Effect of Kaixinsan on Keap-1/Nrf2/MnSOD Signaling Pathway in Rats with Alzheimer's Disease Induced by A<italic style="font-style: italic">β</italic><sub>1-42</sub>

Jiang-hua LIU; Jing YANG; Jing-lan ZHANG; Wen ZHANG; Fei WANG

doi:10.13422/j.cnki.syfjx.20210103

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Effect of Kaixinsan on Keap-1/Nrf2/MnSOD Signaling Pathway in Rats with Alzheimer's Disease Induced by Aβ_1-42

Classic Prescriptions | 更新时间：2021-02-09

- Effect of Kaixinsan on Keap-1/Nrf2/MnSOD Signaling Pathway in Rats with Alzheimer's Disease Induced by Aβ_1-42
- Chinese Journal of Experimental Traditional Medical Formulae Vol. 27, Issue 5, Pages: 25-32(2021)
- 作者机构：
  
  武汉市中医医院，武汉 430000
- 作者简介：
- 基金信息：
- DOI：10.13422/j.cnki.syfjx.20210103
  CLC： R2-0;R22;R285.5;R289
- Published：05 March 2021，
  
  Published Online：06 January 2021，
  
  Received：21 October 2020，
- 稿件说明：
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刘江华,杨晶,张京兰等.开心散对Aβ_1-42诱导Alzheimer病大鼠模型Keap-1/Nrf2/MnSOD信号通路的作用[J].中国实验方剂学杂志,2021,27(05):25-32.

LIU Jiang-hua,YANG Jing,ZHANG Jing-lan,et al.Effect of Kaixinsan on Keap-1/Nrf2/MnSOD Signaling Pathway in Rats with Alzheimer's Disease Induced by Aβ_1-42[J].Chinese Journal of Experimental Traditional Medical Formulae,2021,27(05):25-32.
刘江华,杨晶,张京兰等.开心散对Aβ_1-42诱导Alzheimer病大鼠模型Keap-1/Nrf2/MnSOD信号通路的作用[J].中国实验方剂学杂志,2021,27(05):25-32. DOI： 10.13422/j.cnki.syfjx.20210103.

LIU Jiang-hua,YANG Jing,ZHANG Jing-lan,et al.Effect of Kaixinsan on Keap-1/Nrf2/MnSOD Signaling Pathway in Rats with Alzheimer's Disease Induced by Aβ_1-42[J].Chinese Journal of Experimental Traditional Medical Formulae,2021,27(05):25-32. DOI： 10.13422/j.cnki.syfjx.20210103.

摘要

目的

基于Kelch样环氧氯丙烷相关蛋白-1（Keap-1）/核转录因子E2相关因子2（Nrf2）/锰超氧化物歧化酶（MnSOD）信号通路探讨开心散改善阿尔茨海默病（AD）模型大鼠认知障碍的可能机制。

方法

通过侧脑室注射

淀粉样蛋白1-42（A

1-42

，5 μL）建立AD模型。造模后将大鼠随机分为模型组，多奈哌齐组和开心散低、中、高剂量组，并另设正常组。多奈哌齐组给予多奈哌齐片（1.8 g·kg

-1

·d

-1

），开心散低、中、高剂量组给予开心散制成的药液（10，20，40 g·kg

-1

·d

-1

），正常组和模型组给予等体积的纯水。采用Morris水迷宫检测大鼠的学习记忆力。采用比色法检测血清中髓过氧化酶（MPO），诱导型一氧化氮合酶（iNOS），超氧化物歧化酶（SOD）的表达水平。采用尼氏染色观察海马CA3区病理形态。采用免疫组化（IHC）和蛋白免疫印迹法（Western bolt）检测海马中Keap-1，Nrf2，MnSOD的蛋白表达水平。

结果

与正常组比较，模型组大鼠平台潜伏期、游泳总路程和第1次抵原平台时间显著增加（

0.01），穿越平台次数和目标象限时间显著降低（

0.01）；与模型组比较，多奈哌齐组和开心散低、中、高组大鼠平台潜伏期、游泳总路程和第1次抵原平台时间明显减少（

0.05，

0.01），穿越平台次数和目标象限时间明显增加（

0.05，

0.01）。与正常组比较，模型组大鼠血清中MPO，iNOS表达水平显著升高（

0.01），而SOD表达水平降低（

0.01）。与模型组比较，多奈哌齐组和开心散低、中、高组大鼠血清中MPO，iNOS表达水平明显降低（

0.05，

0.01），而SOD表达水平明显升高（

0.05，

0.01）。正常组大鼠海马CA3区神经元排列整齐，未有尼氏体固缩。模型组大鼠海马CA3区神经元排列欠整齐，有明显的神经元丢失和尼氏体固缩。多奈哌齐组和开心散低、中、高组大鼠海马CA3区神经元排列较整齐，神经元数量增多，尼氏体固缩减少。与正常组比较，模型组大鼠海马中Keap-1的积分吸光度

和蛋白水平降低（

0.01），而Nrf2，MnSOD的

和蛋白水平显著升高（

0.01）。与模型组比较，多奈哌齐组和开心散低、中、高组大鼠海马中Keap-1和MnSOD的

和蛋白水平明显升高（

0.05，

0.01），而Nrf2的

和蛋白水平降低（

0.05，

0.01）。

结论

开心散可通过调节Keap-1/Nrf2/MnSOD信号通路缓解AD模型大鼠的认知障碍。

Abstract

Objective

To explore the possible mechanism of Kaixinsan in improving cognitive impairment in Alzheimer's disease （AD） model rats based on the epichlorohydrin associated protein-1 （Keap-1）/nuclear factor E2 related factor （Nrf2）/manganese superoxide dismutase （MnSOD） signaling pathway.

Method

The AD model was established by injecting Amyloid

1-42

（A

1-42

， 5 μL） into the lateral ventricle. After modeling， the experimental rats were randomly divided into model group， donepezil group， and Kaixinsan low dose， medium dose and high dose groups. Another normal control group was also established. The donepezil group received donepezil tablets （1.8 g·kg

-1

·d

-1

）， Kaixinsan low dose， medium dose and high dose groups received corresponding doses of Kaixinsan （10， 20， 40 g·kg

-1

·d

-1

， respectively）， and the normal control group and model group were given with equal volume of pure water. Morris water maze was used to test the learning and memory ability of rats. The pathological morphology of hippocampal CA3 area was observed by Nissl staining. The expression levels of myeloperoxidase （MPO）， inducible nitric oxide synthase （iNOS） and superoxide dismutase （SOD） in serum were detected by colorimetry， and the protein expression levels of Keap-1， Nrf2 and MnSOD in hippocampus were detected by immunohistochemistry （IHC） and Western bolt.

Result

Compared with the normal control group， the escape latency， total swimming distance and first arrival time of the plateau in the model group increased （

0.01）， while the times of crossing the plateau and the time in target quadrant decreased （

0.01）. Compared with the model group， the rats in donepezil group and Kaixinsan groups showed less latency， lower total swimming distance and first arrival time on the platform （

0.05，

0.01）， while the times of crossing the platform and time in target quadrant increased （

0.05，

0.01）. Compared with the normal control group， the expression levels of MPO and iNOS in serum of the model group increased （

0.01）， while the expression levels of SOD decreased （

0.01）. Compared with model group， the expression of MPO and iNOS in serum of donepezil group and Kaixinsan groups decreased （

0.05，

0.01）， while the expression of SOD increased （

0.05，

0.01）. In the normal control group， the neurons in the hippocampal CA3 of the rats were arranged neatly， without obvious Nissl body shrinkage. The neurons in the CA3 of the hippocampus of the model group were not arranged neatly， with obvious neuron loss and pyknosis of Nissl body. The neurons in the CA3 of the hippocampus of the rats in the donepezil group and Kaixinsan groups were arranged neatly， with increased number of neurons and decreased Nissl body shrinkage. Compared with the normal control group， the integrated optical density （

） and protein level of Keap-1 in the hippocampus of the model group decreased（

0.01）， while the

and protein level of Nrf2 and MnSOD increased （

0.01）. Compared with model group，

and protein levels of Keap-1 and MnSOD in hippocampus of rats in donepezil group and Kaixinsan groups increased （

0.05，

0.01）， while

and protein levels of Nrf2 decreased （

0.05，

0.01）.

Conclusion

Kaixinsan could alleviate memory impairment in AD rats， and its mechanism may be related to its regulation of Keap-1/Nrf2/MnSOD signaling pathway.

关键词

开心散阿尔茨海默病（AD）认知障碍氧化应激Kelch样环氧氯丙烷相关蛋白-1（Keap-1）/核因子E2相关因子2（Nrf2）/锰超氧化物歧化酶（MnSOD）信号通路机制

Keywords

KaixinsanAlzheimer's diseasecognitive impairmentoxidative stressepichlorohydrin associated protein-1 （Keap-1）/nuclear factor E2 related factor （Nrf2）/manganese superoxide dismutase （MnSOD） signaling pathwaymechanism

references

JIA L，QUAN M，FU Y，et al.Dementia in China： epidemiology，clinical management，and research advances［J］.Lancet Neurol，2020，19（1）：81-92.

王涛，肖世富.治疗阿尔茨海默病新药的临床研究进展［J］.重庆医科大学学报，2019，44（4）：401-403.

苏芮，韩振蕴，范吉平，等.中医对老年性痴呆病因病机及中药治疗研究［J］.中华中医药杂志，2011，26（9）：1917-1920.

袁德培，邱幸凡，王平，等.肾虚髓衰、脑络痹阻是老年性痴呆的基本病机［J］.中华中医药杂志，2008，23（8）：732-734.

周小江，王瑾，董宪喆，等.开心散对快速老化小鼠学习记忆能力和线粒体功能的影响［J］.中国药业，2020，29（17）：13-17.

安继东，郭旭彤，陈分乔，等.近5年中药治疗抑郁症及其作用机制研究进展［J］.辽宁中医药大学学报，2020，22（8）：139-142.

李牧函，张静，赵润清，等.6首开心散类方对阿尔兹海默病模型小鼠的药理作用及机制研究［J］.中国中药杂志，2016，41（7）：1269-1274.

韩丽君，费洪新，张英华，等.开心散含药血清对阿尔茨海默病小鼠血脑屏障通透性和海马NF-κB p65的影响［J］.中国老年学杂志，2017，37（23）：5784-5787.

毕婷婷，战丽彬，张栎婧.基于中药整合药理学平台探究开心散治疗AD的物质基础与作用机制［J］.中国实验方剂学杂志，2019，25（16）：135-141.

龙清华.补肾调心健脾法防治失眠健忘的理论探讨及生慧汤对APP/PS1痴呆小鼠神经发生的作用研究［D］.武汉：湖北中医药大学，2020.

TÖNNIES E，TRUSHINA E.Oxidative stress，synaptic dysfunction，and Alzheimer's disease［J］.J Alzheimers Dis，2017，57（4）：1105-1121.

BUTTERFIELD D A，BOYD-KIMBALL D.Oxidative stress，amyloid-β peptide，and altered key molecular pathways in the pathogenesis and progression of Alzheimer's disease［J］.J Alzheimers Dis，2018，62（3）：1345-1367.

NAKHATE K T，BHARNE A P，VERMA V S，et al.Plumbagin ameliorates memory dysfunction in streptozotocin induced Alzheimer's disease via activation of Nrf2/ARE pathway and inhibition of β-secretase［J］.Biomed Pharmacother，2018，101（5）：379-390.

GUO S，WANG J，XU H，et al.Classic prescription，Kai-Xin-San，ameliorates Alzheimer's disease as an effective multitarget treatment： from neurotransmitter to protein signaling pathway［J］.Oxid Med Cell Longev，2019，doi：10.1155/2019/9096409http://dx.doi.org/10.1155/2019/9096409.

WANG Z，XU P，CHEN B，et al.Identifying circRNA-associated-ceRNA networks in the hippocampus of Aβ1-42-induced Alzheimer's disease-like rats using microarray analysis［J］.Aging （Albany NY），2018，10（4）：775-788.

普元柱，苏灿.灯盏细辛及其活性成分防治阿尔茨海默病的药理作用研究进展［J］.中国中药杂志，2020，45（23）：5650-5657.

TEIXEIRA J P，CASTRO A A，SOARES F V，et al.Future therapeutic perspectives into the Alzheimer's Disease targeting the oxidative stress hypothesis［J］.Molecules，2019，24（23）：4410-4425.

CASSIDY L，FERNANDEZ F，JOHNSON J B，et al.Oxidative stress in alzheimer's disease： a review on emergent natural polyphenolic therapeutics［J］.Complement Ther Med，2020，49（10）：122-134.

DERRY P J，HEGDE M L，JACKSON G R，et al.Revisiting the intersection of amyloid，pathologically modified tau and iron in Alzheimer's disease from a ferroptosis perspective［J］.Prog Neurobiol，2020，184（5）：1017-1026.

ZHANG W，FENG C，JIANG H.Novel target for treating Alzheimer's diseases： crosstalk between the Nrf2 pathway and autophagy［J］.Ageing Res Rev，2020，31（10）：1012-1027.

付燕，张业廷，罗笑，等.有氧运动对Aβ1-42诱导阿尔茨海默病大鼠学习记忆能力及海马炎症状态的影响［J］.中国运动医学杂志，2018，37（8）：40-48.

冯超，姜霁芳，唐美霞，等.天麻素对Aβ1-42致痴呆大鼠模型的保护作用及机制探究［J］.天然产物研究与开发，2018，30（1）：89-96.

殷明.氧化应激与阿尔茨海默病［J］.中国老年学杂志，2013，33（16）：4090-4093.

LI X N，MA L Y，JI H，et al.Resveratrol protects against oxidative stress by activating the Keap-1/Nrf2 antioxidant defense system in obeseasthmatic rats［J］.Exp Ther Med，2018，16（6）：4339-4348.

ESTHER C，ENRIQUE B，RAMÍREZ B E，et al.Sitagliptin ameliorates oxidative stress in experimental diabetic nephropathy by diminishing the miR-200a/Keap-1/Nrf2 antioxidant pathway［J］.Diabetes Metab Syndr Obes，2017，10（7）：207-222.

TAO L，GU X，XU E，et al.Osthole protects against Ang Ⅱ-induced endotheliocyte death by targeting NF-κB pathway and Keap-1/Nrf2 pathway［J］.Am J Transl Res，2019，11（1）：142-159.

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Effect of Kaixinsan on Keap-1/Nrf2/MnSOD Signaling Pathway in Rats with Alzheimer's Disease Induced by Aβ1-42

DOI：10.13422/j.cnki.syfjx.20210103

摘要

Abstract

关键词

Keywords

references

Effect of Kaixinsan on Keap-1/Nrf2/MnSOD Signaling Pathway in Rats with Alzheimer's Disease Induced by Aβ_1-42