通讯作者: 胡玉英, 13878847908@163.com

DOI：10.12201/bmr.202601.00070

• 摘要：目的:探讨中药补肾止颤方通过调控核因子红细胞相关因子2/谷胱甘肽过氧化物酶4（Nrf2/GPX4）通路抑制帕金森病（PD）大鼠多巴胺（DA）能神经元铁死亡的作用机制研究。方法:将42只SD大鼠随机分为对照组、模型组、Nrf2抑制剂组、中药补肾止颤方低、中、高剂量组、多巴丝肼组，每组6只大鼠。除对照组外，余各组大鼠均采用蛋白酶抑制因子(PSI)制备PD大鼠模型，继则给予Nrf2抑制剂组大鼠腹腔注射50mg/kg Nrf2抑制剂（ML385），其余各组注射同等剂量生理盐水，均在1周内于周一、周三、周五同一时间点完成，共3次。待模型稳定1周后，模型组及对照组予等体积生理盐水灌胃，余各组则予所对应药物剂量灌胃，均连续灌胃3周。期间采用滚筒试验、悬挂试验进行行为学测试，于治疗结束后取大鼠中脑黑质组织，采用Western blot法检测Nrf2、白细胞介素-4（IL-4）、白细胞介素 - 13（IL-13）表达，实时荧光定量聚合酶链反应PCR（RT-PCR法）检测Nrf2、铁蛋白重链 1（FTH1）、转铁蛋白受体 1（TfR1）mRNA表达，酶联免疫吸附试验（ELISA）检测GPX4、亚铁离子（Fe2+）、丙二醛（MDA）含量。结果:造模后，与对照组相比，余各组大鼠运动协调性显著降低，滚筒试验、悬挂试验行为学评分升高（P<0.05），Nrf2蛋白、Nrf2、FTH1 mRNA及GPX4表达水平均显著降低（P<0.05），IL-4、IL-13蛋白及TfR1 mRNA表达显著升高（P<0.05），Fe2+、MDA含量显著增加（P<0.05）；治疗后，中药补肾止颤方各剂量组PD模型大鼠与模型组、Nrf2抑制剂组大鼠相比，运动协调性明显提高，大鼠行为学评分降低（P<0.05），Nrf2蛋白、Nrf2、FTH1 mRNA及GPX4表达水平均显著升高（P<0.05），IL-4、IL-13蛋白及TfR1 mRNA表达显著降低（P<0.05），Fe2+、MDA含量显著降低（P<0.05），其中以补肾止颤方高剂量组改善最为明显（P<0.05）；与模型组相比，Nrf2抑制剂组黑质区Nrf2蛋白、Nrf2、FTH1 mRNA及GPX4表达水平均显著降低（P<0.05），IL-4、IL-13蛋白及TfR1 mRNA表达显著升高（P<0.05），Fe2+、MDA含量显著增加（P<0.05）。结论:补肾止颤方能显著改善PD模型大鼠运动协调能力，其机制可能是通过激活Nrf2表达，调控Nrf2/GPX4通路，促进FTH1及抑制TfR1表达，减少细胞内游离Fe2+蓄积，抑制脂质过氧化产物MDA及促炎因子IL-4、IL-13生成，从而抑制PD大鼠铁死亡以达到治疗PD的目的。

  关键词： 补肾止颤方; 帕金森病; 铁死亡; Nrf2/GPX4通路

   

  Abstract: Objective: To investigate the mechanism by which the Chinese herbal formula Bushen Zhichan Decoction inhibits ferroptosis of dopaminergic (DA)-ergic neurons in rats with Parkinsons disease (PD) by regulating the expression of Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2), Interleukin-4 (IL-4), and Interleukin-13 (IL-13).Methods: Seventy Sprague-Dawley (SD) rats were randomly divided into 7 groups (10 rats per group): control group, model group, Nrf2 inhibitor group, Bushen Zhichan Decoction low-dose group (15 g·kg?1·d?1), Bushen Zhichan Decoction medium-dose group (30 g·kg?1·d?1), Bushen Zhichan Decoction high-dose group (60 g·kg?1·d?1), and Levodopa and Benserazide group (2 g·kg?1·d?1). PD models were established using the proteasome inhibitor (PSI). Subsequently, rats in the Nrf2 inhibitor group were intraperitoneally injected with 50 mg/kg Nrf2 inhibitor (ML385), while rats in the other groups were injected with the same volume of normal saline; these injections were performed 3 times (on Mondays, Wednesdays, and Fridays) within 1 week. After the models were stabilized for 1 week, the model group and control group were given normal saline via gavage, and the remaining groups were given the corresponding drugs via gavage for 3 consecutive weeks. Behavioral tests were conducted during the treatment period. After treatment, the midbrain substantia nigra tissue was collected from the rats. Western blotting was used to detect the protein expression of Nrf2, IL-4, and IL-13; quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the mRNA expression of Nrf2; and enzyme-linked immunosorbent assay (ELISA) was used to measure the content of malondialdehyde (MDA).Results: After model establishment, compared with the control group, the other groups showed significantly decreased motor coordination, increased behavioral scores (P<0.05), significantly reduced Nrf2 mRNA and protein expression levels (P<0.05), significantly increased expression of IL-4 and IL-13 (P<0.05), and significantly elevated MDA content (P<0.05). After treatment, compared with the model group and Nrf2 inhibitor group, the Bushen Zhichan Decoction low-, medium-, and high-dose groups exhibited significantly improved motor coordination, decreased behavioral scores (P<0.05), significantly increased Nrf2 mRNA and protein expression in the substantia nigra (P<0.05), reduced expression of IL-4 and IL-13 (P<0.05), and decreased MDA content (P<0.05). Among these, the high-dose Bushen Zhichan Decoction group showed the most significant improvements (P<0.05). Compared with the model group, the Nrf2 inhibitor group had significantly lower Nrf2 mRNA and protein expression levels in the substantia nigra (P<0.05), higher expression of IL-4 and IL-13 (P<0.05), and significantly increased MDA content (P<0.05).

  Key words: Bushen Zhichan Formula; Parkinsons disease; Iron death; Nrf2

  提交时间：2026-01-26

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• 序号	提交日期	编号	操作
  1	2025-12-30	10.12201/bmr.202601.00070V1	下载

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