寿尔智胶囊对阿尔茨海默病模型大鼠神经元突触损伤的保护作用及机制研究
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摘要
背景和目的
阿尔茨海默病(Alzheimer Disease, AD)是一种原因不明的进行性变性疾病,以记忆和其他认知功能衰退直至发展为严重痴呆为特征。研究发现：阿尔茨海默病患者的大脑内不但存在有突触数目减少、结构异常、而且包括功能蛋白(突触后致密区蛋白PSD-95)以及对突触存活起重要作用的神经生长因子NGF及其受体TrKA、细胞外调节蛋白激酶ERK都有不同程度的表达异常。迄今为止,尚无对突触保护特别有效的治疗和预防药物。因此,加强对AD突触的保护研究具有一定的理论意义。祖国医学认为中药的干预对阿尔茨海默病的治疗是有效的；根据补肾健脑,活血祛瘀,化痰开窍的治法组方的寿尔智胶囊,用于治疗阿尔茨海默病取得了确切的疗效。前期的研究显示寿尔智胶囊在对AD模型小鼠学习和记忆的改善中有多方面的作用机理,但对其在突触保护方面有无作用未有研究。本研究通过经脑立体定位仪向SD大鼠海马区注射凝聚态Aβ25-35,建立阿尔茨海默病大鼠模型,应用具有补肾健脑,活血祛瘀,化痰开窍作用的中药寿尔智胶囊进行治疗,观察寿尔智胶囊对阿尔茨海默病模型大鼠行为学、海马突触超微结构、海马突触后致密区蛋白PSD-95、神经生长因子NGF及其受体TrKA、细胞外调节蛋白激酶ERK1、ERK2基因及蛋白的表达以及寿尔智胶囊对它们的影响,探讨突触损伤与AD的发病两者之间的关系以及寿尔智胶囊在突触保护方面的作用机制。
方法
将实验动物随机分为4组：假手术组、模型组、寿尔智组、盐酸多奈哌齐组,每组10只。采用经脑立体定位仪向SD大鼠海马CA1区注射凝聚态Aβ25-35,建立阿尔茨海默病大鼠模型。造模成功后,治疗组分别给予盐酸多奈哌齐和寿尔智胶囊进行四周的治疗,同时假手术组和模型组给予等体积的生理盐水。四周后,运用Morris水迷宫测试检测大鼠的学习和记忆能力；学习和记忆能力测试结束,行HE染色对大鼠海马CA1区神经元形态进行观察；用透射电子显微镜对大鼠海马CA1区的突触超微结构进行观察；并用图像分析仪测量和分析大鼠海马CA1区突触界面结构参数；免疫组化法测定海马CA1区突触后致密区蛋白PSD-95、神经生长因子NGF及其受体TrKA、细胞外调节蛋白激酶ERK1、ERK2的表达；RT-PCR测定海马组织PSD-95 mRNA, NGF mRNA、TrKA mRNA、ERK1 mRNA、ERK2 mRNA的表达,并观察寿尔智胶囊对上述指标的影响。
结果
1.寿尔智胶囊能明显改善AD模型大鼠的学习和记忆能力：定位航行试验中,与假手术组比较,模型组平均逃避潜伏期明显延长,差异具有显著性(P<0.01)；盐酸多奈哌齐组和寿尔智组大鼠的平均逃避潜伏期较模型组缩短,差异具有显著性(P<0.01),但是与假手术组比较,差异不显著(P>0.05)；且寿尔智组与盐酸多奈哌齐组相比无显著性差异(P>0.05)。空间探索试验中,与假手术组比较,模型组原平台象限活动时间明显缩短,差异具有显著性(P<0.01)；寿尔智组和盐酸多奈哌齐组与模型组比较,原平台象限活动时间均明显延长,差异具有显著性(P<0.05),与假手术组比较,差异不显著(P>0.05)；且寿尔智组与盐酸多奈哌齐组相比无显著性差异(P>0.05)。
2.与假手术组相比,模型组大鼠海马CA1区细胞排列不整齐,数目明显减少,突触结构损伤较明显；与模型组相比,盐酸多奈呱齐组和寿尔智组大鼠海马CA1区细胞排列较整齐,数目明显增多,突触结构损伤较轻。
3.与假手术组相比,模型组大鼠海马CA1区突触后致密区厚度变薄,突触间隙宽度明显增大,差异具有显著性(P<0.01)；而盐酸多奈呱齐组和寿尔智组能逆转上述病理性变化：使海马CA1区突触后致密区厚度显著变厚,突触间隙宽度明显减小,差异具有显著性(P<0.01)；且寿尔智组与盐酸多奈哌齐组相比无显著性差异(P>0.05)。
4.与假手术组相比,模型组大鼠海马组织CA1区PSD-95、TrKA、ERK1、ERK2表达明显减少(P<0.01)；盐酸多奈呱齐组和寿尔智组大鼠海马组织PSD-95、TrKA、ERK1、ERK2表达较模型组增加(P<0.05或P<0.01),但低于假手术组的表达(P<0.05或P<0.01)；盐酸多奈呱齐组与寿尔智组之间比较差异无显著性(P>0.05)。且NGF在各组海马CA1区中的表达变化无显著性差异(P>0.05)。
5.与假手术组相比,模型组大鼠海马组织区PSD-95mRNA、TrKA mRNA、ERK1mRNA、ERK2 mRNA表达明显减少(P<0.01)；盐酸多奈呱齐组和寿尔智组大鼠海马组织PSD-95 mRNA、TrKA mRNA、ERK1 mRNA、ERK2 mRNA表达较模型组增加(P<0.05或P<0.01),但低于假手术组的表达(P<0.05或P<0.01)；盐酸多奈呱齐组与寿尔智组之间比较差异无显著性(P>0.05)。且NGFmRNA在各组海马组织中的表达变化无显著性差异(p>0.05)。
结论
1.向大鼠海马内注射Aβ25-35建立的AD模型可模拟AD患者临床表现和部分病理特征,且重复性好,是AD实验研究较理想的模型。
2.引起海马突触结构损伤、海马PSD-95、TrKA、ERK1、ERK2表达明显减少,神经元存活信号途径障碍可能是Aβ25-35导致AD模型大鼠突触损伤的重要机制。
3.逆转海马CA1区突触结构损伤：使触后致密区厚度显著变厚,突触间隙宽度显著减小可能是寿尔智胶囊保护AD模型大鼠突触结构的重要机制。
4.促使海马PSD95、TrKA、ERK1、ERK2的表达上调,激活神经元存活信号途径,可能是寿尔智胶囊保护AD大鼠突触功能的重要机制。
Background and Objective
Alzheimer disease (AD) is a progressively disease of unknown cause charactered by progressively reduced cognitive funcition. Scientists have pointed that not only the synapse's numbers and structure altered but also the levels of expression of the functional proteins (postsynPatie density protein 95), Nerve growth factor,Tyrosine receptor and the important nuclear factor kinase Extracellular signal regulatory protein kinase which may play an important role in the synapse's survival changed in AD patients. What'more, we still havn't found accurately effective treatment to it. so there are some theoretical significance to study on the neuroprotective effects of synapse of AD. Traditional Chinese medicine have found that some Chinese medicines may have curative effects to the intelligence of AD patients. We used shou er zhi capsules which have the main function of invigorating the kidney, eliminating phlegm,and activating blood flow to the treatment of Alzheimer disease and found they have accurately curative effects on AD patients. Previous researches have found that shou er zhi capsules have mechanisms on improving the intelligence of AD rat's in many aspects. But shou er zhi capsules's contribution to the neuroprotective effects of synapse is still untouched. This research state the relationship between AD and impairments of synapses and the possible mechanisms about shou er zhi capsules's effect to this neuroprotective effects through observing the changes of behavior of the AD rats, ultramicrostructure of synapses, the levels of expression of PSD-95,NGF, TrkA,ERK1 and ERK2 and the shou er zhi capsules's influence to these indicators.
Method
Forty Sprague-Dawley(SD) rats were divided into four groups randomly:sham-operated group, model group, Donepezil group and shou er zhi group. AD animal model was duplicated by injected 25-35 fragments of Aβinto the double hippocampus of rat's. Three days later, shou er zhi groups were given shou er zhi.Donepezil groups were given Donepezi. The sham-operated group and model group were treated with equale Sodium Chloride respectively.28 days later, Behavioral changes were inspected to determine the learning and memory of AD rats through Morris water maze test; the neuronal morphous in CA1 of the hippocampus were viewed through HE stain; the ultramicrostructure of synapse in CA1 of the hippocampus were observed by using transmission electron microscope and the parameters of the synaptic interface in area CA1 of the hippocampus were analyzed through image analyzer. The levels of expression of PSD-95,NGF,TrkA,ERK1,ERK2 in area CA1 of the hippocampus was determined by immunity tissue method; RT-PCR was used to measured the levels of expression of PSD-95mRNA, NGF mRNA, TrkA mRNA ERK1 mRNA andERK2 mRNA in the hippocampus.
Result
1. shou er zhi can improve the intelligence of AD rats. In place navigation test, compared with the sham-operated group, the escape latency was significantly longer in the model group(P<0.01); In shou er zhi group and Donepezil group the the escape latency were significantly shorter than that in the model group (P<0.01). In spatial probe test, the test showed that swimming time in the platform of first quadrant was significantly shorter in model group than that in the sham-operated group (P<0.01), in shou er zhi groups and Donepezil groups, swimming time in the platform of first quadrant were significantly longer than that in the model group (P<0.05),and there was no significantly difference between Donepezil group and shou er zhi groups.
2. Compared with the sham-operated group, the numbers of neurons in the hippocampal CA1 areas of the rats in model group reduced remark-ably, the neurons arranged irregularerly, the impairments of the structure of synapse in CA1 area are especially obvious. But in shou er zhi group and Donepezil group, the numbers obviously increased, the distribution became regularer and the impairments reduced apparently.
3. Compared with the sham-operated group,the width of synaptic cleft in the hippocampal CA1 areas of the rats in model group was remarkably increased, the thickness of PSD reduced apparently (P<0.01). But shou er zhi group and Donepezil group can reverse these pathological changes of synaptic interface significantly (P<0.01); and there was no difference between Donepezil group and shou er zhi groups.
4. Compared with the sham-operated group, The expression of PSD-95、TrKA、ERK1、ERK2 in the hippocampal CA1 area of the rats in model group were prominently decreased(P<0.01); but in shou er zhi group and donepezil group,the expression were obviously increased (P<0.05/P<0.01); and there was no difference between Donepezil group and shou er zhi groups.
5. Compared with the sham-operated group, The expression of PSD-95 mRNA. TrKA mRNA、ERK1 mRNA、ERK2 mRNA in the hippocampal of the rats in model group were prominently decreased(P<0.01); but in shou er zhi group and donepezil group,the expression were obviously increased(P<0.05/P<0.01); and there was no difference between Donepezil group and shou er zhi groups.
Conclusion
1. We injected Aβ25-35 into the rat's hippocampus in order to duplicated the model of AD. This model can simulate the behavior and pathological features of AD and had a better reproducibility and stabilization. This model was an ideal model for research in AD.
2. AD models induced by Aβ25-35 existed the damage of synapses and the mechanism is presumably related to inducing the structural impairment of synapse, reducing the expression of PSD-95、TrKA、ERK1、ERK2 in the hippocampus apparently and obstacling neuronal survival signal transduction pathways.
3. Shou er zhi has a protective effect on neurons and synapses damaged by Aβ25-35 and the mechanism is presumably related to relieving the damage of the synapses of strucyure in area CA1 of the hippocampal of the rats in model group.
4. Shou er zhi has protective effect on neurons and synapses impaired by Aβ25-35 and the presumably mechanism is related to increasing the expression of PSD-95、TrKA、ERK1、ERK2 in area CA1 of the hippocampal of the rats in model group, stimulating neuronal survival signal transduction pathways.
阿尔茨海默病(Alzheimer Disease, AD)是一种原因不明的进行性变性疾病,以记忆和其他认知功能衰退直至发展为严重痴呆为特征。研究发现：阿尔茨海默病患者的大脑内不但存在有突触数目减少、结构异常、而且包括功能蛋白(突触后致密区蛋白PSD-95)以及对突触存活起重要作用的神经生长因子NGF及其受体TrKA、细胞外调节蛋白激酶ERK都有不同程度的表达异常。迄今为止,尚无对突触保护特别有效的治疗和预防药物。因此,加强对AD突触的保护研究具有一定的理论意义。祖国医学认为中药的干预对阿尔茨海默病的治疗是有效的；根据补肾健脑,活血祛瘀,化痰开窍的治法组方的寿尔智胶囊,用于治疗阿尔茨海默病取得了确切的疗效。前期的研究显示寿尔智胶囊在对AD模型小鼠学习和记忆的改善中有多方面的作用机理,但对其在突触保护方面有无作用未有研究。本研究通过经脑立体定位仪向SD大鼠海马区注射凝聚态Aβ25-35,建立阿尔茨海默病大鼠模型,应用具有补肾健脑,活血祛瘀,化痰开窍作用的中药寿尔智胶囊进行治疗,观察寿尔智胶囊对阿尔茨海默病模型大鼠行为学、海马突触超微结构、海马突触后致密区蛋白PSD-95、神经生长因子NGF及其受体TrKA、细胞外调节蛋白激酶ERK1、ERK2基因及蛋白的表达以及寿尔智胶囊对它们的影响,探讨突触损伤与AD的发病两者之间的关系以及寿尔智胶囊在突触保护方面的作用机制。
方法
将实验动物随机分为4组：假手术组、模型组、寿尔智组、盐酸多奈哌齐组,每组10只。采用经脑立体定位仪向SD大鼠海马CA1区注射凝聚态Aβ25-35,建立阿尔茨海默病大鼠模型。造模成功后,治疗组分别给予盐酸多奈哌齐和寿尔智胶囊进行四周的治疗,同时假手术组和模型组给予等体积的生理盐水。四周后,运用Morris水迷宫测试检测大鼠的学习和记忆能力；学习和记忆能力测试结束,行HE染色对大鼠海马CA1区神经元形态进行观察；用透射电子显微镜对大鼠海马CA1区的突触超微结构进行观察；并用图像分析仪测量和分析大鼠海马CA1区突触界面结构参数；免疫组化法测定海马CA1区突触后致密区蛋白PSD-95、神经生长因子NGF及其受体TrKA、细胞外调节蛋白激酶ERK1、ERK2的表达；RT-PCR测定海马组织PSD-95 mRNA, NGF mRNA、TrKA mRNA、ERK1 mRNA、ERK2 mRNA的表达,并观察寿尔智胶囊对上述指标的影响。
结果
1.寿尔智胶囊能明显改善AD模型大鼠的学习和记忆能力：定位航行试验中,与假手术组比较,模型组平均逃避潜伏期明显延长,差异具有显著性(P<0.01)；盐酸多奈哌齐组和寿尔智组大鼠的平均逃避潜伏期较模型组缩短,差异具有显著性(P<0.01),但是与假手术组比较,差异不显著(P>0.05)；且寿尔智组与盐酸多奈哌齐组相比无显著性差异(P>0.05)。空间探索试验中,与假手术组比较,模型组原平台象限活动时间明显缩短,差异具有显著性(P<0.01)；寿尔智组和盐酸多奈哌齐组与模型组比较,原平台象限活动时间均明显延长,差异具有显著性(P<0.05),与假手术组比较,差异不显著(P>0.05)；且寿尔智组与盐酸多奈哌齐组相比无显著性差异(P>0.05)。
2.与假手术组相比,模型组大鼠海马CA1区细胞排列不整齐,数目明显减少,突触结构损伤较明显；与模型组相比,盐酸多奈呱齐组和寿尔智组大鼠海马CA1区细胞排列较整齐,数目明显增多,突触结构损伤较轻。
3.与假手术组相比,模型组大鼠海马CA1区突触后致密区厚度变薄,突触间隙宽度明显增大,差异具有显著性(P<0.01)；而盐酸多奈呱齐组和寿尔智组能逆转上述病理性变化：使海马CA1区突触后致密区厚度显著变厚,突触间隙宽度明显减小,差异具有显著性(P<0.01)；且寿尔智组与盐酸多奈哌齐组相比无显著性差异(P>0.05)。
4.与假手术组相比,模型组大鼠海马组织CA1区PSD-95、TrKA、ERK1、ERK2表达明显减少(P<0.01)；盐酸多奈呱齐组和寿尔智组大鼠海马组织PSD-95、TrKA、ERK1、ERK2表达较模型组增加(P<0.05或P<0.01),但低于假手术组的表达(P<0.05或P<0.01)；盐酸多奈呱齐组与寿尔智组之间比较差异无显著性(P>0.05)。且NGF在各组海马CA1区中的表达变化无显著性差异(P>0.05)。
5.与假手术组相比,模型组大鼠海马组织区PSD-95mRNA、TrKA mRNA、ERK1mRNA、ERK2 mRNA表达明显减少(P<0.01)；盐酸多奈呱齐组和寿尔智组大鼠海马组织PSD-95 mRNA、TrKA mRNA、ERK1 mRNA、ERK2 mRNA表达较模型组增加(P<0.05或P<0.01),但低于假手术组的表达(P<0.05或P<0.01)；盐酸多奈呱齐组与寿尔智组之间比较差异无显著性(P>0.05)。且NGFmRNA在各组海马组织中的表达变化无显著性差异(p>0.05)。
结论
1.向大鼠海马内注射Aβ25-35建立的AD模型可模拟AD患者临床表现和部分病理特征,且重复性好,是AD实验研究较理想的模型。
2.引起海马突触结构损伤、海马PSD-95、TrKA、ERK1、ERK2表达明显减少,神经元存活信号途径障碍可能是Aβ25-35导致AD模型大鼠突触损伤的重要机制。
3.逆转海马CA1区突触结构损伤：使触后致密区厚度显著变厚,突触间隙宽度显著减小可能是寿尔智胶囊保护AD模型大鼠突触结构的重要机制。
4.促使海马PSD95、TrKA、ERK1、ERK2的表达上调,激活神经元存活信号途径,可能是寿尔智胶囊保护AD大鼠突触功能的重要机制。
Background and Objective
Alzheimer disease (AD) is a progressively disease of unknown cause charactered by progressively reduced cognitive funcition. Scientists have pointed that not only the synapse's numbers and structure altered but also the levels of expression of the functional proteins (postsynPatie density protein 95), Nerve growth factor,Tyrosine receptor and the important nuclear factor kinase Extracellular signal regulatory protein kinase which may play an important role in the synapse's survival changed in AD patients. What'more, we still havn't found accurately effective treatment to it. so there are some theoretical significance to study on the neuroprotective effects of synapse of AD. Traditional Chinese medicine have found that some Chinese medicines may have curative effects to the intelligence of AD patients. We used shou er zhi capsules which have the main function of invigorating the kidney, eliminating phlegm,and activating blood flow to the treatment of Alzheimer disease and found they have accurately curative effects on AD patients. Previous researches have found that shou er zhi capsules have mechanisms on improving the intelligence of AD rat's in many aspects. But shou er zhi capsules's contribution to the neuroprotective effects of synapse is still untouched. This research state the relationship between AD and impairments of synapses and the possible mechanisms about shou er zhi capsules's effect to this neuroprotective effects through observing the changes of behavior of the AD rats, ultramicrostructure of synapses, the levels of expression of PSD-95,NGF, TrkA,ERK1 and ERK2 and the shou er zhi capsules's influence to these indicators.
Method
Forty Sprague-Dawley(SD) rats were divided into four groups randomly:sham-operated group, model group, Donepezil group and shou er zhi group. AD animal model was duplicated by injected 25-35 fragments of Aβinto the double hippocampus of rat's. Three days later, shou er zhi groups were given shou er zhi.Donepezil groups were given Donepezi. The sham-operated group and model group were treated with equale Sodium Chloride respectively.28 days later, Behavioral changes were inspected to determine the learning and memory of AD rats through Morris water maze test; the neuronal morphous in CA1 of the hippocampus were viewed through HE stain; the ultramicrostructure of synapse in CA1 of the hippocampus were observed by using transmission electron microscope and the parameters of the synaptic interface in area CA1 of the hippocampus were analyzed through image analyzer. The levels of expression of PSD-95,NGF,TrkA,ERK1,ERK2 in area CA1 of the hippocampus was determined by immunity tissue method; RT-PCR was used to measured the levels of expression of PSD-95mRNA, NGF mRNA, TrkA mRNA ERK1 mRNA andERK2 mRNA in the hippocampus.
Result
1. shou er zhi can improve the intelligence of AD rats. In place navigation test, compared with the sham-operated group, the escape latency was significantly longer in the model group(P<0.01); In shou er zhi group and Donepezil group the the escape latency were significantly shorter than that in the model group (P<0.01). In spatial probe test, the test showed that swimming time in the platform of first quadrant was significantly shorter in model group than that in the sham-operated group (P<0.01), in shou er zhi groups and Donepezil groups, swimming time in the platform of first quadrant were significantly longer than that in the model group (P<0.05),and there was no significantly difference between Donepezil group and shou er zhi groups.
2. Compared with the sham-operated group, the numbers of neurons in the hippocampal CA1 areas of the rats in model group reduced remark-ably, the neurons arranged irregularerly, the impairments of the structure of synapse in CA1 area are especially obvious. But in shou er zhi group and Donepezil group, the numbers obviously increased, the distribution became regularer and the impairments reduced apparently.
3. Compared with the sham-operated group,the width of synaptic cleft in the hippocampal CA1 areas of the rats in model group was remarkably increased, the thickness of PSD reduced apparently (P<0.01). But shou er zhi group and Donepezil group can reverse these pathological changes of synaptic interface significantly (P<0.01); and there was no difference between Donepezil group and shou er zhi groups.
4. Compared with the sham-operated group, The expression of PSD-95、TrKA、ERK1、ERK2 in the hippocampal CA1 area of the rats in model group were prominently decreased(P<0.01); but in shou er zhi group and donepezil group,the expression were obviously increased (P<0.05/P<0.01); and there was no difference between Donepezil group and shou er zhi groups.
5. Compared with the sham-operated group, The expression of PSD-95 mRNA. TrKA mRNA、ERK1 mRNA、ERK2 mRNA in the hippocampal of the rats in model group were prominently decreased(P<0.01); but in shou er zhi group and donepezil group,the expression were obviously increased(P<0.05/P<0.01); and there was no difference between Donepezil group and shou er zhi groups.
Conclusion
1. We injected Aβ25-35 into the rat's hippocampus in order to duplicated the model of AD. This model can simulate the behavior and pathological features of AD and had a better reproducibility and stabilization. This model was an ideal model for research in AD.
2. AD models induced by Aβ25-35 existed the damage of synapses and the mechanism is presumably related to inducing the structural impairment of synapse, reducing the expression of PSD-95、TrKA、ERK1、ERK2 in the hippocampus apparently and obstacling neuronal survival signal transduction pathways.
3. Shou er zhi has a protective effect on neurons and synapses damaged by Aβ25-35 and the mechanism is presumably related to relieving the damage of the synapses of strucyure in area CA1 of the hippocampal of the rats in model group.
4. Shou er zhi has protective effect on neurons and synapses impaired by Aβ25-35 and the presumably mechanism is related to increasing the expression of PSD-95、TrKA、ERK1、ERK2 in area CA1 of the hippocampal of the rats in model group, stimulating neuronal survival signal transduction pathways.
引文
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