Pretreatment with kaempferol attenuates microglia-mediate neuroinflammation by inhibiting MAPKs–NF–κB signaling pathway and pyroptosis after secondary spinal cord injury

神经炎症 小胶质细胞 山奈酚 氧化应激 神经保护 p38丝裂原活化蛋白激酶 NF-κB 炎症 神经科学 药理学 NADPH氧化酶 化学 脊髓损伤 信号转导 MAPK/ERK通路 医学 脊髓 免疫学 生物 生物化学 槲皮素 抗氧化剂
作者
Zhongyuan Liu,Xinqiang Yao,Bai-Hui Sun,Wangsheng Jiang,Congrui Liao,Xiangheng Dai,Yu Chen,Jianting Chen,Ruoting Ding
出处
期刊:Free Radical Biology and Medicine [Elsevier]
卷期号:168: 142-154 被引量:63
标识
DOI:10.1016/j.freeradbiomed.2021.03.037
摘要

Spinal cord injury (SCI) is a devastating injury that characterized by oxidative stress and inflammatory response. Kaempferol is reported to be an anti-neuroinflammation in neurologic disorders. Nevertheless, the role and mechanism of kaempferol in SCI remains unclear. The present study aims to investigate effects of kaempferol on SCI and its possible underlying mechanisms in in vivo and in vitro models. A C5 hemi-contusion injury was induced in Sprague-Dawley rats to investigate the neuroprotective effects of kaempferol after SCI. For in vitro study, the BV2 microglia cell lines were pretreated with or without kaempferol. A combination of molecular and histological methods was used to clarify the mechanism and explore the signaling pathway both in vivo and in vitro. One-way analysis of variance (ANOVA) was conducted with Bonferroni post hoc tests to examine the differences between groups. The in vivo studies showed that kaempferol could improve the recovery of hindlimb motor function and ameliorate tissue damage in the spinal cord after SCI. Moreover, administration of kaempferol reduced microglia activation and oxidative stress level in the spinal cord. The in vitro studies showed that kaempferol suppressed the microglia activation resulting from the administration of LPS with ATP to BV-2 cells. Pretreated BV2 cells with kaempferol reduced the generation of reactive oxygen species (ROS) by inhibiting NADPH oxidase 4, and then, suppressed the phosphorylation of p38 MAPK and JNK, which subsequently inhibited nuclear translocation of NF-κB p65 to express pro-inflammatory factors. We also observed that kaempferol could inhibite the pyroptosis related proteins (NLRP3 Caspase-1 p10 ASC N-GSDMD) and reduce the release of IL-18 and IL-1β. In conclusion, kaempferol was able to reduce oxidative stress and inflammatory response through down-regulation of ROS dependent MAPKs- NF-κB and pyroptosis signaling pathway, which suggested that kaempferol might be a novel promising therapeutic agent for SCI.
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