中国临床药理学与治疗学 ›› 2026, Vol. 31 ›› Issue (1): 14-27.doi: 10.12092/j.issn.1009-2501.2026.01.002
新吉乐1(
), 刘晶2, 张欣翼2, 郭家缘3, 韩文卓1, 孙怡馨3, 赵乐1, 冯卫生1, 郑晓珂1,*()
收稿日期:2024-09-25
修回日期:2025-01-28
出版日期:2026-01-26
发布日期:2026-02-13
通讯作者:
郑晓珂
E-mail:xlz515@163.com;zhengxk.2006@163.com
作者简介:新吉乐，男，博士，讲师，主要从事神经药理学研究。E-mail：基金资助:
Jile XIN1(), Jing LIU2, Xinyi ZHANG2, Jiayuan GUO3, Wenzhuo HAN1, Yixin SUN3, Le ZHAO1, Weisheng FENG1, Xiaoke ZHENG1,*()
Received:2024-09-25
Revised:2025-01-28
Online:2026-01-26
Published:2026-02-13
Contact:
Xiaoke ZHENG
E-mail:xlz515@163.com;zhengxk.2006@163.com
摘要：
目的: 筛选调控帕金森病（Parkinson's disease，PD）发病关键基因及相关转录因子表达的小分子化合物。方法: 分析PD患者的基因表达谱数据，筛选PD发病关键基因及转录因子。Connectivity Map（CMap）筛选可调控转录因子表达的小分子药物，并在6-羟基多巴胺（6-OHDA）诱导损伤的PC12细胞和PD小鼠模型评价其PD治疗作用。结果: 维拉帕米（verapamil，Ver）为潜在的候选药物。Ver对6-OHDA损伤的PC12细胞具有保护作用，同时对6-OHDA诱导的PAX5、LEF1、MTF1、IKZF3和SP140等转录因子，以及ITGA6、CDH1、CD40、ESR1、SMAD3、CXCR4等PD发病基因的表达具有调控作用。PD模型小鼠中，Ver可对α-突触核蛋白（α-Syn）表达有一定抑制作用，但对上述PD发病基因及其转录因子和调控作用较弱。结论: Ver对PD的治疗作用部分依赖于对PD发病基因及其相关转录因子的调控作用。
中图分类号:
新吉乐, 刘晶, 张欣翼, 郭家缘, 韩文卓, 孙怡馨, 赵乐, 冯卫生, 郑晓珂. 基于Connectivity Map的药物重定位评价维拉帕米作为治疗帕金森病的药物[J]. 中国临床药理学与治疗学, 2026, 31(1): 14-27.
Jile XIN, Jing LIU, Xinyi ZHANG, Jiayuan GUO, Wenzhuo HAN, Yixin SUN, Le ZHAO, Weisheng FENG, Xiaoke ZHENG. Connectivity Map-based drug repositioning evaluation of verapamil as a therapeutic agent for Parkinson's disease[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2026, 31(1): 14-27.
图 1
Fig.1 Differential gene expression analysis A: Box diagram of normalization of samples. The box plot illustrates the transcriptional expression values of the 12 samples in the Parkinson's disease (PD) expression profile dataset GSE169755. B: Differential expression analysis. The volcano plot displays differentially expressed genes (DEGs) associated with PD onset in the GSE169755 dataset. Red dots indicate downregulated genes, while blue dots represent upregulated genes.
图 2
Fig.2 Protein-protein interaction (PPI) network and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis A: PPI network constructed from PD-onset-associated DEGs. Node color closer to red and larger node size indicate higher criticality. B: GO enrichment analysis results. C: KEGG analysis results.
图 3
Fig.3 PPI network of hub pathways implicated in PD onset
图 4
Fig.4 Transcription factors that regulate hub genes implicated in PD onset and screening of small molecules that regulate the expression of transcription factors A: Regulatory network of transcription factors interacting with PD-associated genes. B: Connectivity Map (CMap) screening for potential small-molecule drugs that modulate the aforementioned transcription factors. The CMap prediction results indicated that verapamil (Ver) exhibited a raw_cs value of -100, the lowest among all compounds, making it the optimal therapeutic candidate.
图 5
Fig.5 Protective effect of verapamil (Ver) against 6-hydroxydopamine (6-OHDA)-induced cytotoxicity in PC12 cells ($ \overline{x} $±s, n=3) A: Cytotoxic effects of 6-OHDA on PC12 cells. B: Effects of Ver on the growth rate of 6-OHDA-induced damaged PC12 cells. C: Effects of Ver on the apoptosis rate of 6-OHDA-induced damaged PC12 cells. bP<0.05, cP<0.01, compared with the control group; fP<0.01, compared with the 6-OHDA group.
图 6 bP<0.05, cP<0.01, compared with the control group; eP<0.05, fP<0.01, compared with the 6-OHDA group.
Fig.6 The regulatory effects of Ver on the expression of transcription factors such as PAX5, LEF1, MTF1, IKZF3, and SP140 in 6-OHDA exposed PC12 cells ($ \overline{x} $±s, n=3) bP<0.05, cP<0.01, compared with the control group; eP<0.05, fP<0.01, compared with the 6-OHDA group.
图 7 cP<0.01, compared with the control group; fP<0.01, compared with the 6-OHDA group.
Fig.7 The regulatory effects of Ver on the expression of hub genes implicated in PD onset, such as ITGA6, CDH1, CD40, ESR1, SMAD3, and CXCR4 in 6-OHDA exposed PC12 cells ($ \overline{x} $±s, n=3) cP<0.01, compared with the control group; fP<0.01, compared with the 6-OHDA group.
图 8
Fig.8 Effect of Ver on tyrosine hydroxylase (TH) expression in a 6-OHDA-induced rat model of Parkinson’s disease ($ \overline{x} $±s, n=6) cP<0.01, compared with the control group; fP<0.01, compared with the 6-OHDA group. Scale bar=100 μm; the white arrow represent the TH-positive neuronal cell with brown color.
图 9
Fig.9 Effect of Ver on α-synuclein expression in a 6-OHDA induced rat model of PD ($ \overline{x} $±s, n=6) cP<0.01, compared with the control group; fP<0.01, compared with the 6-OHDA group. MFI: mean fluorescence intensity; Scale bar=50 μm; the white arrow represent the α-Syn-positive neuronal cell with red fluorescence.
图 10
Fig.10 Western blot detection of the effect of Ver on the expression of TH and α-Syn in the substantia nigra compacta of the 6-OHDA-induced PD mouse model ($ \overline{x} $±s, n=6) cP<0.01, compared with the control group; fP<0.01, compared with the 6-OHDA group.
图 11
Fig.11 The regulatory effects of Ver on the expression of transcription factors such as PAX5, LEF1, MTF1, IKZF3, and SP140 in a 6-OHDA induced rat model of PD ($ \overline{x} $±s, n=6) cP<0.01, compared with the control group; fP<0.01, compared with the 6-OHDA group.
图 12 bP<0.05, cP<0.01, compared with the control group; fP<0.01, compared with the 6-OHDA group.
Fig.12 The regulatory effects of Ver on the expression of hub genes implicated in PD onset, such as ITGA6, CDH1, CD40, ESR1, SMAD3, and CXCR4 in the 6-OHDA induced rat model of PD ($ \overline{x} $±s, n=6) bP<0.05, cP<0.01, compared with the control group; fP<0.01, compared with the 6-OHDA group.
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