[1]刘万根,李敏,于宏伟.灯盏花素通过Wnt/β-catenin通路对阿尔茨海默病大鼠模型Aβ跨血脑屏障的转运清除机制研究[J].卒中与神经疾病杂志,2022,29(05):410-415,437.[doi:10.3969/j.issn.1007-0478.2022.05.003]
　Liu Wangen*,Li Min,Yu Hongwei.Breviscapine promotes the transportof Aβ across the blood-brain barrier via Wnt/β-catenin pathway in a rat model of Alzheimer's disease[J].Stroke and Nervous Diseases,2022,29(05):410-415,437.[doi:10.3969/j.issn.1007-0478.2022.05.003]
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灯盏花素通过Wnt/β-catenin通路对阿尔茨海默病大鼠模型Aβ跨血脑屏障的转运清除机制研究()
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《卒中与神经疾病》杂志[ISSN:1007-0478/CN:42-1402/R]

卷:
第29卷
期数:
2022年05期
页码:
410-415,437
栏目:
论著
出版日期:
2022-10-10

文章信息/Info

Title:
Breviscapine promotes the transportof Aβ across the blood-brain barrier via Wnt/β-catenin pathway in a rat model of Alzheimer's disease
文章编号:
1007-0478(2022)05-0410-07
作者:
刘万根; 李敏; 于宏伟
061000 河北省沧州市中心医院神经内六科（刘万根）；沧州市人民医院脑血管病介入科（李敏）；唐山市第八医院内分泌科（于宏伟）
Author(s):
Liu Wangen*;  Li Min;  Yu Hongwei
*Department of Neurology, Cangzhou Central Hospital, Cangzhou 061000
关键词:
灯盏花素; 阿尔茨海默病; 淀粉样蛋白β; Wnt/β-连环蛋白通路
Keywords:
Breviscapine; Alzheimer's disease; Aβ; Wnt/β-catenin pathway
分类号:
R742
DOI:
10.3969/j.issn.1007-0478.2022.05.003
文献标志码:
A
摘要:
目的 探讨灯盏花素（Breviscapine，BRE）对阿尔茨海默病（Alzheimer disease，AD）大鼠模型淀粉样蛋白β（Amyloid β，Aβ）跨血脑屏障（blood brain barrier，BBB）的转运清除的影响及其可能作用机制。 方法 随机选择15只Wistar大鼠作为空白组，剩余大鼠于侧脑室内注射淀粉样蛋白β25-35（Aβ25-35）以诱导AD大鼠模型；后随机分为模型组、BRE低（50 mg·kg-1·d-1）、高（100 mg·kg-1·d-1）剂量组及多奈哌齐组（1 mg·kg-1·d-1），每组各15只，连续灌服给药21 d；Morris水迷宫行为测试检测大鼠空间学习记忆能力；海马组织行尼氏、刚果红染色；酶联免疫吸附试验（Enzyme linked immunosorbent assay，ELISA）法检测海马组织中Aβ42、肿瘤坏死因子-α（Tumor necrosis factor-α，TNF-α）、白细胞介素1β（Interleukin 1β，IL-1β）、丙二醛（Malondialdehyde，MDA）、超氧化物歧化酶（Superoxide dismutase，SOD）水平；Western blot法检测海马Wnt3a/β-连环蛋白（β-catenin）通路因子及Aβ相关转运体蛋白表达水平。 结果 与空白组比较，模型组大鼠逃避潜伏期延长，穿台次数减少，海马CA3区存活神经元数减少，Aβ斑块状严重沉积，Aβ42，TNF-α，IL-1β，MDA水平升高，SOD水平、Wnt3a，β-catenin、低密度脂蛋白受体相关蛋白1（Low density lipoprotein receptor-associated protein 1，LRP-1）及P糖蛋白（P glycoprotein，P-gp）相对表达水平降低，磷酸化糖原合酶激酶3β（Phosphorylated GSK3 β，p-GSK3β）、轴抑制蛋白2（Axis inhibition protein 2，Axin2）相对表达水平升高（P<0.05）；与模型组比较，BRE低、高剂量组及多奈哌齐组大鼠逃避潜伏期缩短，穿台次数增加，海马CA3区存活神经元数增加，Aβ斑块状沉积减轻，Aβ42，TNF-α，IL-1β，MDA水平降低，SOD水平、Wnt3a，β-catenin，LRP-1及P-gp相对表达水平升高，p-GSK3β，Axin2相对表达水平降低（P<0.05）；低、高剂量BRE及多奈哌齐作用效果逐渐增强（P<0.05）。 结论 BRE可促进AD大鼠模型Aβ跨BBB转运清除，其作用机制可能与激活Wnt/β-catenin通路有关。
Abstract:
Objective To investigate the effect of breviscapine (BRE) on Amyloid-β (Aβ)transport and clearance through the blood-brain barrier (BBB) in a rat model of Alzheimer's disease (AD), and to illustrate the molecular mechanism. Methods Fifteen Wistar rats were randomly selected as the blank group. The remaining rats were injected with Aβ25-35 into the lateral ventricle to induce AD rat model. The rats were randomly divided into the model group, BRE low dose (50 mg·kg-1·d-1), BRE high dose (100 mg·kg-1·d-1) group, and Donepezil group (1 mg·kg-1·d-1), with 15 rats in each group. Morris water maze test was used to detect the spatial learning and memory ability of the rats. The hippocampal sections were stained with Nessie's and Congo red. The levels of Aβ42, tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), malondialdehyde (MDA), and superoxide dismutase (SOD) in the hippocampus were determined by ELISA. Western blot was used to detect the expression of Wnt3a/β-catenin pathway and Aβ-associated transporter protein in the hippocampus. Results Compared with the blank group, the rats in the model group had longer escape latency time, reduced number of stage penetration, reduced number of surviving neurons in the CA3 region of the hippocampus, more severe Aβ plaque-like deposition, increased levels of Aβ42, TNF-α, IL-1β, MDA, and decreased levels of SOD, Wnt3a, β-catenin, low density lipoprotein receptor-associated protein 1 (LRP-1), P glycoprotein (P-gp), phosphorylated glycogen synthase kinase 3β (phosphorylated GSK3 β (p-GSK3β), and axis inhibition protein 2 (Axin 2) (P<0.05). Compared with the model group, rats in the low and high dose BRE and donepezil groups had shorter escape latency, increased number of stage penetration, increased number of surviving neurons in the hippocampal CA3 area, reduced Aβ plaque-like deposition, decreased expression level of Aβ42, TNF-α, IL-1β, MDA levels, SOD levels, Wnt3a, β-catenin, LRP-1, P-gp protein, p-GSK3β and Axin2 (P<0.05).The effects of BRE and donepezil are dose-dependent (P<0.05). Conclusion BRE could promote the trans-BBB transport and clearance of Aβ in AD rats, and its mechanism may be related to the activation of the Wnt/β-catenin pathway.

参考文献/References:

[1] Crous-Bou M, Minguillón C, Gramunt N, et al. Alzheimer's disease prevention: from risk factors to early intervention[J]. Alzheimers Res Ther, 2017, 9(1): 71.
[2] Rao CV, Asch AS, Carr D, et al. "Amyloid-beta accumulation cycle" as a prevention and/or therapy target for Alzheimer's disease[J]. Aging Cell, 2020, 19(3): e13109.
[3] Cordaro M, Salinaro AT, Siracusa R, et al. Key mechanisms and potential implications of hericium erinaceus in NLRP3 inflammasome activation by reactive Oxygen species during alzheimer's disease[J]. Antioxidants (Basel), 2021, 10(11): 1664.
[4] Dubois B, Hampel H, Feldman HH, et al. Preclinical alzheimer's disease: definition, natural history, and diagnostic criteria[J]. Alzheimers Dement, 2016, 12(3): 292-323.
[5] 张云莎,郭茂娟,李虎虎,等.Aβ的外周清除与阿尔茨海默病[J].现代生物医学进展,2016,16(22):4398-4400, 4338.
[6] Jia L, Pia-Crespo J, Li Y. Restoring Wnt/β-catenin signaling is a promising therapeutic strategy for Alzheimer's disease[J]. Mol Brain, 2019, 12(1): 104.
[7] Li Z, Zhang XB, Gu JH, et al. Breviscapine exerts neuroprotective effects through multiple mechanisms in APP/PS1 transgenic mi-ce[J]. Mol Cell Biochem, 2020, 468(1/2): 1-11.
[8] Liu M, Guo HB, Li CY, et al. Cognitive improvement of compound danshen in an Aβ25-35 peptide-induced rat model of Alzheimer's disease[J]. BMC Complement Altern Med, 2015, 15(1): 382.
[9] Zuroff L, Daley D, Black KL, et al. Clearance of cerebral Aβ in Alzheimer's disease: reassessing the role of microglia and monocytes[J]. Cell Mol Life Sci, 2017, 74(12): 2167-2201.
[10]Wanek T, Zoufal V, Brackhan M, et al. Brain distribution of dual ABCB1/ABCG2 substrates is unaltered in a Beta-Amyloidosis mouse model[J]. Int J Mol Sci, 2020, 21(21): 8245.
[11]Elfakhri KH, Duong QV, Langley C, et al. Characterization of hit compounds identified from high-throughput screening for their effect on blood-brain barrier integrity and amyloid-β clearance: in vitro and in vivo studies[J]. Neuroscience, 2018, 379(2): 269-280.〖ZK)〗
[12]Zhao J, Li K, Wan K, et al. Organoplatinum-Substituted polyoxometalate inhibits β-amyloid aggregation for alzheimer's therapy[J]. Angew Chem Int Ed Engl, 2019, 58(50): 18032-18039.
[13]Janyou A, Wicha P, Jittiwat J, et al. Dihydrocapsaicin attenuates blood brain barrier and cerebral damage in focal cerebral ischemia/reperfusion via oxidative stress and inflammatory[J]. Sci Rep, 2017, 7(1): 10556.
[14]Christopher KI, Xie W, Zhu H, et al. γ-Glutamyl-Transpeptidase-Resistant glutathione analog attenuates progression of alzheimer's disease-like pathology and neurodegeneration in a mouse model[J]. Antioxidants (Basel), 2021, 10(11): 1796.
[15]Li Y, Li S, Li D. Breviscapine alleviates cognitive impairments induced by transient cerebral ischemia/reperfusion through its Anti-Inflammatory and Anti-Oxidant properties in a rat model[J]. ACS Chem Neurosci, 2020, 11(24): 4489-4498.
[16]Storck SE, Hartz A, Bernard J, et al. The concerted amyloid-beta clearance of LRP1 and ABCB1/P-gp across the blood-brain barrier is linked by PICALM[J]. Brain Behav Immun, 2018, 73(2): 21-33.
[17]Peng HB, Bukuroshi P, Durk MR, et al. Impact of age, hypercholesterolemia, and the vitamin D receptor on brain endogenous β-amyloid peptide accumulation in mice[J]. Biopharm Drug Dispos, 2021, 42(8): 372-388.
[18]Mohamed LA, Keller JN, Kaddoumi A. Role of P-glycoprotein in mediating rivastigmine effect on amyloid-β brain load and related pathology in Alzheimer's disease mouse model[J]. Biochim Biophys Acta, 2016, 1862(4): 778-787.
[19]Nusse R, Clevers H. Wnt/β-Catenin signaling, disease, and emerging therapeutic modalities[J]. Cell, 2017, 169(6): 985-999.
[20]Tapia-Rojas C, Inestrosa NC. Loss of canonical Wnt signaling is involved in the pathogenesis of Alzheimer's disease[J]. Neural Regen Res, 2018, 13(10): 1705-1710.
[21]Singh S, Mishra A, Shukla S. ALCAR exerts neuroprotective and Pro-Neurogenic effects by inhibition of glial activation and oxidative stress via activation of the Wnt/β-Catenin signaling in parkinsonian rats[J]. Mol Neurobiol, 2016, 53(7): 4286-4301.
[22]Ning WJ, Lv RJ, Xu N, et al. Lycopene-Loaded microemulsion regulates neurogenesis in rats with Aβ-Induced alzheimer's disease rats based on the Wnt/β-catenin pathway[J]. Neural Plast, 2021 (13): 5519330.
[23]Laksitorini MD, Yathindranath V, Xiong W, et al. Modulation of Wnt/β-catenin signaling promotes blood-brain barrier phenotype in cultured brain endothelial cells[J]. Sci Rep, 2019, 9(1): 19718.
[24]Rivera DS, Lindsay C, Codocedo JF, et al. Andrographolide recovers cognitive impairment in a natural model of Alzheimer's disease (Octodon degus)[J]. Neurobiol Aging, 2016, 46(2): 204-220.

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备注/Memo

备注/Memo:
基金项目：河北省2021年度医学科学研究课题计划（20211632）
更新日期/Last Update: 2022-10-10