期刊
FRONTIERS IN PHARMACOLOGY
卷 13, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2022.847605
关键词
XPO1; KPT-8602; Parkinson's disease; NLRP3 inflammasome; NF-kappa B
资金
- National Natural Science Foundation of China [81701187]
- Open Project of Modern Preparation of TCM, Ministry of Education, Jiangxi University of Traditional Chinese Medicine [TCM-201914]
This study demonstrates that KPT-8602 has potent anti-inflammatory effects and could be used as a novel therapeutic agent for inflammasome-related diseases, such as Parkinson's disease, through the regulation of the NF-kappa B signaling pathway and the NLRP3 inflammasome.
Exportin 1 (XPO1) is an important transport receptor that mediates the nuclear export of various proteins and RNA. KPT-8602 is a second-generation inhibitor of XPO1, demonstrating the lowest level of side effects, and is currently in clinical trials for the treatment of cancers. Previous studies suggest that several first-generation inhibitors of XPO1 demonstrate anti-inflammation activities, indicating the application of this drug in inflammation-related diseases. In this study, our results suggested the potent anti-inflammatory effect of KPT-8602 in vitro and in vivo. KPT-8602 inhibited the activation of the NF-kappa B pathway by blocking the phosphorylation and degradation of I kappa B alpha, and the priming of NLRP3. Importantly, the administration of KPT-8602 attenuated both lipopolysaccharide (LPS)-induced peripheral inflammation and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neuroinflammation in vivo. In addition, the tissue damage was also ameliorated by KPT-8602, indicating that KPT-8602 could be used as a novel potential therapeutic agent for the treatment of inflammasome-related diseases such as Parkinson's disease, through the regulation of the NF-kappa B signaling pathway and the NLRP3 inflammasome.
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