参枝苓口服液对APPswe/PSldE9小鼠学习记忆和突触超微结构的影响
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摘要
目的观察参枝苓口服液对双转基因(APPswe/PSldE9)小鼠学习记忆和突触超微结构的影响,探讨其在阿尔茨海默病(AD)早期发挥治疗作用的可能作用机制。方法将75只APPswe/PSldE9小鼠随机分为5组:模型组、多奈哌齐组、参枝苓大剂量组、中剂量组和小剂量组,每组15只;同背景C57/BL6J小鼠15只作为正常对照组。参枝苓大剂量[50 g/(kg·d)]、中剂量[25 g/(kg·d)]、小剂量[12. 5 g/(kg·d)]组,多奈哌齐组[0. 92 mg/(kg·d)],分别給予灌胃治疗3个月,正常组和模型组小鼠给予等体积蒸馏水灌胃。治疗3个月后,采用Morris水迷宫测试评价各组小鼠空间学习记忆能力,运用透射电镜观察海马CA1区突触的超微结构。结果 Morris水迷宫测试显示模型组与正常组小鼠相比,逃避潜伏期、游泳距离显著延长(P <0. 01),穿越平台次数和目标象限停留时间明显减少(P <0. 01),治疗后参枝苓中、小剂量组逃避潜伏期、游泳距离明显缩短(P <0. 05),穿越平台次数和目标象限停留时间明显增加(P <0. 05)。结论参枝苓能改善APPswe/PSldE9小鼠学习记忆能力,其潜在机制可能与改善小鼠海马CA1区突触结构和数目,进而改善突触可塑性有关。
Objective To observe the effects of shenzhiling( SZL) oral liquid on learning,memory and synaptic structure of APPswe/PSldE9 mice. Methods Seventy-five APPswe/PSldE9 mice were randomly divided into model group,donepezil group( 0. 92 mg/( kg·d)),high-dose SZL( 50 g/( kg·d)) group,mid-dose SZL( 25 g/( kg·d)) group,and low-dose( 12. 5 g/( kg·d)) SZL groups( n =15 in each group). 15 C57/BL6 J mice were used as the normal control group. For the model and normal group,mice were administered oral gavage of distilled water while the interventional groups received corresponding medicine for three months. Learning and memory was evaluated by using Morris water maze test,and the ultrastructure of the synapses were observed with transmission electron microscope.Results Compared with the normal group,mice in the model group had a longer escape latency and swimming distance( P < 0. 01); reduced times across the platform and stay in the target platform quadrant( P < 0. 01). After SZL treatment,escape latency was reduced and the swimming distances was shorter( P < 0. 05); times across the platform and stay in the target platform quadrant were increased,especially in the mid-dose and low-dose groups( P < 0. 01). The ultrastructure of the synapses was improved in the SZL groups than that in the model group,especially in the mid-dose and lowdose groups.Conclusion SZL oral liquid could improve learning and memory ability,and improve ultrastructure of the synapses in APPswe/PSldE9 mice. This may be one of the important mechanisms of improving cognitive function.
Objective To observe the effects of shenzhiling( SZL) oral liquid on learning,memory and synaptic structure of APPswe/PSldE9 mice. Methods Seventy-five APPswe/PSldE9 mice were randomly divided into model group,donepezil group( 0. 92 mg/( kg·d)),high-dose SZL( 50 g/( kg·d)) group,mid-dose SZL( 25 g/( kg·d)) group,and low-dose( 12. 5 g/( kg·d)) SZL groups( n =15 in each group). 15 C57/BL6 J mice were used as the normal control group. For the model and normal group,mice were administered oral gavage of distilled water while the interventional groups received corresponding medicine for three months. Learning and memory was evaluated by using Morris water maze test,and the ultrastructure of the synapses were observed with transmission electron microscope.Results Compared with the normal group,mice in the model group had a longer escape latency and swimming distance( P < 0. 01); reduced times across the platform and stay in the target platform quadrant( P < 0. 01). After SZL treatment,escape latency was reduced and the swimming distances was shorter( P < 0. 05); times across the platform and stay in the target platform quadrant were increased,especially in the mid-dose and low-dose groups( P < 0. 01). The ultrastructure of the synapses was improved in the SZL groups than that in the model group,especially in the mid-dose and lowdose groups.Conclusion SZL oral liquid could improve learning and memory ability,and improve ultrastructure of the synapses in APPswe/PSldE9 mice. This may be one of the important mechanisms of improving cognitive function.
引文
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[23]王慧,孔立红,李威,等.不同频率电针对阿尔茨海默病大鼠海马神经元突触形态可塑性的影响研究[J].中医药学报,2015,43(5):20-23.Wang H,Kong LH,Li W,et al. Effects of different frequency electroacupuncture on synaptic plasticity in hippocampal neurons of rats with Alzheimer’s disease[J].Acta Chinese Medicine and Pharmacology,2015,43(5):20-23.
[24]王颖,李威,张亢亢,等.不同频率电针对阿尔茨海默病大鼠学习记忆能力和海马突触的影响[J].中国康复理论与实践,2016,22(6):635-639.Wang Y,Li W,Zhang KK,et al. Effect of electroacupuncture with different frequencies on learning and memory ability and synapse in hippocamp in rats with Alzheimer’s disease[J]. Chinese Journal of Rehabilitation Theory and Practice,2016,22(6):635-639.
[25]袁电杰,张印发,姚春香.灵芝多糖对阿尔茨海默病模型大鼠海马内突触及突触素表达的影响[J].中国实验方剂学杂志,2011,17(3):151-154.Yuan DJ,Zhang YF,Yao CX. Effects of ganoderma lucidum polysaccharides on synapsis and hippocampal synaptophysin expression in Alzheimer’s Rats Model[J]. Chinese Journal of Experimental Traditional Medical Formulae,2011,17(3):151-154.
[26]王蓬文,李瑞晟,王虹,等.姜黄素对阿尔茨海默双转基因小鼠海马超微结构的影响[J].北京中医药大学学报,2011,34(7):465-470.Wang PW,Li RS,Wang H,et al. Influence of curcumin on hippocampus ultrastructure in APPswe/PSld E9 double transgenic mice[J]. Journal of Beijing University of Traditional Chinese Medicine,2011,34(7):465-470.
[2]Prince M,Wimo A,Guerchet M,et al. World Alzheimer Report 2016. Alzheimer’s Disease International(ADI),2016.
[3]Chan KY,Wang W,Wu JJ,et al. Epidemiology of Alzheimer’s disease and other forms of dementia in China,1990-2010:a systematic review and analysis[J]. Lancet,2013,381(9882):2016-2023.
[4]Silva T,Reis J,Teixeira J,et al. Alzheimer’s disease,enzyme targets,and drug discovery struggles:from natural products to drug prototypes[J]. Ageing Res Rev,2014,15:116-145.
[5]Colovic MB,Krstic DZ,Lazarevic-pasti TD,et al. Acetylcholinesterase inhibitors:pharmacology and toxicology[J].Curr Neuropharmacol,2013,11(3):315-335.
[6]Coleman P,Federoff H,Kurlan R. A focus on the synapse for neuroprotection in Alzheimer disease and other dementias[J]. Neurology,2004,63(7):1155-1162.
[7]Pan W,Wang Q,Kwak S,et al. Shen-zhi-ling oral liquid improves behavioral and psychological symptoms dementia in Alzheimer’s disease[J/OL]. Evid Based Complement Alternat Med,2014,(2014):913687[2018-10-24]. https://www. ncbi. nlm. nih. gov/pmc/articles/PMC4052178/.DOI:10. 1155/2014/913687.
[8]Laferla FM,Green KN,Oddo S,Intracellular amyloid-beta In Alzheimer’s disease[J]. Neurosci,2007,8(7):499-509.
[9] Boeckers TM. The postsynaptic density[J]. Cell Tissue Res,2006,326(2):409-422.
[10]Overk CR,Masliah E. Pathogenesis of synaptic degeneration in Alzheimer’s disease and Lewy body disease[J].Biochem Pharmacol,2014,88(4):508-516.
[11]Terry RD,Masliah E,Salmon DP,et al. Physical basis of cognitive alterations in Alzheimer’s disease:synapse loss is the major correlate of cognitive impairment[J].Ann Neurol,1991,30(4):572-580.
[12]Selkoe DJ. Alzheimer’s disease is a synaptic failure[J].Science,2002,298(5594):789-791.
[13]Neha,Sodhi RK,Jaggi AS,et al. Animal models of dementia and cognitive dysfunction[J]. Life Sci,2014,109(2):73-86.
[14] Li X,Bao X,Wang R. Experimental models of Alzheimer’s disease for deciphering the pathogenesis and therapeutic screening(Review)[J]. Int J Mol Med,2016,37(2):271-283.
[15]Xiong H,Callaghan D,Wodzinska J,et al. Biochemical and behavioral characterization of the double transgenic mouse model(APPswe/PSld E9)of Alzheimer’s disease[J]. Neurosci Bull,2011,27(4):221-232.
[16]高雅,王鲁宁,张红红. APPswe/PSld E9双转基因阿尔茨海默病模型小鼠生物学特征[J].中华老年心脑血管病杂志,2015,17(1):106-108.Gao Y,Wang LN,Zhang HH. Biological characteristics of APPswe/PSld E9 double transgenic Alzheimer’s disease model mice[J]. Chin J Geriatr Heart Brain Vessel Dis,2015,17(1):106-108.
[17]Nunez J. Morris Water Maze Experiment[J]. J Vis Exp,2008,24(19):897-899.
[18]Morris R. Developments of a water-maze procedure for studying spatial learning in the rat[J]. J Neurosci Methods,1984,11(1):47-60.
[19]吴继全.傅仁杰教授治疗老年性痴呆经验摭拾[J].实用中医内科杂志,2007,21(5):14-15.Wu JQ. Professor Fu Renjie’s experience in treating senile dementia[J]. Journal of Practical Traditional Chinese Internal Medicine,2007,21(5):14-15.
[20]林水淼,杨柏灿.养心健脑液治疗Alzheimer痴呆的临床研究[J].上海中医药大学上海市中医药研究院学报,1996,10(2):44-47.Lin SM,Yang BC. Clinical study on heart-nourishing and brain-tonifying liquid in treating Alzheimer dementia[J].Academic Journal of Shanghai University of Traditional Chinese Medicine,1996,10(2):44-47.
[21]温薇,刘学伟,李福东,等.开心散抗老年性痴呆的研究进展[J].中医药信息,2013,30(4):140-142.Wen W,Liu XW,Li FD,et al. Research Progress of Kaixinsan for Anti-senile Dementia[J]. Information on Traditional Chinese Medicine,2013,30(4):140-142.
[22]陈久林,孙申维,郁志华,等.参枝苓口服液治疗轻度认知功能损害的临床疗效观察[J].中西医结合心脑血管病杂志,2017,15(3):365-368.Chen JL,Sun SW,Yu ZH,et al. Clinical observation on dhenzhiling oral liquid in the treatment of mild cognitive impairment[J]. Chinese Journal of Integrative Medicine on Cardio-/Cerebrovascular Disease,2017,15(3):365-368.
[23]王慧,孔立红,李威,等.不同频率电针对阿尔茨海默病大鼠海马神经元突触形态可塑性的影响研究[J].中医药学报,2015,43(5):20-23.Wang H,Kong LH,Li W,et al. Effects of different frequency electroacupuncture on synaptic plasticity in hippocampal neurons of rats with Alzheimer’s disease[J].Acta Chinese Medicine and Pharmacology,2015,43(5):20-23.
[24]王颖,李威,张亢亢,等.不同频率电针对阿尔茨海默病大鼠学习记忆能力和海马突触的影响[J].中国康复理论与实践,2016,22(6):635-639.Wang Y,Li W,Zhang KK,et al. Effect of electroacupuncture with different frequencies on learning and memory ability and synapse in hippocamp in rats with Alzheimer’s disease[J]. Chinese Journal of Rehabilitation Theory and Practice,2016,22(6):635-639.
[25]袁电杰,张印发,姚春香.灵芝多糖对阿尔茨海默病模型大鼠海马内突触及突触素表达的影响[J].中国实验方剂学杂志,2011,17(3):151-154.Yuan DJ,Zhang YF,Yao CX. Effects of ganoderma lucidum polysaccharides on synapsis and hippocampal synaptophysin expression in Alzheimer’s Rats Model[J]. Chinese Journal of Experimental Traditional Medical Formulae,2011,17(3):151-154.
[26]王蓬文,李瑞晟,王虹,等.姜黄素对阿尔茨海默双转基因小鼠海马超微结构的影响[J].北京中医药大学学报,2011,34(7):465-470.Wang PW,Li RS,Wang H,et al. Influence of curcumin on hippocampus ultrastructure in APPswe/PSld E9 double transgenic mice[J]. Journal of Beijing University of Traditional Chinese Medicine,2011,34(7):465-470.