石榴皮鞣质通过调节AKT-FOXO4抑制新生缺氧缺血性脑损伤大鼠的过度自噬并改善脑功能。
Punicalagin inhibits excessive autophagy and improves cerebral function in neonatal rats with hypoxia-ischemia brain injury by regulating AKT-FOXO4.
作者信息
Shen Ming, Lu Junhong, Li Caiyan, Li Yujiang, Yu Qianqian, Gao Xinyu, Wang Zhouguang, Yang Guanhu, Li Shengcun, Lin Zhenlang
机构信息
Department of Neonatology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou 325000, Zhejiang, PR China; Key Laboratory of Rehabilitation, Key Laboratory of Perinatal Medicine of Wenzhou, Wenzhou 325024, Zhejiang, China.
Department of Neonatology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou 325000, Zhejiang, PR China.
出版信息
Phytomedicine. 2025 Jan;136:156330. doi: 10.1016/j.phymed.2024.156330. Epub 2025 Jan 1.
BACKGROUND
Neonatal hypoxic-ischemic encephalopathy (HIE) has a high incidence and mortality rate, representing a significant patient burden. Therefore, treatment strategies that work synergistically with hypothermic therapies are urgently required. Punicalagin (PUN) is a natural and safe polyphenol with anti-inflammatory functions whose excellent water solubility and safety make it an advantageous perinatal medication. However, its underlying mechanisms of action in HIE remain unclear.
OBJECTIVES
This study investigated the role and associated mechanism of action PUN in HIE.
METHODS
We used the Rice Vannucci method to construct an in vivo HIE model in rats, from which we extracted primary cortical neurons to construct an in vitro oxygen and glucose deprivation/reoxygenation (OGD/R) model. The mechanisms of action of PUN were investigated using transcriptome sequencing, laser speckle contrast imaging, 2,3,5-triphenyltetrazolium chloride-staining, the Morris water maze test, western blotting, qPCR, immunofluorescence, and histochemistry.
RESULTS
HIE rats demonstrated excessive autophagy and inflammation. PUN reduced brain tissue damage and neuronal apoptosis, and improved cerebral blood flow perfusion, learning, and cognitive abilities. PUN attenuated autophagic overexpression following HIE and inhibited the AKT-FOXO4 (forkhead box O4) signaling pathway. The neuroprotective effects of PUN were inhibited by treatment with the AKT signaling pathway and autophagy inhibitor 3-MA. Furthermore, brain tissue damage was significant and PUN was ineffective in siFOXO4 rats.
CONCLUSIONS
PUN significantly reduces cerebral infarction, neuroinflammation, and excessive autophagy caused by HIE, thereby exerting short- and long-term neuroprotective effects. Mechanistically, the neuroprotective effect of PUN is mediated by activation of the AKT-FOXO4 pathway. Therefore, PUN may be a potential therapy for HIE.
背景
新生儿缺氧缺血性脑病（HIE）发病率和死亡率高，给患者带来沉重负担。因此，迫切需要与低温疗法协同作用的治疗策略。石榴皮苷（PUN）是一种具有抗炎功能的天然安全多酚，其出色的水溶性和安全性使其成为一种有利的围产期药物。然而，其在HIE中的潜在作用机制尚不清楚。
目的
本研究探讨PUN在HIE中的作用及相关作用机制。
方法
我们采用赖斯-万努奇方法在大鼠体内构建HIE模型，并从中提取原代皮质神经元构建体外氧糖剥夺/复氧（OGD/R）模型。使用转录组测序、激光散斑对比成像、2,3,5-三苯基四氮唑氯化物染色、莫里斯水迷宫试验、蛋白质免疫印迹法、定量聚合酶链反应、免疫荧光和组织化学研究PUN的作用机制。
结果
HIE大鼠表现出过度的自噬和炎症。PUN减少了脑组织损伤和神经元凋亡，改善了脑血流灌注、学习和认知能力。PUN减轻了HIE后自噬的过度表达，并抑制了AKT-FOXO4（叉头框O4）信号通路。用AKT信号通路和自噬抑制剂3-MA处理可抑制PUN的神经保护作用。此外，在siFOXO4大鼠中脑组织损伤显著且PUN无效。
结论
PUN显著降低HIE引起的脑梗死、神经炎症和过度自噬，从而发挥短期和长期神经保护作用。机制上，PUN的神经保护作用是通过激活AKT-FOXO4通路介导的。因此，PUN可能是HIE的一种潜在治疗方法。
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