电针神庭、百会对脑卒中后认知障碍的临床及机制研究
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摘要
目的
1本课题临床研究部分旨在通过观察电针特定穴“神庭”和“百会”对脑卒中后认知障碍患者认知功能和日常生活能力的影响,以期进一步为电针治疗脑卒中后认知障碍临床标准化提供科学的临床和实践依据。
2通过建立局灶性脑缺血再灌注损伤大鼠模型,运用动物行为学、组织病理学、分子生物学等多种现代实验技术手段,探讨电针“神庭”和“百会”对脑缺血再灌注损伤大鼠认知能力的影响及其作用机制,为临床电针“神庭”和“百会”治疗脑卒中后认知功能障碍提供理论依据。
方法
1临床研究
将符合纳入标准的84例脑卒中后认知障碍患者随机分为电针组和常规治疗组,每组各42例。电针组穴位取神庭、百会,常规治疗组不给予电针治疗。两组病例入院后均行常规治疗,包括降颅压、改善脑循环、良肢位摆放、认知功能训练在内的康复训练等。电针组患者在常规治疗的基础上电针神庭、百会,每日治疗一次,每周进行6天治疗,休息一天,共治疗4周。在患者治疗前、治疗两周时、治疗结束时利用蒙特利尔认知功能评估量表(MoCA)、洛文斯顿认知评定成套测验(LOTCA)、改良Bathel旨数(BI)全面评价电针“神庭”和“百会”对脑卒中后患者神经心理学、认知功能及日常生活能力的影响。
2实验研究
将120只健康雄性SD大鼠随机分为假手术组,模型组和电针组,每组各40只。建立局灶性脑缺血再灌注损伤动物模型；电针神庭和百会进行干预处理,每天一次,共10天,每天电针结束后进行动物神经功能学评分,利用Morris水迷宫和跳台实验评估实验动物的学习、记忆功能；TTC染色观察电针对大鼠脑梗塞体积的影响；HE染色观察大鼠前脑皮质病理学的变化,TUNEL法检测前脑皮质中细胞凋亡的变化,采用激光共聚焦显微镜检测NF-KB-p65激活-核转运,Western Blot检测法观察缺血再灌注前脑皮质组织NF-κB-p65、p-IκB、IκB蛋白及其下游Fas、Bax蛋白的表达并且进行图像分析,RT-PCR技术检测其基因调控机制,并运用统计学分析动物行为学改变与基因调控、蛋白表达的关系。
结果
1临床观察结果
试验结束时统计脱落病例4例,其中电针组脱落2例,常规治疗组脱落2例。蒙特利尔认知功能评测(MoCA)、洛文斯顿认知评定成套测验(LOTCA)、改良Barthel指数(BI)结果均显示：两组患者治疗前上述评分差异均不具有统计学意义(P>0.05),两组患者治疗前基线资料具有可比性。电针组治疗2周后、4周后与治疗前相比,在蒙特利尔认知功能评测(MoCA)、洛文斯顿认知评定成套测验(LOTCA).及改良Barthel指数(BI)评分上,差异具有统计学意义(P<0.05),提示电针神庭、百会可以改善脑卒中后患者的认知功能及日常生活能力。电针组电针4周后在蒙特利尔认知功能评测(MoCA)、洛文斯顿认知评定成套测验(LOTCA)、改良Barthel指数(BI)与电针2周后比较,评分上明显提高,差异具有统计学意义(P<0.05),说明电针治疗具有时间依赖性,在一定范围内,疗效越长,效果越好。电针组与常规治疗组比较,治疗2周,电针组疗效较常规治疗组在蒙特利尔认知功能评测(MOCA)、洛文斯顿认知评定成套测验评定中定向、知觉、视运动上及日常生活能力评定有明显提高,差异具有统计学意义(P<0.05),但在洛文斯顿认知评定成套测验思维运作、注意和集中,两组差异不具有统计学意义(P>0.05)。电针治疗4周后电针组与常规治疗组相比在蒙特利尔认知功能评测(MoCA)、洛文斯顿认知评定成套测验各项评分(LOTCA)、改良Barthel指数(BI)评分上均有明显提高,差异具有统计学意义(P<0.05),说明患者注意和集中能力的改善滞后于其他认知能力。
2实验研究结果
(1)动物神经行为学及认知功能评测结果：从造模后第1天至动物处死(造模后第10天),造模后模型组和电针组动物的神经行为学症状都有损害,随着电针天数增加,电针组大鼠神经行为学损害症状好转,评分开始下降,与模型组相比,差异具有统计学意义(P<0.05)；电针后第4天开始进行水迷宫实验,随着电针天数的增加,动物在90秒内找到平台所经过的路程、找到平台逃避潜伏期均明显缩短,电针组与模型组相比,差异具有统计学意义(P<0.05),提示从电针后第4天开始,动物的学习能力开始改善。电针第9天撤去平台后测动物在90秒内经过平台的次数,发现电针组大鼠经过平台的次数明显多于模型组,差异具有统计学意义(P<0.05),说明电针干预9天可以改善模型大鼠的记忆能力；电针第9天开始进行跳台实验,发现动物在3分钟内受到电击次数,电针组明显少于模型组,差异具有统计学意义(P<0.05),24小时后测动物从平台跳下的平均潜伏期,电针组明显长于模型组,差异具有统计学意义(P<0.05),动物的被动学习、记忆能力在电针9天后也有明显改善。
(2)TTC染色结果显示：电针后第10天,电针组动物脑梗塞体积明显小于模型组,差异具有统计学意义(p<0.05),说明电针可以改善脑缺血再灌注损伤大鼠的脑梗塞体积。
(3)HE染色结果显示：模型组大鼠缺血脑组织中神经细胞数目稀少、排列疏松,存在广泛的神经细胞溶解,细胞结构模糊、变形,少数神经细胞染色加深,组织间质疏松。电针组损伤较模型组相比,细胞溶解较轻,排列致密,结构较为完整,假手术组则无病理改变,提示电针可以减轻模型大鼠缺血脑组织的病理损伤。
(4)Tunel结果显示：模型组大鼠凋亡阳性细胞比率(46.7±9.7%)明显高于假手术(1.2±0.3%),电针(18.9±4.5%)明显减少了大鼠凋亡细胞比率,差异具有统计学意义(P<0.05),说明电针可以抑制模型大鼠缺血脑组织中细胞凋亡。
(5)激光共聚焦显微镜观察NF-κB-p65激活核转位结果显示：模型组大鼠NF-κB-p65蛋白阳性细胞数目及核转位率均明显高于假手术组,电针明显减少了NF-κB-p65蛋白阳性细胞数目及核转位率,差异具有统计学意义(P<0.05),提示电针可以抑制NF-κB-p65蛋白的核转运。
(6)RT-PCR和Western blot观察大鼠前脑皮质组织NF-κB-p65/IκB/p-IκB/Fas/Bax转录及翻译水平结果显示：模型组大鼠脑缺血组织中NF-κB-p65/Fas/Bax mRNA扩增产物电泳条带光密度及蛋白表达条带光密度较假手术组明显升高,IκB mRNA扩增产物电泳条带光密度及蛋白表达条带光密度较假手术组明显降低,差异具有统计学意义(n=6,P<0.05)。与模型组相比,电针组大鼠前脑皮质组织中NF-κB-p65/Fas/Bax mRNA扩增产物电泳条带光密度及蛋白表达条带光密度明显降低,IκB mRNA扩增产物电泳条带光密度及蛋白表达条带光密度明显升高,差异具有统计学意义(n=6,P<0.05),模型组大鼠前脑皮质组织中P-IkB蛋白表达条带光密度较假手术组明显升高(n=6,P<0.05),说明电针通过抑制NF-KB信号通路活化从而抑制组织中细胞促凋亡基因的转录和翻译水平可能是其改善脑卒中后认知功能的作用机制之一。
结论
1电针神庭、百会可以改善患者的整体认知功能,同时提高患者的日常生活能力,但患者思维运作与注意集中能力的改善滞后于其它认知功能的改善,电针治疗效果与疗程有关,在一定时间阶段,疗程越长,效果越好。
2电针神庭、百会可以改善局灶性脑缺血再灌注损伤大鼠的认知功能,同时对缺血损伤组织具有神经保护作用,通过抑制NF-KB信号通路激活而拮抗细胞凋亡可能是其作用的机制之一。
Objective
1To study the effects of treating cognitive impairment after stroke by electroacupuncture at "Shenting" and "Baihui" in the cognitive function and activity of daily living, for the further promotion and application providing the scientific clinical and practice basis.
2Using a rat model with focal cerebral ischemia/reperfusion (I/R) injury, in the present study we evaluated the therapeutic efficacy of electroacupuncture against post-stroke cognitive impairment and explored the molecular mechanisms from the ethology/histopathology/molecular boilogy and other kinds of modern experiment technology, for providing the scientific theory basis.
Methods:
1Clinlal Research
There are84patients who matched the inclusion criteria were randomly divided into two groups with every42cases to the clinical observations, the therapeutic group who were used electroacupuncture treatment and the control group who were used foundation treatment only. The conventional therapy was given to patients in two groups, incluing the reducing intracranial pressure, improving the brain circulation, good limb position, cognitive function rehabilitation and so on. The electroacupuncture group was treated with electroacupuncture at "Shenting" and "Baihui" on the basis of the treatment for the control group, once a day,6days every week, total4weeks. Useing the Montreal cognitive function assessment scale (MoCA)、the Loewenste inoccupational therapy cognition assessment (LOTCA) and improved Bathel index (BI) to evaluate the effects of electroacupuncture at "Shenting" and "Baihui" on the neuropsychology/cognition function and the influence of daily living skills after stroke in the before treatment, treatment two weeks and at the end of the treatment.
2Experiments Researeh
120male SD rats were randomly diveded into the sham operation control group (SC), ischemia control group (IC) and electroacupuncture group (EA),40rats in each group. Using a rat model with focal cerebral ischemia/reperfusion (I/R) injury, in the present study we evaluated the therapeutic efficacy of electroacupuncture against post-stroke cognitive impairment with the Morris water maze and the step down test, TTC staining was used to observe the effect of the cerebral infarct volume, HE staining was used to observe the pathomorphism of the brain, Tunel staining was used to observe the effect of electroacupuncture on apoptotic cell induced by focal cerevbral ischemia in rats, NF-κB-p65activaton-nuclear transfer was observed by laser scanning confocal Microscopy, the activity of translation and transcription NF-κB-p65/IκB/p-IκB/Bax/Fas was also tested by western bloting and RT-PCR in the10d with electroacupuncture at "Shenting" and "Baihui" after MCAO. Then we analysis the relationship between the animal behavior changing and the gene/proterin regulation.
Results
1Clinical Result
At the end of the test, we found1patients withdrew in the EA group and3patients in the control group. There were not statistically significant (P>0.05) between the treatment group and the control group in the eassessmen of MoCA, LOCAT and BI index before treatment, the baseline of both groups were in order and the comparability was good. Significant differences in the eassessmen of MoCA, LOCAT and BI index were found between two groups electroacupuncture2weeks and4weeks (P<0.05, compaire with before treatment), which indicated electroacupuncture at "Baihui" and "Shenting" can significantly improve the cognitive function and the ability of daily living. Compaired with electroacupuncture2weeks, the socres of MoCA, LOCAT and BI index were also significance improved in electroacupuncture4weeks (P<0.05), which demonstrated, to some extent, the curative effect of electroacupuncture has a time-dependent. There was a significant difference in MoCA, the orientation/perception/the visual motion perception in LOCAT and BI between electroacupuncture group and the control group (P<0.05), however, there are no achieve statistical signigicance in the thinking operation/the attention and concentration in LOCAT (P>0.05) in electroacupuncture2weeks. There was a significant difference in MoCA/LOCAT and BI index between electroacupuncture group and the control group in electroacupuncture4weeks (P<0.05), which indicated the improvment of the attention lag behind from other cognitive functions.
2Experimental Result
(1) Result of neurological deficits and the cognitive impairment in cerebral I/R injured rats indicates that:The neuroprotective effect of electroacupuncture at "Shenting" and "Baihui" acupoints was evaluated by examining the neurological deficit scores. As expected, rats in sham operation group (SC) did not show any manifestation of neurological deficits, whereas all rats in both ischemia control (IC) and electroacupuncture (EA) groups displayed obvious signs of cerebral injury(P<0.05). To evaluate the effect of electroacupuncture on cognitive function, we performed Morris water maze test from the fourth to the ninth day after MCAO surgery. In the Morris water maze test the latency and route for IC group rats to reach the hidden platform markedly increased, whereas the times that rats crossed the location of the platform were significantly decreased in the9th day after MCAO(P<0.05versus SC group), indicating that cerebral I/R injury resulted in cognitive impairment. However, electroacupuncture significantly decreased the latency and route and increased the times of crossing the area which the platform located in Morris water maze test (P<0.05, versus IC group). Collectively, these data suggested that electroacupuncture at "Shenting" and "Baihui" could ameliorate cognitive impairment in cerebral I/R injured rats. Compaire with the ischemia control group, eletroacupuncture could reduce the times which the cerebral I/R injured rats was shocked by electric current (P<0.05) in3min and increase the average latency jumping from the safe plat in the step down test in the ninth and the tenth day (P<0.05).
(2) TTC staining shows that:Electroacupuncture treatment profoundly reduced cerebral infarct volumes in I/R injured rats (P<0.05, EA group versus IC group). Taken together, it was suggested that electroacupuncture at "Shenting" and "Baihui" acupoints had therapeutic efficacy against cerebral I/R injury.
(3) HE staining shows that:In the IC group, the number of the nerve cells detected, arranged loosely, lysis, the cellular structure fuzzy and deformation and has a few nerve cell dyeing deepen. However, in the EA group, the lysis was ligher and the tightly and the structure was relatively completely. There was no pathological changes in the sham group.
(4) TUNEL staining shows that:The percentage of TUNEL-positive cells in SC or IC group was1.2±0.3%or46.7±9.7%(P<0.05), indicating that I/R injury profoundly promoted cerebral cell apoptosis. However, electroacupuncture significantly inhibited I/R-induced apoptosis of neural cells as the percentage of TUNEL-positive cells in EA group was18.9±4.5%(P<0.05, versus IC group), suggesting that electroacupuncture at "Shenting" and "Baihui" inhibited ischemia-mediated cerebral cell apoptosis.
(5) Immunofluorescence staining to examine the nuclear translocation of NF-κB shows that:The cerebral I/R injury profoundly induced in the nuclear translocation of NF-κB p65 subunit, which however was inhibited by electro acupuncture.
(6) The activity of translation and transcription of NF-κB-p65/p-IκB/IκB/Bax/Fas by western bloting and RT-PCR in the10d after MCAO. To further investigate the mechanism of NF-κB signal pathway of activity of electroacupuncture, we examined the mRNA level and protein expression of NF-κB-p65/IκB/Bax/Fas in ischemic cerebral tissues using RT-PCR and Western Blotting, respectively. The results show:cerebral I/R injury remarkably enhanced NF-κB-p65/Bax/Fas expression at both transcriptional and translational levels and weakened the IκB/p-IκB expression, which, however, was significantly neutralized by electroacupuncture (n=6, P<0.05).
Conclusion
(1) Electroacupuncture at "Shenting" and "Baihui" can improve patient,s overall cognitive function and the activities of daily living, however, the improve of daily living lag in the cognitive function. Close relationships were found between the disease course and the curative, the sooner of the intervention, the more obvious of the improvment in the cognitive function and the daily living.
(2) Electroacupuncture at "Shenting" and "Baihui" can improve the cognitive function and has protective effect in cerebral ischemia-reperfusion injured rats. The inhibition of NF-κB-mediated neuronal cell apoptosis might be one of the mechanisms whereby electroacupuncture at "Shenting" and "Baihui" exerts therapeutic effect on post-stroke cognitive impairment.
1本课题临床研究部分旨在通过观察电针特定穴“神庭”和“百会”对脑卒中后认知障碍患者认知功能和日常生活能力的影响,以期进一步为电针治疗脑卒中后认知障碍临床标准化提供科学的临床和实践依据。
2通过建立局灶性脑缺血再灌注损伤大鼠模型,运用动物行为学、组织病理学、分子生物学等多种现代实验技术手段,探讨电针“神庭”和“百会”对脑缺血再灌注损伤大鼠认知能力的影响及其作用机制,为临床电针“神庭”和“百会”治疗脑卒中后认知功能障碍提供理论依据。
方法
1临床研究
将符合纳入标准的84例脑卒中后认知障碍患者随机分为电针组和常规治疗组,每组各42例。电针组穴位取神庭、百会,常规治疗组不给予电针治疗。两组病例入院后均行常规治疗,包括降颅压、改善脑循环、良肢位摆放、认知功能训练在内的康复训练等。电针组患者在常规治疗的基础上电针神庭、百会,每日治疗一次,每周进行6天治疗,休息一天,共治疗4周。在患者治疗前、治疗两周时、治疗结束时利用蒙特利尔认知功能评估量表(MoCA)、洛文斯顿认知评定成套测验(LOTCA)、改良Bathel旨数(BI)全面评价电针“神庭”和“百会”对脑卒中后患者神经心理学、认知功能及日常生活能力的影响。
2实验研究
将120只健康雄性SD大鼠随机分为假手术组,模型组和电针组,每组各40只。建立局灶性脑缺血再灌注损伤动物模型；电针神庭和百会进行干预处理,每天一次,共10天,每天电针结束后进行动物神经功能学评分,利用Morris水迷宫和跳台实验评估实验动物的学习、记忆功能；TTC染色观察电针对大鼠脑梗塞体积的影响；HE染色观察大鼠前脑皮质病理学的变化,TUNEL法检测前脑皮质中细胞凋亡的变化,采用激光共聚焦显微镜检测NF-KB-p65激活-核转运,Western Blot检测法观察缺血再灌注前脑皮质组织NF-κB-p65、p-IκB、IκB蛋白及其下游Fas、Bax蛋白的表达并且进行图像分析,RT-PCR技术检测其基因调控机制,并运用统计学分析动物行为学改变与基因调控、蛋白表达的关系。
结果
1临床观察结果
试验结束时统计脱落病例4例,其中电针组脱落2例,常规治疗组脱落2例。蒙特利尔认知功能评测(MoCA)、洛文斯顿认知评定成套测验(LOTCA)、改良Barthel指数(BI)结果均显示：两组患者治疗前上述评分差异均不具有统计学意义(P>0.05),两组患者治疗前基线资料具有可比性。电针组治疗2周后、4周后与治疗前相比,在蒙特利尔认知功能评测(MoCA)、洛文斯顿认知评定成套测验(LOTCA).及改良Barthel指数(BI)评分上,差异具有统计学意义(P<0.05),提示电针神庭、百会可以改善脑卒中后患者的认知功能及日常生活能力。电针组电针4周后在蒙特利尔认知功能评测(MoCA)、洛文斯顿认知评定成套测验(LOTCA)、改良Barthel指数(BI)与电针2周后比较,评分上明显提高,差异具有统计学意义(P<0.05),说明电针治疗具有时间依赖性,在一定范围内,疗效越长,效果越好。电针组与常规治疗组比较,治疗2周,电针组疗效较常规治疗组在蒙特利尔认知功能评测(MOCA)、洛文斯顿认知评定成套测验评定中定向、知觉、视运动上及日常生活能力评定有明显提高,差异具有统计学意义(P<0.05),但在洛文斯顿认知评定成套测验思维运作、注意和集中,两组差异不具有统计学意义(P>0.05)。电针治疗4周后电针组与常规治疗组相比在蒙特利尔认知功能评测(MoCA)、洛文斯顿认知评定成套测验各项评分(LOTCA)、改良Barthel指数(BI)评分上均有明显提高,差异具有统计学意义(P<0.05),说明患者注意和集中能力的改善滞后于其他认知能力。
2实验研究结果
(1)动物神经行为学及认知功能评测结果：从造模后第1天至动物处死(造模后第10天),造模后模型组和电针组动物的神经行为学症状都有损害,随着电针天数增加,电针组大鼠神经行为学损害症状好转,评分开始下降,与模型组相比,差异具有统计学意义(P<0.05)；电针后第4天开始进行水迷宫实验,随着电针天数的增加,动物在90秒内找到平台所经过的路程、找到平台逃避潜伏期均明显缩短,电针组与模型组相比,差异具有统计学意义(P<0.05),提示从电针后第4天开始,动物的学习能力开始改善。电针第9天撤去平台后测动物在90秒内经过平台的次数,发现电针组大鼠经过平台的次数明显多于模型组,差异具有统计学意义(P<0.05),说明电针干预9天可以改善模型大鼠的记忆能力；电针第9天开始进行跳台实验,发现动物在3分钟内受到电击次数,电针组明显少于模型组,差异具有统计学意义(P<0.05),24小时后测动物从平台跳下的平均潜伏期,电针组明显长于模型组,差异具有统计学意义(P<0.05),动物的被动学习、记忆能力在电针9天后也有明显改善。
(2)TTC染色结果显示：电针后第10天,电针组动物脑梗塞体积明显小于模型组,差异具有统计学意义(p<0.05),说明电针可以改善脑缺血再灌注损伤大鼠的脑梗塞体积。
(3)HE染色结果显示：模型组大鼠缺血脑组织中神经细胞数目稀少、排列疏松,存在广泛的神经细胞溶解,细胞结构模糊、变形,少数神经细胞染色加深,组织间质疏松。电针组损伤较模型组相比,细胞溶解较轻,排列致密,结构较为完整,假手术组则无病理改变,提示电针可以减轻模型大鼠缺血脑组织的病理损伤。
(4)Tunel结果显示：模型组大鼠凋亡阳性细胞比率(46.7±9.7%)明显高于假手术(1.2±0.3%),电针(18.9±4.5%)明显减少了大鼠凋亡细胞比率,差异具有统计学意义(P<0.05),说明电针可以抑制模型大鼠缺血脑组织中细胞凋亡。
(5)激光共聚焦显微镜观察NF-κB-p65激活核转位结果显示：模型组大鼠NF-κB-p65蛋白阳性细胞数目及核转位率均明显高于假手术组,电针明显减少了NF-κB-p65蛋白阳性细胞数目及核转位率,差异具有统计学意义(P<0.05),提示电针可以抑制NF-κB-p65蛋白的核转运。
(6)RT-PCR和Western blot观察大鼠前脑皮质组织NF-κB-p65/IκB/p-IκB/Fas/Bax转录及翻译水平结果显示：模型组大鼠脑缺血组织中NF-κB-p65/Fas/Bax mRNA扩增产物电泳条带光密度及蛋白表达条带光密度较假手术组明显升高,IκB mRNA扩增产物电泳条带光密度及蛋白表达条带光密度较假手术组明显降低,差异具有统计学意义(n=6,P<0.05)。与模型组相比,电针组大鼠前脑皮质组织中NF-κB-p65/Fas/Bax mRNA扩增产物电泳条带光密度及蛋白表达条带光密度明显降低,IκB mRNA扩增产物电泳条带光密度及蛋白表达条带光密度明显升高,差异具有统计学意义(n=6,P<0.05),模型组大鼠前脑皮质组织中P-IkB蛋白表达条带光密度较假手术组明显升高(n=6,P<0.05),说明电针通过抑制NF-KB信号通路活化从而抑制组织中细胞促凋亡基因的转录和翻译水平可能是其改善脑卒中后认知功能的作用机制之一。
结论
1电针神庭、百会可以改善患者的整体认知功能,同时提高患者的日常生活能力,但患者思维运作与注意集中能力的改善滞后于其它认知功能的改善,电针治疗效果与疗程有关,在一定时间阶段,疗程越长,效果越好。
2电针神庭、百会可以改善局灶性脑缺血再灌注损伤大鼠的认知功能,同时对缺血损伤组织具有神经保护作用,通过抑制NF-KB信号通路激活而拮抗细胞凋亡可能是其作用的机制之一。
Objective
1To study the effects of treating cognitive impairment after stroke by electroacupuncture at "Shenting" and "Baihui" in the cognitive function and activity of daily living, for the further promotion and application providing the scientific clinical and practice basis.
2Using a rat model with focal cerebral ischemia/reperfusion (I/R) injury, in the present study we evaluated the therapeutic efficacy of electroacupuncture against post-stroke cognitive impairment and explored the molecular mechanisms from the ethology/histopathology/molecular boilogy and other kinds of modern experiment technology, for providing the scientific theory basis.
Methods:
1Clinlal Research
There are84patients who matched the inclusion criteria were randomly divided into two groups with every42cases to the clinical observations, the therapeutic group who were used electroacupuncture treatment and the control group who were used foundation treatment only. The conventional therapy was given to patients in two groups, incluing the reducing intracranial pressure, improving the brain circulation, good limb position, cognitive function rehabilitation and so on. The electroacupuncture group was treated with electroacupuncture at "Shenting" and "Baihui" on the basis of the treatment for the control group, once a day,6days every week, total4weeks. Useing the Montreal cognitive function assessment scale (MoCA)、the Loewenste inoccupational therapy cognition assessment (LOTCA) and improved Bathel index (BI) to evaluate the effects of electroacupuncture at "Shenting" and "Baihui" on the neuropsychology/cognition function and the influence of daily living skills after stroke in the before treatment, treatment two weeks and at the end of the treatment.
2Experiments Researeh
120male SD rats were randomly diveded into the sham operation control group (SC), ischemia control group (IC) and electroacupuncture group (EA),40rats in each group. Using a rat model with focal cerebral ischemia/reperfusion (I/R) injury, in the present study we evaluated the therapeutic efficacy of electroacupuncture against post-stroke cognitive impairment with the Morris water maze and the step down test, TTC staining was used to observe the effect of the cerebral infarct volume, HE staining was used to observe the pathomorphism of the brain, Tunel staining was used to observe the effect of electroacupuncture on apoptotic cell induced by focal cerevbral ischemia in rats, NF-κB-p65activaton-nuclear transfer was observed by laser scanning confocal Microscopy, the activity of translation and transcription NF-κB-p65/IκB/p-IκB/Bax/Fas was also tested by western bloting and RT-PCR in the10d with electroacupuncture at "Shenting" and "Baihui" after MCAO. Then we analysis the relationship between the animal behavior changing and the gene/proterin regulation.
Results
1Clinical Result
At the end of the test, we found1patients withdrew in the EA group and3patients in the control group. There were not statistically significant (P>0.05) between the treatment group and the control group in the eassessmen of MoCA, LOCAT and BI index before treatment, the baseline of both groups were in order and the comparability was good. Significant differences in the eassessmen of MoCA, LOCAT and BI index were found between two groups electroacupuncture2weeks and4weeks (P<0.05, compaire with before treatment), which indicated electroacupuncture at "Baihui" and "Shenting" can significantly improve the cognitive function and the ability of daily living. Compaired with electroacupuncture2weeks, the socres of MoCA, LOCAT and BI index were also significance improved in electroacupuncture4weeks (P<0.05), which demonstrated, to some extent, the curative effect of electroacupuncture has a time-dependent. There was a significant difference in MoCA, the orientation/perception/the visual motion perception in LOCAT and BI between electroacupuncture group and the control group (P<0.05), however, there are no achieve statistical signigicance in the thinking operation/the attention and concentration in LOCAT (P>0.05) in electroacupuncture2weeks. There was a significant difference in MoCA/LOCAT and BI index between electroacupuncture group and the control group in electroacupuncture4weeks (P<0.05), which indicated the improvment of the attention lag behind from other cognitive functions.
2Experimental Result
(1) Result of neurological deficits and the cognitive impairment in cerebral I/R injured rats indicates that:The neuroprotective effect of electroacupuncture at "Shenting" and "Baihui" acupoints was evaluated by examining the neurological deficit scores. As expected, rats in sham operation group (SC) did not show any manifestation of neurological deficits, whereas all rats in both ischemia control (IC) and electroacupuncture (EA) groups displayed obvious signs of cerebral injury(P<0.05). To evaluate the effect of electroacupuncture on cognitive function, we performed Morris water maze test from the fourth to the ninth day after MCAO surgery. In the Morris water maze test the latency and route for IC group rats to reach the hidden platform markedly increased, whereas the times that rats crossed the location of the platform were significantly decreased in the9th day after MCAO(P<0.05versus SC group), indicating that cerebral I/R injury resulted in cognitive impairment. However, electroacupuncture significantly decreased the latency and route and increased the times of crossing the area which the platform located in Morris water maze test (P<0.05, versus IC group). Collectively, these data suggested that electroacupuncture at "Shenting" and "Baihui" could ameliorate cognitive impairment in cerebral I/R injured rats. Compaire with the ischemia control group, eletroacupuncture could reduce the times which the cerebral I/R injured rats was shocked by electric current (P<0.05) in3min and increase the average latency jumping from the safe plat in the step down test in the ninth and the tenth day (P<0.05).
(2) TTC staining shows that:Electroacupuncture treatment profoundly reduced cerebral infarct volumes in I/R injured rats (P<0.05, EA group versus IC group). Taken together, it was suggested that electroacupuncture at "Shenting" and "Baihui" acupoints had therapeutic efficacy against cerebral I/R injury.
(3) HE staining shows that:In the IC group, the number of the nerve cells detected, arranged loosely, lysis, the cellular structure fuzzy and deformation and has a few nerve cell dyeing deepen. However, in the EA group, the lysis was ligher and the tightly and the structure was relatively completely. There was no pathological changes in the sham group.
(4) TUNEL staining shows that:The percentage of TUNEL-positive cells in SC or IC group was1.2±0.3%or46.7±9.7%(P<0.05), indicating that I/R injury profoundly promoted cerebral cell apoptosis. However, electroacupuncture significantly inhibited I/R-induced apoptosis of neural cells as the percentage of TUNEL-positive cells in EA group was18.9±4.5%(P<0.05, versus IC group), suggesting that electroacupuncture at "Shenting" and "Baihui" inhibited ischemia-mediated cerebral cell apoptosis.
(5) Immunofluorescence staining to examine the nuclear translocation of NF-κB shows that:The cerebral I/R injury profoundly induced in the nuclear translocation of NF-κB p65 subunit, which however was inhibited by electro acupuncture.
(6) The activity of translation and transcription of NF-κB-p65/p-IκB/IκB/Bax/Fas by western bloting and RT-PCR in the10d after MCAO. To further investigate the mechanism of NF-κB signal pathway of activity of electroacupuncture, we examined the mRNA level and protein expression of NF-κB-p65/IκB/Bax/Fas in ischemic cerebral tissues using RT-PCR and Western Blotting, respectively. The results show:cerebral I/R injury remarkably enhanced NF-κB-p65/Bax/Fas expression at both transcriptional and translational levels and weakened the IκB/p-IκB expression, which, however, was significantly neutralized by electroacupuncture (n=6, P<0.05).
Conclusion
(1) Electroacupuncture at "Shenting" and "Baihui" can improve patient,s overall cognitive function and the activities of daily living, however, the improve of daily living lag in the cognitive function. Close relationships were found between the disease course and the curative, the sooner of the intervention, the more obvious of the improvment in the cognitive function and the daily living.
(2) Electroacupuncture at "Shenting" and "Baihui" can improve the cognitive function and has protective effect in cerebral ischemia-reperfusion injured rats. The inhibition of NF-κB-mediated neuronal cell apoptosis might be one of the mechanisms whereby electroacupuncture at "Shenting" and "Baihui" exerts therapeutic effect on post-stroke cognitive impairment.
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