脂多糖诱导的慢性帕金森病小鼠模型α-突触核蛋白的出现和转移变化

中国临床药理学与治疗学 ›› 2017, Vol. 22 ›› Issue (3): 241-248.

• 基础研究 • 下一篇

脂多糖诱导的慢性帕金森病小鼠模型α-突触核蛋白的出现和转移变化

葛波波，屈洪党，陈育华，胡彩彩，李理，姜牧君，许娟娟

蚌埠医学院第一附属医院神经内科，蚌埠 233000，安徽

收稿日期:2016-11-30 修回日期:2017-01-23 出版日期:2017-03-26 发布日期:2017-03-29
通讯作者: 屈洪党，男，本科，主任医师，教授，研究生导师，研究方向：神经病学。 Tel：13500567863 E-mail：qhd820@163.com
作者简介:葛波波，男，硕士研究生，研究方向：神经免疫方向。 Tel：15655276953 E-mail：drgebobo1123@163.com
基金资助:
国家自然科学基金（81641050）；安徽省教育厅重点项目（KJ2104A163）；蚌埠医学院研究生创新计划（Byycx1519）

LPS-induced chronic Parkinson's disease in mice α-synuclein in the emergence and metastasis

GE Bobo，QU Hongdang，CHEN Yuhua，HU Caicai，LI Li，JIANG Mujun，XU Juanjuan

Department of Neurology, First Affiliated Hospital of Bengbu Medical College，Bengbu 233000，Anhui，China

Received:2016-11-30 Revised:2017-01-23 Online:2017-03-26 Published:2017-03-29

摘要/Abstract

摘要：

目的: 建立脂多糖（LPS）诱导的慢性帕金森病(PD)小鼠模型，探讨PD模型小鼠的行为学改变和肠壁中α-突触核蛋白聚集物的出现和转移变化情况。方法: 将48只雄性C57BL/6J小鼠，6周龄，随机分为生理盐水对照组、PD 模型组。采用腹腔注射LPS制备PD小鼠模型，通过转棒实验和旷场试验检测小鼠的行为学变化；通过免疫组化技术，观察PD模型组小鼠多巴胺能神经元丢失和α-突触核蛋白出现和转移变化。结果: PD模型小鼠行为学改变与生理盐水对照组具有差异性（P<0.01）；PD模型组小鼠的中脑黑质致密部的多巴胺能神经元出现严重损失；α-突触核蛋白（α-Syn）聚集最先出现在肠道，随着时间的延长，α-Syn转移到中脑黑质致密部。结论: 在LPS诱导的PD模型中，其典型的病理改变（α-Syn的沉聚）起始于结肠神经，并逐渐发展到中脑黑质致密部,进而导致多巴胺能神经元的损伤与丢失。

关键词: 脂多糖, 帕金森病, α-突触核蛋白, 多巴胺能神经元

Abstract:

AIM: To establish a mouse model of chronic Parkinson's disease(PD) induced by lipopolysaccharide (LPS) and to investigate the behavioral changes of PD mice and the appearance and metastasis of α-synuclein(α-Syn) aggregates in the intestinal wall. METHODS: 48 male C57BL/6J mice were randomly divided into normal saline control group and PD model group at 6 weeks of age. The PD mice model was established by intraperitoneal injection of LPS. Behavioral changes of the experimental mice were detected by the rotating bar test and field test. The dopaminergic neuron loss and α-Syn were observed by immunohistochemistry nuclear protein expression and metastasis. RESULTS:Behavioral changes of PD model mice exhibited significance difference (P<0.01). PD model mice's substantia nigra pars compacta α-Syn aggregation first appeared in the gut, and over time, the α-Syn was transferred to the substantia nigra of the mesencephalon, and the dopaminergic neurons were severely damaged. CONCLUSION: In the LPS-induced PD model, the typical pathological changes (α-Syn aggregation) begin in the colon nerves, and gradually develop into the substantia nigra pars compacta, resulting in dopaminergic neuron damage and loss.

Key words: lipopolysaccharide, Parkinson's disease, α-synuclein, dopaminergic neurons

中图分类号:

R965.2

葛波波，屈洪党，陈育华，胡彩彩，李理，姜牧君，许娟娟. 脂多糖诱导的慢性帕金森病小鼠模型α-突触核蛋白的出现和转移变化[J]. 中国临床药理学与治疗学, 2017, 22(3): 241-248.

GE Bobo，QU Hongdang，CHEN Yuhua，HU Caicai，LI Li，JIANG Mujun，XU Juanjuan. LPS-induced chronic Parkinson's disease in mice α-synuclein in the emergence and metastasis[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2017, 22(3): 241-248.

参考文献

［1］Goetz CG. The history of Parkinson's disease: early clinical descriptions and neurological therapies［J］. Cold Spring Harb Perspect Med, 2011, 1(1): a008862.
［2］Dickson DW, Braak H, Duda JE, et al. Neuropathological assessment of Parkinson's disease: refining the diagnostic criteria［J］.Lancet Neurol, 2009,8: 1150-1157.
［3］屈洪党, 史肖锦. 内质网应激介导的白藜芦醇对MPTP 诱导的小鼠帕金森病模型的神经保护作用［J］. 中国临床药理学与治疗学, 2016,21(1) : 28-32.
［4］Beach TG, Corbillé AG, Letournel F, et al. Multicenter assessment of immunohistochemical methods for pathological alpha-synuclein in sigmoid colon of autopsied Parkinson's disease and control subjects［J］. J Parkinsons Dis, 2016, 6(4):761-770.
［5］Marras C, Lang A. Parkinson's disease subtypes: lost in translation［J］? J Neurol Neurosurg Psychiatry, 2013, 84: 409-415.
［6］Luk KC, Kehm VM, Zhang B, et al. Intracerebral inoculation of pathological a-synuclein initiates a rapidly progressive neurodegenerative a-synucleinopathy in mice［J］. J Exp Med, 2012,209(5):975-986.
［7］Del TK, Hawkes CH, Ghebremedhin E, et al. Lewy pathology in the submandibular gland of individuals with incidental Lewy body disease and sporadic Parkinson's disease［J］. Acta Neuropathol, 2010,119（6）:703-713.
［8］Beach TG, Adler CH, Sue LI, et al. Multi-organ distribution of phosphorylated alpha-synuclein histopathology in subjects with Lewy body disorders［J］. Acta Neuropathol, 2010, 119（6）:689-702.
［9］Iwanaga K, Wakabayashi K, Yoshimoto M, et al. Lewy body-type degeneration in cardiac plexus in Parkinson's and incidental Lewy body diseases［J］. Neurology, 1999, 52（6）: 1269-1271.
［10］Fumimura Y, Ikemura M, Saito Y, et al. Analysis of the adrenal gland is useful for evaluating pathology of the peripheral autonomic nervous system in lewy body disease［J］. J Neuropathol Exp Neurol, 2007, 66(5): 354-362.
［11］Lebouvier T,Neunlist M,Bruley des VS,et al.Colonic biopsies to assess the neuropathology of Parkinson's disease and its relationship with symptoms［J］. PLoS One,2011,5（9）:e12728.
［12］Shannon KM, Keshavarzian A, Mutlu E, et al. Alpha-synuclein in colonic submucosa in early untreated Parkinson's disease［J］.Mov Disord, 2012,27(6): 709-715.
［13］Ling Z, Gayle DA, Ma SY, et al. In utero bacterial endotoxin exposure causes loss of tyrosine hydroxylase neurons in the postnatal rat midbrain［J］. Mov Disord, 2002, 17(1): 116-124.
［14］Gao HM, Jiang J, Wilson B, et al. Microglial activation-mediated delayed and progressive degeneration of rat nigral dopaminergic neurons: relevance to Parkinson's disease［J］. J Neurochem, 2002, 81(6): 1285-1297.
［15］Beach TG, Adler CH, Sue LI, et al. Multi-organ distribution of phosphorylated alpha-synuclein histopathology in subjects with Lewy body disorders［J］. Acta Neuropathol ,2010, 119（6）: 689-702.
［16］Del Tredici K, Hawkes CH, Ghebremedhin E, et al. Lewy pathology in the submandibular gland of individuals with incidental Lewy body disease and sporadic Parkinson's disease［J］. Acta Neuropathol 2010, 119(6): 703-713.
［17］Khoo TK, Yarnall AJ, Duncan GW, et al. The spectrum of non-motor symptoms in early Parkinson's disease［J］. Neurology, 2013, 80(3): 276-281.
［18］Postuma RB, Aarsland D, Barone P, et al. Identifying prodromal Parkinson's disease:pre-motor disorders in Parkinson's disease［J］. Mov Disord, 2012, 27(5): 617-626.
［19］Braak H, de Vos RA, Bohl J, et al. Gastric alpha-synuclein immunoreactive inclusions in Meissner's and Auerbach's plexuses in cases staged for Parkinson's disease-related brain pathology［J］. Neurosci Lett, 2006,396(1):67-72.
［20］Kumari R, Kumar JB, Luthra PM. Post-lesion administration of 7-NI attenuated motor and non-motor deficits in 6-OHDA induced bilaterally lesioned female rat model of Parkinson's disease［J］. Neurosci Lett, 2015, 589:191-195.
［21］Beal MF. Mitochondria take center stage in aging and neurodegeneration［J］. Ann Neurol, 2005, 58(4): 495-505.
［22］Patil SP, Jain PD, Ghumatkar PJ, et al. Neuroprotective effect of metformin in MPTP-induced Parkinson's disease in mice［J］. Neuroscience, 2014, 277:747-754.
［23］Dickson DW.Parkinson's disease and parkinsonism: neuropathology［J］.Cold Spring Harb Perspect Med,2012,2(8):pii:a009258.
［24］Masters CL, Kril JJ, Halliday GM, et al. Overview and recent advances in neuropathology. Part 2: Neurodegeneration［J］. Pathology, 2011,43(2): 93-102.
［25］Spillantini MG, Schmidt ML, Lee VM, et al. Alpha-synuclein in Lewy bodies［J］. Nature,1997,388(6645): 839-840.
［26］Goedert M, Spillantini MG, Del Tredici K, et al. 100 years of Lewy pathology［J］. Nat Rev Neurol, 2013, 99(1): 13-24.
［27］LiuY, Qiang M, Wei Y, et al. A novel molecular mechanism for nitrated α-synuclein-induced cell death［J］. J Mol Cell Biol,2011, 3(4):239-249.
［28］ Lee JK, Tran T, Tansey MG. Neuroinflammation in Parkinson's disease［J］. J Neuroimmune Pharmacol, 2009, 4(4): 419-429.
［29］Breidert T, Callebert J, Heneka MT, et al. Protective action of the peroxisome proliferator-activated receptor-gamma agonist pioglitazone in a mouse model of Parkinson's disease［J］. J Neurochem, 2002, 82（3）, 615-624.
［30］Gao HM, Hong JS. Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression［J］. Trends Immunol, 2008, 29(8): 357-365.

[1]	廖梦玲, 汪艳, 罗静, 王诺妍, 华玲, 张瑜, 邓非, 袁月, 周军, 周红. 青蒿琥酯抑制巨噬细胞释放前炎症细胞因子的分子作用机制研究[J]. 中国临床药理学与治疗学, 2023, 28(9): 969-978.
[2]	王金刚, 李强, 孙会艳, 王洪权. 鼠尾草酸在帕金森病中的神经保护作用机制研究进展[J]. 中国临床药理学与治疗学, 2023, 28(9): 1073-1080.
[3]	张蕾, 肖兴鹏, 丁煌. 沉默ZKSCAN3基因表达加重脂多糖诱导的小鼠肺损伤[J]. 中国临床药理学与治疗学, 2023, 28(2): 164-170.
[4]	占珠琴, 白海涛. 不同剂量地塞米松对脓毒症肾损伤大鼠血管紧张素II及其受体、NO水平变化的影响[J]. 中国临床药理学与治疗学, 2021, 26(9): 995-1004.
[5]	樊文香, 张锦璐, 徐驰. α7烟碱型乙酰胆碱受体在中枢神经系统性疾病中作用的研究进展[J]. 中国临床药理学与治疗学, 2021, 26(9): 1065-1072.
[6]	陆宸宇, 杨君, 刘怡希, 郑云. 帕金森氏病关联miRNAs的功能和调控[J]. 中国临床药理学与治疗学, 2020, 25(7): 775-783.
[7]	傅小媚，霍然，邓赛，林潮金，范景皓，王萍，李松沛，秦爱萍，邹明辉，余细勇. 脂多糖刺激的骨髓间充质干细胞来源外泌体改善小鼠心肌梗死后炎症和纤维化[J]. 中国临床药理学与治疗学, 2019, 24(8): 841-851.
[8]	刘焕淼，陈焯辉，吴迪，黄雪婷，万齐全. 胰岛素通过PI3K/AKT及PI3K/ERK通路减轻脂多糖对钠泵α1亚基的抑制[J]. 中国临床药理学与治疗学, 2019, 24(8): 896-902.
[9]	章水晶, 杜仲燕. 基于网络药理学研究丹参治疗帕金森病的作用机制[J]. 中国临床药理学与治疗学, 2019, 24(6): 601-607.
[10]	韩晨阳，张晓玲，杨毅，郭丽，官俏兵. α-突触核蛋白激活NLRP3炎性小体介导神经细胞焦亡的发生[J]. 中国临床药理学与治疗学, 2019, 24(6): 637-643.
[11]	陈少忠，林梅瑟，程黎民，朱乐乐. 红景天苷注射液对脂多糖诱导脓毒性休克肺损伤大鼠肺血管通透性的影响[J]. 中国临床药理学与治疗学, 2019, 24(11): 1256-1262.
[12]	曹迎亚，陈群，王箴，吴敬医，姜小敢，金孝岠，鲁卫华. 巨噬细胞在脂多糖诱导肠上皮细胞凋亡中的作用[J]. 中国临床药理学与治疗学, 2019, 24(10): 1142-1146.
[13]	常永丽，王春雷，原丽，郭晓姝，韩玲娜. 外侧隔GABA_A受体在帕金森病模型大鼠焦虑样行为中的作用[J]. 中国临床药理学与治疗学, 2018, 23(7): 734-742.
[14]	周荣，李玮，胡万华. 颐脑解郁方治疗肾虚肝郁型帕金森病抑郁的临床疗效评价及对血清DA、5-HT、NE的影响[J]. 中国临床药理学与治疗学, 2018, 23(4): 434-439.
[15]	郑爽，付秦磊，周玲萍，彭传鹏，徐红蕾. IL-17A与脂多糖诱导的小鼠急性肺损伤早期反应的关系[J]. 中国临床药理学与治疗学, 2018, 23(2): 148-153.

脂多糖诱导的慢性帕金森病小鼠模型α-突触核蛋白的出现和转移变化

LPS-induced chronic Parkinson's disease in mice α-synuclein in the emergence and metastasis

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 15

编辑推荐

Metrics

本文评价