Depression of Pyroptosis by Inhibiting Caspase-1 Activation Improves Neurological Outcomes of Kernicterus Model Rats

作者全名："Li, Siyu; Huang, Hongmei; Wei, Qian; He, Chunmei; Feng, Jie; Wang, Yao; Li, Mengwen; Zhang, Qiannan; Xia, Xuhua; Hua, Ziyu"

作者地址："[Li, Siyu; Huang, Hongmei; Wei, Qian; He, Chunmei; Feng, Jie; Wang, Yao; Li, Mengwen; Zhang, Qiannan; Xia, Xuhua; Hua, Ziyu] Chongqing Med Univ, Dept Neonatol, Key Lab Child Dev & Disorders, Childrens Hosp,Minist Educ, Chongqing 400014, Peoples R China; [Li, Siyu; Huang, Hongmei; Wei, Qian; He, Chunmei; Zhang, Qiannan; Xia, Xuhua; Hua, Ziyu] China Int Sci & Technol Cooperat Base Child Dev &, Chongqing 400014, Peoples R China; [Li, Siyu; Huang, Hongmei; Wei, Qian; He, Chunmei] Chongqing Key Lab Child Infect & Immun, Chongqing 400014, Peoples R China"

通信作者："Hua, ZY (corresponding author), Chongqing Med Univ, Dept Neonatol, Key Lab Child Dev & Disorders, Childrens Hosp,Minist Educ, Chongqing 400014, Peoples R China.; Hua, ZY (corresponding author), China Int Sci & Technol Cooperat Base Child Dev &, Chongqing 400014, Peoples R China."

来源：ACS CHEMICAL NEUROSCIENCE

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:000683719700019

JCR分区：Q1

影响因子：5

年份：2021

卷号：12

期号：5

开始页：2929

结束页：2939

文献类型：Article

关键词：Unconjugated bilirubin; caspase-1; VX-765; neurological outcomes; rats

摘要："Kernicterus is a severe complication of extreme neonatal hyperbilirubinemia. Prolonged exposure to high-level unconjugated bilirubin (UCB) directly damages brain tissue. Neuroinflammation is believed to contribute to UCB-induced neurotoxicity. Pyroptosis has been as a highly inflammatory form of programmed cell death. Therefore, this study aimed to explore whether pyroptosis was involved in the pathogenesis of UCB neurotoxicity in kernicterus model rats. VX-765, a specific inhibitor of caspase-1, was intraperitoneally administered to the model rats to observe its effects on the short-term and long-term outcomes of the model animals at the molecular, cellular, morphological, and behavioral levels. The results indicated that UCB significantly induced the activation of caspase-1 and gasdermin D(GSDMD), and VX-765 inhibited caspase-1-GSDMD pathway. Compared with those of the UCB group and the vehicle+UCB group, VX-765-treated rats released lower levels of IL-1 beta and IL-18. Furthermore, H&E and TUNEL staining showed that nerve cells in the VX765-treated group were better preserved and had less DNA fragmentation. Most importantly, VX-765 improved both the short-term and long-term neurological functions of kernicterus model rats. This study demonstrated that pyroptosis was involved in the pathogenesis of kernicterus through caspase-1 activation, which could be inhibited by VX-765, exerting a neuroprotective effect in kernicterus model rats."

基金机构：National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81971426]; Project of Basic and Frontier Research Plan of Chongqing [CSTC2018jcyjAX0284]

基金资助正文：This work was supported by the National Natural Science Foundation of China (Grant 81971426) and the Project of Basic and Frontier Research Plan of Chongqing (Grant CSTC2018jcyjAX0284).