Zhao Shiyan, Lu Jun, Zhao Yanyan, Qi Chang, Han Chunrong
Department of Pathology, Nanjing Lishui District People's Hospital, Nanjing, Jiangsu, China.
Department of Electrocardiogram, Nanjing Lishui District People's Hospital, Nanjing, Jiangsu, China.
Neurol Res. 2025 May 12:1-12. doi: 10.1080/01616412.2025.2505242.
Ischemic stroke is a leading cause of mortality and disability worldwide, yet effective therapeutic options remain limited. In this study, bioinformatics analyses were used to identify potential therapeutic targets and small-molecule compounds for ischemic stroke. A mouse model of cerebral ischemia was subsequently used to validate their neuroprotective efficacy.
Bioinformatics methods were used to analyze and identify key signaling pathways and hub genes associated with ischemic stroke. Additionally, the Connectivity Map (CMap) database was queried to identify potential small-molecule compounds for ischemic stroke treatment. Finally, a middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model was employed to further evaluate the neuroprotective effects of the identified compounds.
GO and KEGG pathway enrichment analyses revealed that key signaling pathways such as TNF, NF-κB, and IL-17 play crucial roles in ischemic stroke. PPI network analysis identified five hub genes-IL-1β, IL-6, ICAM-1, Jun, and Fos-all closely associated with neuroinflammatory responses. The small-molecule compound PP2, a selective Src kinase inhibitor, was identified by CMap database. In the MCAO/R mouse model, PP2 exhibited significant neuroprotective effects. It reduced infarct volume and brain edema and improved neurological function. Mechanistically, PP2 inhibited Src phosphorylation, thereby suppressing the NF-κB signaling pathway and reducing levels of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6.
This study identifies Src kinase as a promising therapeutic target for ischemic stroke and highlights the value of bioinformatics in drug discovery and mechanistic research.
缺血性中风是全球范围内导致死亡和残疾的主要原因之一，但有效的治疗选择仍然有限。在本研究中，运用生物信息学分析来识别缺血性中风的潜在治疗靶点和小分子化合物。随后使用脑缺血小鼠模型来验证它们的神经保护功效。
采用生物信息学方法分析和识别与缺血性中风相关的关键信号通路和枢纽基因。此外，查询连通性图谱（CMap）数据库以识别用于缺血性中风治疗的潜在小分子化合物。最后，采用大脑中动脉闭塞/再灌注（MCAO/R）小鼠模型进一步评估所识别化合物的神经保护作用。
基因本体（GO）和京都基因与基因组百科全书（KEGG）通路富集分析显示，TNF、NF-κB和IL-17等关键信号通路在缺血性中风中起关键作用。蛋白质-蛋白质相互作用（PPI）网络分析确定了五个枢纽基因——IL-1β、IL-6、细胞间黏附分子-1（ICAM-1）、Jun和Fos——均与神经炎症反应密切相关。通过CMap数据库鉴定出小分子化合物PP2，一种选择性Src激酶抑制剂。在MCAO/R小鼠模型中，PP2表现出显著的神经保护作用。它减小了梗死体积和脑水肿，并改善了神经功能。机制上，PP2抑制Src磷酸化，从而抑制NF-κB信号通路并降低促炎细胞因子水平，包括TNF-α、IL-1β和IL-6。
本研究确定Src激酶是缺血性中风有前景的治疗靶点，并突出了生物信息学在药物发现和机制研究中的价值。
