楮实子对APP/PS1双转基因小鼠海马神经发生的影响
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摘要
目的探讨楮实子对APP/PS1双转基因小鼠海马神经发生的影响。方法 40只APP/PS1双转基因小鼠随机分为模型组、阳性药组(10 mg/kg多奈哌齐)及楮实子低、高剂量组(1.8、3.6 g/kg),C57BL/6小鼠作为对照组,每组10只,灌胃给药6周。然后,Morris水迷宫实验检测小鼠学习记忆能力,TUNEL法检测小鼠海马区神经细胞凋亡,免疫荧光染色法检测小鼠海马区NeuN/BrdU阳性细胞表达,Western blot法检测GSK-3β、β-catenin蛋白表达。结果与模型组比较,楮实子高剂量组学习记忆能力显著改善(P<0.05),凋亡细胞数显著减少(P<0.01),NeuN/Brdu阳性细胞数显著增加(P<0.01),GSK-3β蛋白表达显著降低(P<0.05),β-catenin蛋白表达显著升高(P<0.05)。结论楮实子能促进APP/PS1双转基因小鼠海马神经发生,其机制可能与激活Wnt/β-catenin信号通路有关。
AIM To explore the effects of Broussonetiae Fructus on hippocampal neurogenesis in double transgenic APP/PS1 mice.METHODS Forty double transgenic APP/PS1 mice were randomly divided into model group, positive drug group(10 mg/kg donepezil) and low-dose, high-dose Broussonetiae Fructus groups(1.8, 3.6 g/kg), and C57 BL/6 mice were recruited into control group, 10 mice in each group, and intragastric administration went on for 6 weeks. Subsequently, Morris water maze test was used to detect mouse learning and memory activities, TUNEL assay and immunofluorescence staining method were applied to detecting nerve cell apoptosis and NeuN/BrdU positive cell expression in mouse hippocampal area, respectively, Western blot was adopted in the protein expression detection of GSK-3β and β-catenin.RESULTS Compared with the model group, the high-dose Broussonetiae Fructus group demonstrated significantly improved learning and memory activities(P<0.05), markedly reduced apoptosis cell count(P<0.01), obviously increased NeuN/BrdU positive cell count(P<0.01), significantly decreased GSK-3β protein expression(P<0.05), and markedly elevated β-catenin protein expression(P<0.05). CONCLUSION Broussonetiae Fructus can promote hippocampal neurogenesis in double transgenic APP/PS1 mice, whose mechanisms may be related to the activation of Wnt/β-catenin signaling pathway.
AIM To explore the effects of Broussonetiae Fructus on hippocampal neurogenesis in double transgenic APP/PS1 mice.METHODS Forty double transgenic APP/PS1 mice were randomly divided into model group, positive drug group(10 mg/kg donepezil) and low-dose, high-dose Broussonetiae Fructus groups(1.8, 3.6 g/kg), and C57 BL/6 mice were recruited into control group, 10 mice in each group, and intragastric administration went on for 6 weeks. Subsequently, Morris water maze test was used to detect mouse learning and memory activities, TUNEL assay and immunofluorescence staining method were applied to detecting nerve cell apoptosis and NeuN/BrdU positive cell expression in mouse hippocampal area, respectively, Western blot was adopted in the protein expression detection of GSK-3β and β-catenin.RESULTS Compared with the model group, the high-dose Broussonetiae Fructus group demonstrated significantly improved learning and memory activities(P<0.05), markedly reduced apoptosis cell count(P<0.01), obviously increased NeuN/BrdU positive cell count(P<0.01), significantly decreased GSK-3β protein expression(P<0.05), and markedly elevated β-catenin protein expression(P<0.05). CONCLUSION Broussonetiae Fructus can promote hippocampal neurogenesis in double transgenic APP/PS1 mice, whose mechanisms may be related to the activation of Wnt/β-catenin signaling pathway.
引文
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[13] Claeysen S, Cochest M, Donneger R, et al. Alzheimer culprits: cellular crossroads and interplay[J]. Cell Signal, 2012, 24(9):1831-1840.
[14] 朱红梅, 张凤兰, 肖志成, 等. 淀粉样前体蛋白在神经发生中的作用与阿尔茨海默病关系的研究进展[J]. 中国民族民间医药, 2017, 26(12):74-79,81.
[15] 张丽, 赵丽红, 张兰, 等. 山茱萸环烯醚萜苷促进成体大鼠海马神经干细胞增殖和分化的影响[J]. 中国新药杂志, 2015, 24(5):550-553,564.
[16] Maruszak A, Pilarski A, Murphy T, et al. Hippocampal neurogenesis in Alzheimer’s disease: is there a role for dietary modulation?[J]. J Alzheimers Dis, 2014, 38(1):11-38.
[17] Pluta R, Bogucka-Kocka A, U?amek-Kozio? M, et al. Neurogenesis and neuroprotection in postischemic brain neurodegeneration with Alzheimer phenotype: is there a role for curcumin?[J].Folia Neuropathol, 2015, 53(2):89-99.
[18] Borchelt D R, Ratovitski T, van Lare J, et al. Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins[J]. Neuron, 1997, 19(4):939-945.
[19] Holcomb L, Gordon M N, McGowan E, et al. Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes[J]. Nat Med, 1998, 4(1):97-100.
[20] Ho C, Hsu Y C, Lei C C, et al. Curcumin rescues diabetic renal fibrosis by targeting superoxide-mediated Wnt signaling pathways[J]. Am J Med Sci, 2016, 351(3):286-295.
[21] Hirota Y, Sawada M, Huang S H, et al. Roles of Wnt signaling in the neurogenic niche of the adult mouse ventricular-subventricular zone[J]. Neurochem Res, 2016, 41(1-2):222-230.
[22] Nishiya N. Screening for chemical suppressors of the Wnt/β-catenin signaling pathway[J]. Yakugaku Zasshi, 2017, 137(2):133-136.
[23] Chen X M, Zhou B H, Yan T T,et al. Peroxynitrite enhances self-renewal, proliferation and neuronal differentiation of neural stem/progenitor cells through activating HIF-1α and Wnt/β-catenin signaling pathway[J]. Free Radic Biol Med, 2018, 117:158-167.
[2] Mao N, Liu Y, Chen K, et al. Combinations of multiple neuroimaging markers using logistic regression for auxiliary diagnosis of Alzheimer disease and mild cognitive impairment[J]. Neurodegener Dis, 2018, 18(2-3):91-106.
[3] Chen C J, Bando K, Ashino H, et al. Biological evaluation of the radioiodinated imidazo[1,2-a]pyridine derivative DRK092 for amyloid-β imaging in mouse model of Alzheimer’s disease[J]. Neurosci Lett, 2014, 581:103-108.
[4] Mayeux R, Stern Y. Epidemiology of Alzheimer disease[J]. Cold Spring Harb Perspect Med, 2012, 2(8):a006239.
[5] Escribano L, Simon A M, Gimeno E, et al. Rosiglitazone rescues memory impairment in Alzheimer’s transgenic mice: mechanisms involving a reduced amyloid and tau pathology[J]. Neuropsychopharmacology, 2010, 35(7):1593-1604.
[6] Karran E, Mercken M, De Strooper B. The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics[J]. Nat Rev Drug Discov, 2011, 10(9):698-712.
[7] Wang S L, Yu L J, Yang H, et al. Oridonin attenuates synaptic loss and cognitive deficits in an aβ1-42-induced mouse model of Alzheimer’s disease[J]. PLoS One, 2016, 11(3):e0151397.
[8] 陈康, 贺燕勤, 于顾然. 楮实子水煎剂对H2O2介导PC12细胞凋亡的影响[J]. 四川中医, 2017, 35(2):41-44.
[9] 陈晓玲, 倪新强, 李映红. 中医药治疗老年性痴呆的实验研究进展[J]. 深圳中西医结合杂志, 2016, 26(18):195-198.
[10] 熊山, 叶祖光. 楮实子化学成分及药理作用研究进展[J]. 中国中医药信息杂志, 2009, 16(5):102-103.
[11] 杨金枝, 尹皎琳, 任汉阳, 等. 楮实子油对亚急性衰老模型小鼠脑组织抗氧化作用的实验研究[J]. 四川中医, 2008, 26(9):16-17.
[12] Pang S Q, Wang G Q, Huang B K, et al. Studies on chemical constituents of fructus broussonetiae[J]. J Chin Med Mat, 2009, 32(8):1229-1231.
[13] Claeysen S, Cochest M, Donneger R, et al. Alzheimer culprits: cellular crossroads and interplay[J]. Cell Signal, 2012, 24(9):1831-1840.
[14] 朱红梅, 张凤兰, 肖志成, 等. 淀粉样前体蛋白在神经发生中的作用与阿尔茨海默病关系的研究进展[J]. 中国民族民间医药, 2017, 26(12):74-79,81.
[15] 张丽, 赵丽红, 张兰, 等. 山茱萸环烯醚萜苷促进成体大鼠海马神经干细胞增殖和分化的影响[J]. 中国新药杂志, 2015, 24(5):550-553,564.
[16] Maruszak A, Pilarski A, Murphy T, et al. Hippocampal neurogenesis in Alzheimer’s disease: is there a role for dietary modulation?[J]. J Alzheimers Dis, 2014, 38(1):11-38.
[17] Pluta R, Bogucka-Kocka A, U?amek-Kozio? M, et al. Neurogenesis and neuroprotection in postischemic brain neurodegeneration with Alzheimer phenotype: is there a role for curcumin?[J].Folia Neuropathol, 2015, 53(2):89-99.
[18] Borchelt D R, Ratovitski T, van Lare J, et al. Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins[J]. Neuron, 1997, 19(4):939-945.
[19] Holcomb L, Gordon M N, McGowan E, et al. Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes[J]. Nat Med, 1998, 4(1):97-100.
[20] Ho C, Hsu Y C, Lei C C, et al. Curcumin rescues diabetic renal fibrosis by targeting superoxide-mediated Wnt signaling pathways[J]. Am J Med Sci, 2016, 351(3):286-295.
[21] Hirota Y, Sawada M, Huang S H, et al. Roles of Wnt signaling in the neurogenic niche of the adult mouse ventricular-subventricular zone[J]. Neurochem Res, 2016, 41(1-2):222-230.
[22] Nishiya N. Screening for chemical suppressors of the Wnt/β-catenin signaling pathway[J]. Yakugaku Zasshi, 2017, 137(2):133-136.
[23] Chen X M, Zhou B H, Yan T T,et al. Peroxynitrite enhances self-renewal, proliferation and neuronal differentiation of neural stem/progenitor cells through activating HIF-1α and Wnt/β-catenin signaling pathway[J]. Free Radic Biol Med, 2018, 117:158-167.
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