中国药理学与毒理学杂志2026，Vol.40Issue(2)：115-127,13.DOI:10.3867/j.issn.1000-3002.2026.08701
叉分蓼总黄酮调控铁死亡治疗帕金森病的作用机制
Mechanisms of total flavonoids of Polygonum divaricatum L.against Parkinson's disease by regulating ferroptosis
摘要
Abstract
OBJECTIVE To investigate the mechanism through which total flavonoids of Polygonum divaricatum L.(TFP)regulate ferroptosis for the treatment of Parkinson's disease(PD).METHODS① Core ferroptosis-related differential genes involved in TFP's treatment of PD were identified via bioin-formatics analysis and molecular docking technology.② Animal experiments:C57BL/6 mice were randomly divided into the control group,the model group,the model+TFP 0.78 g·kg-1 group,and the model+TFP 1.56 g·kg-1 group.Mice in the model+TFP groups received corresponding treatment once daily by intragastric administration for 14 consecutive days.Except the control group,PD was induced in each group by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)(30 mg·kg-1)on experimental days 5 to 9.Pole climbing and balance beam tests were used to evaluate the motor coordination ability of PD mice.After completion of behavioral tests,immunohistochemistry was performed to detect the expression levels of tyrosine hydroxylase(TH),α-synuclein(α-syn),ionized calcium-binding adaptor molecule-1(IBA-1),and glial fibrillary acidic protein(GFAP)in the substantia nigra-striatum(SN-str)of mice.The levels of total iron(Fe)and ferrous iron(Fe2+)in brain tissue were determined by the ferrozine colorimetric assay.The content of malondialdehyde(MDA)was measured using the thiobarbi-turic acid(TBA)assay while the level of total-superoxide dismutase(T-SOD)was detected by the WST-1 assay.ELISA was used to measure the levels of Fe2+,glutathione synthetase(GSS),glutathione(GSH),and reactive oxygen species(ROS).RT-qPCR was conducted to detect the mRNA expressions of Gss,autophagy-related gene 7(Atg7),and acyl-CoA synthetase long-chain family member 4(Acsl4)in brain tissues.Western blotting was used to determine the protein expression levels of GSS,ATG7,ACSL4,GSH peroxidase 4(GPX4),lysophosphatidylcholine acyltransferase 3(LPCAT3),and nuclear receptor coactivator 4(NCOA4)in brain tissues.RESULTS Bioinformatics analysis and molecular docking confirmed that Gss,Atg7,and Acsl4 were the core targets of TFP in regulating ferroptosis in PD.Animal experiments showed that compared with the control group,there was a significant decrease in motor coordination,massive loss of TH-positive dopaminergic neurons in the substantia nigra-striatum,a surge in α-syn protein levels,and significant increases in the number and expression levels of IBA-1-and GFAP-positive cells accompanied by typical activation-related morphological alterations in the model group.At the mechanistic level,mRNA levels of Atg7 and Acsl4 were significantly elevated,Gss mRNA levels were significantly decreased in brain tissues,ferroptosis-related proteins ACSL4 and LPCAT3 as well as ferri-tinophagy pathway molecules ATG7 and NCOA4 were significantly upregulated,GPX4 protein expres-sion was significantly reduced,the contents of Fe,Fe2+,ROS and MDA in brain tissues were increased while the levels of GSH,GSS and T-SOD were significantly decreased in the model group.Compared with model group,the aforementioned pathological injuries and molecular abnormalities were effectively mitigated in that motor function was significantly restored,the loss of TH-positive neurons was attenuated,α-syn levels were reduced,the abnormal increases in IBA-1-and GFAP-positive cells were significantly inhibited,activation-related morphological alterations were markedly ameliorated,the mRNA levels of Atg7 and Acsl4 were decreased,Gss mRNA levels were significantly increased,the protein expression levels of ACSL4,LPCAT3,ATG7,and NCOA4 were significantly downregulated,the contents of Fe,Fe2+,ROS and MDA were significantly reduced,and the levels of GSH,GSS and T-SOD were significantly elevated in the model+TFP group.However,no significant difference was observed in GPX4 protein expressions.CONCLUSION TFP can effectively ameliorate both pathological damage and motor dysfunction in MPTP-induced PD mice.The underlying mechanism may involve the modulation of the ferroptosis pathway by targeting such core proteins as GSS,ATG7 and ACSL4.关键词
叉分蓼总黄酮/帕金森病/铁死亡/生物信息学/铁过载/氧化应激/脂质过氧化Key words
total flavonoids of Polygonum divaricatum L./Parkinson disease/ferroptosis/bioinfor-matics/iron overload/oxidative stress/lipid peroxidation分类
医药卫生引用本文复制引用
段超慧,梁茹,陈晓冉,焦鸿宇,赵鑫迪,田彩云,张红丽,高博闻..叉分蓼总黄酮调控铁死亡治疗帕金森病的作用机制[J].中国药理学与毒理学杂志,2026,40(2):115-127,13.基金项目
包头医学院博士科研启动基金(BYJJ-BSJJ202306) （BYJJ-BSJJ202306）
包头医学院自然科学基金青苗计划(BYJJ-ZRQM202422) （BYJJ-ZRQM202422）
包头医学院药学提质培育学科建设(YXTZ202501) Doctoral Scientific Research Start-up Fund Project of Baotou Medical College(BYJJ-BSJJ 202306) （YXTZ202501）
Natural Science Foundation Seedling Program Project of Baotou Medical College(BYJJ-ZRQM 202422) （BYJJ-ZRQM 202422）
and Pharmacy Quality Improvement and Cultivation Discipline Construction Project of Baotou Medical College(YXTZ202501) （YXTZ202501）
