group,prevention group,40 mice in each group.All mice mice were bred at the same condition.MPTP was administered intraperitoneally to test group with the dose of 25mg/kg for 5 weeks,2 times per week, control group was injected with the same volume of saline.prevention group were given intraperitoneal injection of PDTC with the dose of 40mg/kg first,and next were given intraperitoneal injection of MPTP in half an hour;after treatment,The changes of ethology and Morphological were determined in mice of three groups at different time,The expression of Bcl-xL was determined by RT-PCR and immunohistochemistry.The expression of tyrosine hydroxylas (TH) were analyzed immunohistochemically.What was analyzed①The expression of Bcl-xL and the time-dependent correlation induced by MPTP injection;The consistent relationship between the expression of Bcl-xL and decrease in number of dopaminergic neurons and behavioral response in chronic mouse model of Parkinson disease induced by MPTP.②The effects of nuclear factor-kappa B (NF-κB) inhibitor-pyrrolidine dithiocarbamate(PDTC) on expression of Bcl-xL and the number of nigral neurona.
Results
(1)Behavior observation results:compared with control group,the test group manifested abnormal behaviors such as trembling,dribble at the mouth,pilo-erection,motor disorders,and the time of pole climbing in test group was are increasing significantly(p<0.05).Contrasting to the test group,but Symptom of the prevention group was not apparent.
(2)Morphologic examination change:after HE staining, compared with the control group,the number of TH positive neurons in SNc was decreasing significantly in the test group,and there was no difference between the prevention group and controls (p > 0.05).
(3)Results of the immunohistochemistry SABC:The integral optical density (IOD) of test group at 12h and 24h were more than that of the control,which indicates that the Bcl-xL expression of test group was increasing.1w～2w,the Bcl-xL expression of test group decreased.At the corresponding time after the last MPTP injection, as compared with the control group,the TH-positive cells of test group decreased (P <0.05).At the 12h~24h in the test group, TH-positive cells were more than these of 1w~2w (P <0.05). Prevention group results contrasted with the test group.
(4)The result of Bcl-xL mRNA by RT-PCR method:In comparison with the control group, The expression of Bcl-xL mRNA at 12h in the test group was obviously increasing(p<0.05),and its levels peaked at 24h;1w～2w,The expression of Bcl-xL mRNA was down-regulated(P<0.05),Prevention group received the opposite conclusion with the test group.
Conclusion
(1)These experiments suggested that expression of Bcl-xL played an important role in chronic mouse model of Parkinson disease induced by MPTP,which was regulated by NF-κB Signaling Pathway.
(2)The results of this experiment implied that there was dual effects of NF-κB pathway on that expression of Bcl-xL,and this effect was time-dependent, but in the end leading to DA neuronal loss.
(3) There was a significance in the prevention of Parkinson disease for nuclear factor kappa-B inhibitor—pyrrolidine dithiocarbamate(PDTC).
引文
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