中国组织工程研究

中国组织工程研究 ›› 2025, Vol. 29 ›› Issue (5): 989-994.doi: 10.12307/2025.294

• 神经组织构建 nerve tissue construction • 上一篇    下一篇

富马酸二甲酯减轻帕金森病模型鼠神经损伤的作用机制

逯冉冉1，周  旭1，张利杰2，杨新玲1，3   

  1. 1新疆医科大学第二附属医院，新疆维吾尔自治区乌鲁木齐市  830028；2新疆生产建设兵团医院，新疆维吾尔自治区乌鲁木齐市  830000；3新疆医科大学，新疆维吾尔自治区乌鲁木齐市  830054
  • 收稿日期:2024-01-25 接受日期:2024-03-16 出版日期:2025-02-18 发布日期:2024-06-03
  • 通讯作者: 杨新玲，博士，主任医师，博士生导师，新疆医科大学第二附属医院，新疆维吾尔自治区乌鲁木齐市 830028；新疆医科大学，新疆维吾尔自治区乌鲁木齐市 830054
  • 作者简介:逯冉冉，女，1991年生，山东省潍坊市人，汉族，新疆医科大学在读博士，医师，主要从事神经退行性疾病的研究，尤其是帕金森病的研究。
  • 基金资助:
    国家自然科学基金项目(82160232)，项目负责人：杨新玲；新疆维吾尔自治区研究生研究创新基金资助项目(XJ2023G177)，项目负责人：逯冉冉

Dimethyl fumarate alleviates nerve damage in a mouse model of Parkinson’s disease 

Lu Ranran1, Zhou Xu1, Zhang Lijie2, Yang Xinling1, 3   

  1. 1The Second Affiliated Hospital of Xinjiang Medical University, Urumqi 830028, Xinjiang Uygur Autonomous Region, China; 2Xinjiang Production and Construction Corps Hospital, Urumqi 830000, Xinjiang Uygur Autonomous Region, China; 3Xinjiang Medical University, Urumqi 830054, Xinjiang Uygur Autonomous Region, China
  • Received:2024-01-25 Accepted:2024-03-16 Online:2025-02-18 Published:2024-06-03
  • Contact: Yang Xinling, MD, Chief physician, Doctoral supervisor, The Second Affiliated Hospital of Xinjiang Medical University, Urumqi 830028, Xinjiang Uygur Autonomous Region, China; Xinjiang Medical University, Urumqi 830054, Xinjiang Uygur Autonomous Region, China
  • About author:Lu Ranran, MD candidate, Physician, The Second Affiliated Hospital of Xinjiang Medical University, Urumqi 830028, Xinjiang Uygur Autonomous Region, China
  • Supported by:
    National Natural Science Foundation of China, No. 82160232 (to YXL); Xinjiang Uygur Autonomous Region Graduate Research Innovation Fund Project, No. XJ2023G177 (to LRR)

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摘要：




文题释义：
富马酸二甲酯(dimethylfumarate，DMF)：是一种获得美国食品药物管理局批准，可以作为临床一线治疗药物。体内的药代动力学显示，DMF在小肠的碱性环境中可部分皂化成其初级代谢产物富马酸单甲酯(monomethylfumarate，MMF)。经研究发现，DMF及MMF均能活化核转录因子E2相关因子2(nuclear factor erythroid 2-related factor 2，Nrf2)，同时能上调抗氧化剂靶基因的表达。
Keap1/Nrf2信号通路：是一个重要的抗氧化和抗炎信号通路，通过调节该通路可以对抗氧化应激和炎症反应，从而保护神经元免受损伤。在神经退行性疾病模型中，Nrf2耗竭会加剧中枢神经系统的症状并增强氧化损伤和炎症；相反Nrf2激活可以改善这些症状。

背景：帕金森病是一种特征为多巴胺能神经元进行性丢失的多因素神经系统疾病，富马酸二甲酯(dimethyl fumarate，DMF)在神经退行性疾病中具有强大的神经保护和免疫调节作用。
目的：探究DMF对MPTP诱导的帕金森病小鼠模型的神经保护机制。
方法：选取24只C57BL/6 系小鼠，随机将其分为对照组、模型组及DMF低剂量和DMF高剂量组。除对照组外，其余各组小鼠腹腔注射MPTP 30 mg/kg，1次/d，连续注射5 d，建立帕金森病的动物模型。每次注射MPTP后间隔30 min给予小鼠灌胃，DMF低剂量组和DMF高剂量组每天分别灌胃DMF 30，50 mg/kg，1次/d，对照组和模型组灌同等剂量的生理盐水，连续灌胃7 d。通过行为学检测、Western Blot、氧化应激标志物检测和免疫组织化学染色等方法，分析DMF对MPTP诱导的帕金森病小鼠氧化应激和Keap1/Nrf2信号通路的调节作用，以及DMF对多巴胺神经元变性的保护机制。
结果与结论：①与模型组比较，DMF低剂量组小鼠的运动迟缓和姿势平衡障碍得到明显改善(P < 0.01)，在DMF高剂量组中的改善更为显著 (P < 0.01)。②与对照组相比，模型组氧化应激标志物丙二醛明显升高，超氧化物歧化酶表达降低(P < 0.01)；与模型组相比，DMF低、高剂量组降低了丙二醛的产生，增加了超氧化物歧化酶的表达(P < 0.01)。③模型组小鼠的中脑黑质多巴胺能神经元数目和酪氨酸羟化酶蛋白表达较对照组明显减少(P < 0.01)，而DMF低剂量组小鼠的黑质多巴胺能神经元数目和蛋白表达增多(P < 0.01)，DMF高剂量组改善更明显(P < 0.01)。④模型组Keap1蛋白表达升高伴随Nrf2蛋白表达降低；与模型组相比，DMF组降低了Keap1蛋白表达且伴随Nrf2蛋白表达增多(P < 0.01)。⑤结果说明，DMF对帕金森病小鼠黑质区Keap1/Nrf2通路有调控作用，且与剂量呈现正相关(P < 0.01)，推测DMF依赖于Keap1/Nrf2信号发挥神经元保护作用。
https://orcid.org/0009-0002-6891-6966(逯冉冉)

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

关键词: 富马酸二甲酯, DMF, Keap1, Nrf2, 帕金森病, 氧化应激, 神经元变性

Abstract: BACKGROUND: Parkinson’s disease is a multifactorial neurological disorder characterized by progressive loss of dopaminergic neurons, and dimethyl fumarate (DMF) has potent neuroprotective and immunomodulatory effects in neurodegenerative diseases.
OBJECTIVE: To explore the neuroprotective mechanism of DMF in a mouse model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson’s disease.
METHODS: Twenty-four C57BL/6 mice were selected and randomly divided into control group, model group, low-dose DMF, and high-dose DMF groups. An animal model of Parkinson’s disease was established in the latter three groups by intraperitoneal injection of 30 mg/kg MPTP, once a day for 5 consecutive days. Intragastric administration was given 30 minutes after each injection of MPTP. Mice in the low-dose DMF group (30 mg/kg) and high-dose DMF group 
(50 mg/kg) were intragastrically administered once a day for 7 consecutive days. The control and model groups were initially administered the same dose of normal saline. Behavioral testing, western blot, oxidative stress marker detection, and immunohistochemical staining were used to analyze the regulatory effects of DMF on oxidative stress and Keap1/Nrf2 signaling pathway in MPTP-induced Parkinson’s disease mice, as well as the protective mechanism of DMF on degeneration of dopamine neurons.
RESULTS AND CONCLUSION: Compared with the model group, mice in the low-dose DMF group exhibited significant improvements in motor retardation and postural imbalance (P < 0.01), with even more remarkable improvements observed in the high-dose DMF group (P < 0.01). Compared with the control group, the model group showed a significant increase in the oxidative stress marker malondialdehyde and a decrease in superoxide dismutase expression 
(P < 0.01). Compared with the model group, the low-dose DMF group reduced malondialdehyde production and increased superoxide dismutase expression (P < 0.01), and similar improvements were observed in the high-dose DMF group (P < 0.01). Immunohistochemical and western blot assays demonstrated a significant decrease in the number of dopaminergic neurons and tyrosine hydroxylase protein expression in the substantia nigra of mice in the model group compared with the control group (P < 0.01). However, in the low-dose DMF group, there was an increase in the number of dopaminergic neurons and tyrosine hydroxylase protein expression in the substantia nigra (P < 0.01), with even more significant improvements in the high-dose DMF group (P < 0.01). Western blot results revealed that the model group exhibited elevated Keap1 protein expression and decreased Nrf2 protein expression. In contrast, the DMF groups showed reduced Keap1 protein expression and increased Nrf2 protein expression compared to the model group (P < 0.01). To conclude, DMF regulates the Keap1/Nrf2 pathway in the substantia nigra of mice with Parkinson’s disease, and this regulatory effect is positively correlated with the dose of DMF (P < 0.01). Therefore, we infer that DMF exerts neuroprotective effects through the Keap1/Nrf2 signaling pathway.


Key words: dimethyl fumarate, DMF, Keap1, Nrf2, Parkinson’s disease, oxidative stress, neuronal degeneration

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