两种频率电项针对AD模型大鼠空间学习记忆能力分子机制的影响
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摘要
目的：探讨两种频率电项针对阿尔茨海默病(Alzheimer's disease, AD)模型大鼠空间学习记忆能力分子机制的影响,以期更好地为电项针治疗AD提供客观的理论依据。
方法：20月龄、健康、清洁级、雄性SD大鼠适应性喂养1周,经Morris水迷宫实验淘汰掉先天愚钝鼠后,根据体重(320±50g)从小到大编号,随机分为空白组、假损伤组、模型组、2Hz治疗组和50Hz治疗组,每组10只。空白组仅给予正常饮食、饮水。假损伤组给予胃饲及腹腔注射与模型组等量的生理盐水。模型组与治疗组大鼠,每天给予20mg·ml-1的AlCl3水溶液2m1胃饲,48mg·kg-1的D-半乳糖腹腔注射,连续8周,余同空白组。
穴位与针具常规消毒,取大鼠项部双侧的“风池”、“供血”,用Φ0.40mm×25mm毫针,直刺10mm,接DJ-6805D型脉冲电针仪,一组导线同侧上下连接,正极连“风池”穴,负极连“供血”穴。治疗组根据频率分为2Hz治疗组和50Hz治疗组。针刺通电持续刺激20min,每天1次,每周休息1天,连续治疗4周。空白组、假损伤组、模型组不予治疗,但采取与治疗组同样时间的抓取、绑定。
以Morris水迷宫实验检测AD大鼠行为学变化；以光、电镜检测海马组织形态学、神经元超微结构；以免疫组化技术观察pCREB1、BDNF、TrkB、 Bcl-2、Bax及Caspase-3蛋白的阳性表达；以原位杂交技术观察pCREB1、 BDNFmRNA的阳性表达。应用motic image3.2软件对图像进行分析,并用SPSS17.0统计软件处理收据。
结果：
1.行为学：造模前各组大鼠的逃避潜伏期、穿越平台次数和靶象限游泳路程百分比无差异(P>0.05)；造模完成后模型组、2Hz治疗组及50Hz治疗组与空白组及假损伤组比较,逃避潜伏期、穿越平台次数和靶象限游泳路程百分比有明显差异(P<0.01)；治疗结束后：与空白组及假损伤组比较,模型组逃避潜伏期、穿越平台次数和靶象限游泳路程百分比有明显差异(P<0.01)；与模型组比较,2Hz治疗组的逃避潜伏期、穿越平台次数和靶象限游泳路程百分比有差异(P<0.05),而50Hz治疗组的有明显差异(P<0.01)；与2Hz治疗组比较,50Hz治疗组的逃避潜伏期、穿越平台次数和靶象限游泳路程百分比有差异(P<0.05)。
2.组织形态学：空白组细胞形态完整、染色均匀,核仁清晰。假损伤组存在少数炎性细胞。模型组细胞固缩,数目明显减少,排列极不规整,部分细胞核溶解固缩,核周出现大量空泡物质。2Hz治疗组有少量细胞形态固缩,染色均匀,排列欠规整。50Hz治疗组偶见细胞固缩,染色均匀,排列较规整,核仁明显,细胞质染色清晰。
3.神经元超微结构：空白组及假损伤组未见明显变化；模型组溶酶体及脂褐素增多,神经元内尼氏体分散,线粒体空化,突触小泡减少。2Hz治疗组较模型组略有改善,有脂褐素存在,突触小泡数目略有增加。50Hz治疗组较模型组改善明显,神经元形态尚可,尼氏体相对较少,突触小泡数目较多,部分线粒体空化。
4.免疫组化结果：(1)与空白组及假损伤组比较,模型组pCREB1、 BDNF、TrkB、Bcl-2、Bax、Caspase-3蛋白阳性细胞表达检测均有显著性差异(P<0.01)。(2)与模型组比较,2Hz治疗组pCREB1、BDNF、TrkB、 Bcl-2、Bax、Caspase-3蛋白阳性细胞表达有差异(P<0.05),50Hz治疗组pCREB1、BDNF、TrkB、Bcl-2、Bax、Caspase-3蛋白阳性细胞表达(P<0.01)。(3)与2Hz治疗组比较50Hz治疗组pCREB1、BDNF、TrkB、 Bcl-2、Bax、Caspase-3蛋白阳性细胞表达(P<0.05)。
5.原位杂交结果：(1)与空白组及假损伤组比较,模型组pCREB1mRNA、BDNFmRNA的阳性细胞表达有明显差异(P<0.01)；(2)与模型组比较,2Hz治疗组pCREB1mRNA、BDNFmRNA阳性细胞表达有明显差异(P<0.05),50Hz治疗组有明显差异(P<0.01)；(3)与2Hz治疗组比较,pCREB1mRNA和BDNFmRNA阳性细胞表达有差异(P<0.05)。
结论：
1.两种频率电项针均可缩短AD模型大鼠的平均逃避潜伏期,提高靶象限游泳路程百分比,增加其穿越平台次数,且50Hz治疗组疗效好于2Hz治疗组。
2.两种频率电项针均可改善AD模型大鼠海马神经细胞组织形态和超微结构,且50Hz治疗组疗效好于2Hz治疗组。
3.两种频率电项针均可增加pCREB1和BDNF蛋白及mRNA、以及TrkB蛋白阳性细胞的表达,从而提高对海马神经元的保护,且50Hz治疗组疗效好于2Hz治疗组。
4.两种频率电项针均可增加Bcl-2阳性细胞的表达,减少Bax和Caspase-3阳性细胞的表达,从而减少海马神经元的凋亡,且50Hz治疗组疗效好于2Hz治疗组。
5.电项针对AD模型大鼠的治疗作用与频率快慢有关,50Hz的疗效优于2Hz的疗效。
Objective:To explore the effect of the molecular mechanism of the spatial learning and memory ability for the rats model of Alzheimer's disease (AD)with two kinds of frequency of electro-nape-acupuncture, in order to better provide objective theoretical basis for the treatment of AD with this therapy method.
Methods:20months of age, clean grade and male Sprague-Dawley (SD) rats feeding adaptation of one week, eliminateding the congenital dull rats by Morris water maze, were randomly divided into blank normal group, sham injury group, model group,2Hz and50Hz groups(n=10) based on body weight(320±50) from small to large numbers. Blank group rats were given a normal diet, drinking water. Sham group rats were given Normal saline with stomach feeding and intraperitoneal injection as the same with the model group. Model group and treatment group rats were given20mg/ml of AICl3solution2ml with stomach feeding and48mg/Kg of D-galactose with intraperitoneal injection every day, lasting8weeks, and feeding as same as blank group.
After routine disinfection, take bilateral "Fengchi" and "Gongxue" as acupoints of the rats,with of Φ0.40X25mm acupuncture needles, piercing10mm, then connected with the pulse electro-acupuncture apparatus (DJ-6805D), ipsilateral upper and lower set of wires connected to the acupoints,which positive connected "Fengchi" and negative connected "Gongxue". The treatment group was divided according to the frequency2Hz and50Hz, energized stimulating contine20min, once a day, resting one day after6times. The therapy time was four weeks. Blank group, sham groupand model group were without treatment, but taking ahold and binding as the same time as the treatment group.
Morris water maze test was used to the behavior changes of AD rats. HE staining and Electron microscope were used to look into the changes of histomorphology. Took Immunohisto chemistry and Insitu hybridization to detect the expression of pCREB1(mRNA), BDNF(mRNA), TrkB, Bcl-2/Bax, Caspase-3. The images were analyzed by the software of Motic image3.2, and the receipt were dealed with the SPSS17.0statistical software.
Results:
1. Behavior changes:Before modeling of rats in each group, the escape latency, the percentage of target quadrant swimming distance and the number of crossing the platform were difference (P>0.05). Compared with the blank and sham groups after the completion of the modeling, the escape latency, the percentage of target quadrant swimming distance and the number of crossing the platform of the model group,2Hz group and50Hz group were significant differences(P<0.01). After the end of treatment, compared with the blank and sham group, the behavioral indices of the model were significant differences (P<0.01); compared with the model group, the behavioral indices of2Hz group were difference(P<0.05), the50Hz group were significantly difference(P<0.01), compared with the2Hz group, the behavioral indices of50Hz group were difference (P<0.05).
2. Tissue morphology:Compared with the blank group, the sham group changed little; the model group improved significantly. Compared with the model group, the degree of injury of the2Hz group were light, the50Hz group were lighter.
3. Neuronal ultrastructure:there were no significant change between blank group and sham group. Lysosomes and lipofuscin of neurons increased, neuronal tigroid body, dispersion, mitochondrial cavitation, reduced synaptic vesicles.
4The results of immunohistochemistry:(1) Compared with blank group and sham group, there were significant differences detected the positive cells expression of pCREB1, BDNF, TrkB, Bcl-2, Bax, Caspase-3protein of model group(P<0.01).(2) Compared with the model group, the positive cells expression of pCREB1, BDNF, TrkB, Bcl-2, Bax, Caspase-3protein of2Hz group were differences (P<0.05), and of50Hz group were significantly differences(P<0.01).(3) Compared with the2Hz group, the positive cells expression of pCREB1, BDNF, TrkB, Bcl-2, Bax, Caspase-3protein of50Hz group were differences (P<0.05).
5The results of in situ hybridization:(1) Compared with control group and sham group, the positive cells expression of pCREB1mRNA and BDNFmRNA of model group had significant difference(P<0.01).(2) Compared with the model group, the positive cells expression of pCREB1mRNA and BDNFmRNA of2Hz group had difference (P<0.05), and50Hz group were significantly differences(P<0.01).(3) Compared with2Hz group, the positive cells expression of pCREBlmRNA and BDNFmRNA of50Hz group were differences (P<0.05).
Conclusion:
1. Two frequency of electro-nape-acupuncture can shorten the average escape latency, improved the times of crossing platform and the percentage of the target quadrant swimming path of the rats model of AD, and the effect of50Hz group was better than2Hz group.
2. Two frequency of electro-nape-acupuncture can improve the morphology of hippocampal neural cells and ultrastructure of the rats model of AD, and the effect of50Hz group was better than2Hz group.
3. Two frequency of electro-nape-acupuncture can increase the positive cells expression of the mRNA of pCREB1and BDNF, and of the protein of pCREB1, BDNF and TrkB of the rats model of AD, in order to improve the protection of hippocampal meuros, and the effect of50Hz group was better than2Hz group.
4Two frequency of electro-nape-acupuncture can increase the positive cells expression of the protein of Bcl-2and reduce the positive cells expression of the protein of Bax and Caspase-3to reduce the apoptosis of hippocampal neurons, and the effect of50Hz group was better than2Hz group.
5. The frequency's speed of the electro-nape-acupuncture determined the therapeutic effect to the rats of AD, and the effect of50Hz group was better than2Hz group.
方法：20月龄、健康、清洁级、雄性SD大鼠适应性喂养1周,经Morris水迷宫实验淘汰掉先天愚钝鼠后,根据体重(320±50g)从小到大编号,随机分为空白组、假损伤组、模型组、2Hz治疗组和50Hz治疗组,每组10只。空白组仅给予正常饮食、饮水。假损伤组给予胃饲及腹腔注射与模型组等量的生理盐水。模型组与治疗组大鼠,每天给予20mg·ml-1的AlCl3水溶液2m1胃饲,48mg·kg-1的D-半乳糖腹腔注射,连续8周,余同空白组。
穴位与针具常规消毒,取大鼠项部双侧的“风池”、“供血”,用Φ0.40mm×25mm毫针,直刺10mm,接DJ-6805D型脉冲电针仪,一组导线同侧上下连接,正极连“风池”穴,负极连“供血”穴。治疗组根据频率分为2Hz治疗组和50Hz治疗组。针刺通电持续刺激20min,每天1次,每周休息1天,连续治疗4周。空白组、假损伤组、模型组不予治疗,但采取与治疗组同样时间的抓取、绑定。
以Morris水迷宫实验检测AD大鼠行为学变化；以光、电镜检测海马组织形态学、神经元超微结构；以免疫组化技术观察pCREB1、BDNF、TrkB、 Bcl-2、Bax及Caspase-3蛋白的阳性表达；以原位杂交技术观察pCREB1、 BDNFmRNA的阳性表达。应用motic image3.2软件对图像进行分析,并用SPSS17.0统计软件处理收据。
结果：
1.行为学：造模前各组大鼠的逃避潜伏期、穿越平台次数和靶象限游泳路程百分比无差异(P>0.05)；造模完成后模型组、2Hz治疗组及50Hz治疗组与空白组及假损伤组比较,逃避潜伏期、穿越平台次数和靶象限游泳路程百分比有明显差异(P<0.01)；治疗结束后：与空白组及假损伤组比较,模型组逃避潜伏期、穿越平台次数和靶象限游泳路程百分比有明显差异(P<0.01)；与模型组比较,2Hz治疗组的逃避潜伏期、穿越平台次数和靶象限游泳路程百分比有差异(P<0.05),而50Hz治疗组的有明显差异(P<0.01)；与2Hz治疗组比较,50Hz治疗组的逃避潜伏期、穿越平台次数和靶象限游泳路程百分比有差异(P<0.05)。
2.组织形态学：空白组细胞形态完整、染色均匀,核仁清晰。假损伤组存在少数炎性细胞。模型组细胞固缩,数目明显减少,排列极不规整,部分细胞核溶解固缩,核周出现大量空泡物质。2Hz治疗组有少量细胞形态固缩,染色均匀,排列欠规整。50Hz治疗组偶见细胞固缩,染色均匀,排列较规整,核仁明显,细胞质染色清晰。
3.神经元超微结构：空白组及假损伤组未见明显变化；模型组溶酶体及脂褐素增多,神经元内尼氏体分散,线粒体空化,突触小泡减少。2Hz治疗组较模型组略有改善,有脂褐素存在,突触小泡数目略有增加。50Hz治疗组较模型组改善明显,神经元形态尚可,尼氏体相对较少,突触小泡数目较多,部分线粒体空化。
4.免疫组化结果：(1)与空白组及假损伤组比较,模型组pCREB1、 BDNF、TrkB、Bcl-2、Bax、Caspase-3蛋白阳性细胞表达检测均有显著性差异(P<0.01)。(2)与模型组比较,2Hz治疗组pCREB1、BDNF、TrkB、 Bcl-2、Bax、Caspase-3蛋白阳性细胞表达有差异(P<0.05),50Hz治疗组pCREB1、BDNF、TrkB、Bcl-2、Bax、Caspase-3蛋白阳性细胞表达(P<0.01)。(3)与2Hz治疗组比较50Hz治疗组pCREB1、BDNF、TrkB、 Bcl-2、Bax、Caspase-3蛋白阳性细胞表达(P<0.05)。
5.原位杂交结果：(1)与空白组及假损伤组比较,模型组pCREB1mRNA、BDNFmRNA的阳性细胞表达有明显差异(P<0.01)；(2)与模型组比较,2Hz治疗组pCREB1mRNA、BDNFmRNA阳性细胞表达有明显差异(P<0.05),50Hz治疗组有明显差异(P<0.01)；(3)与2Hz治疗组比较,pCREB1mRNA和BDNFmRNA阳性细胞表达有差异(P<0.05)。
结论：
1.两种频率电项针均可缩短AD模型大鼠的平均逃避潜伏期,提高靶象限游泳路程百分比,增加其穿越平台次数,且50Hz治疗组疗效好于2Hz治疗组。
2.两种频率电项针均可改善AD模型大鼠海马神经细胞组织形态和超微结构,且50Hz治疗组疗效好于2Hz治疗组。
3.两种频率电项针均可增加pCREB1和BDNF蛋白及mRNA、以及TrkB蛋白阳性细胞的表达,从而提高对海马神经元的保护,且50Hz治疗组疗效好于2Hz治疗组。
4.两种频率电项针均可增加Bcl-2阳性细胞的表达,减少Bax和Caspase-3阳性细胞的表达,从而减少海马神经元的凋亡,且50Hz治疗组疗效好于2Hz治疗组。
5.电项针对AD模型大鼠的治疗作用与频率快慢有关,50Hz的疗效优于2Hz的疗效。
Objective:To explore the effect of the molecular mechanism of the spatial learning and memory ability for the rats model of Alzheimer's disease (AD)with two kinds of frequency of electro-nape-acupuncture, in order to better provide objective theoretical basis for the treatment of AD with this therapy method.
Methods:20months of age, clean grade and male Sprague-Dawley (SD) rats feeding adaptation of one week, eliminateding the congenital dull rats by Morris water maze, were randomly divided into blank normal group, sham injury group, model group,2Hz and50Hz groups(n=10) based on body weight(320±50) from small to large numbers. Blank group rats were given a normal diet, drinking water. Sham group rats were given Normal saline with stomach feeding and intraperitoneal injection as the same with the model group. Model group and treatment group rats were given20mg/ml of AICl3solution2ml with stomach feeding and48mg/Kg of D-galactose with intraperitoneal injection every day, lasting8weeks, and feeding as same as blank group.
After routine disinfection, take bilateral "Fengchi" and "Gongxue" as acupoints of the rats,with of Φ0.40X25mm acupuncture needles, piercing10mm, then connected with the pulse electro-acupuncture apparatus (DJ-6805D), ipsilateral upper and lower set of wires connected to the acupoints,which positive connected "Fengchi" and negative connected "Gongxue". The treatment group was divided according to the frequency2Hz and50Hz, energized stimulating contine20min, once a day, resting one day after6times. The therapy time was four weeks. Blank group, sham groupand model group were without treatment, but taking ahold and binding as the same time as the treatment group.
Morris water maze test was used to the behavior changes of AD rats. HE staining and Electron microscope were used to look into the changes of histomorphology. Took Immunohisto chemistry and Insitu hybridization to detect the expression of pCREB1(mRNA), BDNF(mRNA), TrkB, Bcl-2/Bax, Caspase-3. The images were analyzed by the software of Motic image3.2, and the receipt were dealed with the SPSS17.0statistical software.
Results:
1. Behavior changes:Before modeling of rats in each group, the escape latency, the percentage of target quadrant swimming distance and the number of crossing the platform were difference (P>0.05). Compared with the blank and sham groups after the completion of the modeling, the escape latency, the percentage of target quadrant swimming distance and the number of crossing the platform of the model group,2Hz group and50Hz group were significant differences(P<0.01). After the end of treatment, compared with the blank and sham group, the behavioral indices of the model were significant differences (P<0.01); compared with the model group, the behavioral indices of2Hz group were difference(P<0.05), the50Hz group were significantly difference(P<0.01), compared with the2Hz group, the behavioral indices of50Hz group were difference (P<0.05).
2. Tissue morphology:Compared with the blank group, the sham group changed little; the model group improved significantly. Compared with the model group, the degree of injury of the2Hz group were light, the50Hz group were lighter.
3. Neuronal ultrastructure:there were no significant change between blank group and sham group. Lysosomes and lipofuscin of neurons increased, neuronal tigroid body, dispersion, mitochondrial cavitation, reduced synaptic vesicles.
4The results of immunohistochemistry:(1) Compared with blank group and sham group, there were significant differences detected the positive cells expression of pCREB1, BDNF, TrkB, Bcl-2, Bax, Caspase-3protein of model group(P<0.01).(2) Compared with the model group, the positive cells expression of pCREB1, BDNF, TrkB, Bcl-2, Bax, Caspase-3protein of2Hz group were differences (P<0.05), and of50Hz group were significantly differences(P<0.01).(3) Compared with the2Hz group, the positive cells expression of pCREB1, BDNF, TrkB, Bcl-2, Bax, Caspase-3protein of50Hz group were differences (P<0.05).
5The results of in situ hybridization:(1) Compared with control group and sham group, the positive cells expression of pCREB1mRNA and BDNFmRNA of model group had significant difference(P<0.01).(2) Compared with the model group, the positive cells expression of pCREB1mRNA and BDNFmRNA of2Hz group had difference (P<0.05), and50Hz group were significantly differences(P<0.01).(3) Compared with2Hz group, the positive cells expression of pCREBlmRNA and BDNFmRNA of50Hz group were differences (P<0.05).
Conclusion:
1. Two frequency of electro-nape-acupuncture can shorten the average escape latency, improved the times of crossing platform and the percentage of the target quadrant swimming path of the rats model of AD, and the effect of50Hz group was better than2Hz group.
2. Two frequency of electro-nape-acupuncture can improve the morphology of hippocampal neural cells and ultrastructure of the rats model of AD, and the effect of50Hz group was better than2Hz group.
3. Two frequency of electro-nape-acupuncture can increase the positive cells expression of the mRNA of pCREB1and BDNF, and of the protein of pCREB1, BDNF and TrkB of the rats model of AD, in order to improve the protection of hippocampal meuros, and the effect of50Hz group was better than2Hz group.
4Two frequency of electro-nape-acupuncture can increase the positive cells expression of the protein of Bcl-2and reduce the positive cells expression of the protein of Bax and Caspase-3to reduce the apoptosis of hippocampal neurons, and the effect of50Hz group was better than2Hz group.
5. The frequency's speed of the electro-nape-acupuncture determined the therapeutic effect to the rats of AD, and the effect of50Hz group was better than2Hz group.
引文
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