Depression of Pyroptosis by Inhibiting Caspase-1 Activation Improves Neurological Outcomes of Kernicterus Model Rats
Depression of Pyroptosis by Inhibiting Caspase-1 Activation Improves Neurological Outcomes of Kernicterus Model Rats
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DOI：
10.1021/acschemneuro.1c00287
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发表时间：
2021-08-04
影响因子：
5
通讯作者：
Hua, Ziyu
中科院分区：
文献类型：
--
作者：
Li, Siyu;Huang, Hongmei;Hua, Ziyu
核黄疸是严重新生儿高胆红素血症的严重并发症。长期暴露于高水平的未结合胆红素（UCB）直接损害脑组织。神经炎症被认为有助于UCB诱导的神经毒性。细胞凋亡是一种高度炎症性的细胞程序性死亡.因此，本研究旨在探讨核黄疸模型大鼠UCB神经毒性的发病机制中是否有焦亡的参与。采用Caspase-1特异性抑制剂VX-765腹腔给药，从分子、细胞、形态学和行为学水平观察VX-765对模型动物近期和远期预后的影响。结果表明，UCB显著诱导caspase-1和gasdermin D（GSDMD）的激活，VX-765抑制caspase-1-GSDMD途径。与UCB组和溶剂+UCB组相比，VX-765给药大鼠释放的IL-1 β和IL-18水平较低。此外，H&E和TUNEL染色显示VX-765处理组中的神经细胞保存得更好，并且具有更少的DNA片段。最重要的是，VX-765改善了核黄疸模型大鼠的短期和长期神经功能。本研究表明，焦亡通过激活caspase-1参与了核黄疸的发病机制，VX-765可抑制caspase-1的激活，对核黄疸模型大鼠起到神经保护作用。
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 VX-765-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.