Wu Dong, Zhou Wenjuan, Du Jingyi, Zhao Tiantian, Li Naigang, Peng Fan, Li Anna, Zhang Xinyue, Zhang Meihua, Hao Aijun
Key Laboratory of Maternal and Fetal Medicine of National Health Commission of China, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, China.
Key Laboratory for Experimental Teratology of Ministry of Education, Shandong Key Laboratory of Mental Disorders, Department of Anatomy and Histoembryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Front Pharmacol. 2024 Sep 11;15:1473019. doi: 10.3389/fphar.2024.1473019. eCollection 2024.
White matter injury is a predominant form of brain injury in preterm infants. However, effective drugs for its treatment are currently lacking. Previous studies have shown the neuroprotective effects of Isoliquiritigenin (ISL), but its impact on white matter injury in preterm infants remains poorly understood.
This study aimed to investigate the protective effects of ISL against white matter injury caused by infection in preterm infants using a mouse model of lipopolysaccharide-induced white matter injury, integrating network pharmacology as well as and experiments.
This study explores the potential mechanisms of ISL on white matter injury by integrating network pharmacology. Core pathways and biological processes affected by ISL were verified through experiments, and motor coordination, anxiety-like, and depression-like behaviors of mice were evaluated using behavioral experiments. White matter injury was observed using hematoxylin-eosin staining, Luxol Fast Blue staining, and electron microscopy. The development of oligodendrocytes and the activation of microglia in mice were assessed by immunofluorescence. The expression of related proteins was detected by Western blot.
We constructed a drug-target network, including 336 targets associated with ISL treatment of white matter injury. The biological process of ISL treatment of white matter injury mainly involves microglial inflammation regulation and myelination. Our findings revealed that ISL reduced early nerve reflex barriers and white matter manifestations in mice, leading to decreased activation of microglia and release of proinflammatory cytokines. Additionally, ISL demonstrated the ability to mitigate impairment in oligodendrocyte development and myelination, ultimately improving behavior disorders in adult mice. Mechanistically, we observed that ISL downregulated HDAC3 expression, promoted histone acetylation, enhanced the expression of H3K27ac, and regulated oligodendrocyte pro-differentiation factors.
These findings suggest that ISL can have beneficial effects on white matter injury in preterm infants by alleviating inflammation and promoting oligodendrocyte differentiation.
白质损伤是早产儿脑损伤的主要形式。然而，目前缺乏有效的治疗药物。先前的研究已经表明异甘草素（ISL）具有神经保护作用，但其对早产儿白质损伤的影响仍知之甚少。
本研究旨在利用脂多糖诱导的白质损伤小鼠模型，结合网络药理学及相关实验，探讨ISL对早产儿感染所致白质损伤的保护作用。
本研究通过整合网络药理学探索ISL对白质损伤的潜在作用机制。通过实验验证ISL影响的核心通路和生物学过程，并使用行为实验评估小鼠的运动协调性、焦虑样和抑郁样行为。采用苏木精-伊红染色、髓鞘蓝染色和电子显微镜观察白质损伤情况。通过免疫荧光评估小鼠少突胶质细胞的发育和小胶质细胞的激活情况。采用蛋白质免疫印迹法检测相关蛋白的表达。
我们构建了一个药物-靶点网络，其中包括336个与ISL治疗白质损伤相关的靶点。ISL治疗白质损伤的生物学过程主要涉及小胶质细胞炎症调节和髓鞘形成。我们的研究结果显示，ISL可降低小鼠早期神经反射障碍和白质表现，导致小胶质细胞激活减少和促炎细胞因子释放减少。此外，ISL还表现出减轻少突胶质细胞发育和髓鞘形成受损的能力，最终改善成年小鼠的行为障碍。机制上，我们观察到ISL下调HDAC3表达，促进组蛋白乙酰化，增强H3K27ac的表达，并调节少突胶质细胞前分化因子。
这些研究结果表明，ISL可通过减轻炎症和促进少突胶质细胞分化，对早产儿白质损伤产生有益影响。
