Piezo1 inhibitor isoquercitrin rescues neural impairment mediated by NLRP3 after intracerebral hemorrhage

作者全名：Guo, Tingwang; Chen, Gang; Yang, Lin; Deng, Jia; Pan, Yun

作者地址：[Guo, Tingwang; Chen, Gang; Yang, Lin; Deng, Jia] Chongqing Technol & Business Univ, Coll Environm & Resources, Chongqing 400067, Peoples R China; [Pan, Yun] Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Minist Educ Key Lab Child Dev & Disorders, Dept Gastroenterol,Childrens Hosp,Chongqing Key La, Chongqing, Peoples R China

通信作者：Guo, TW; Yang, L (通讯作者)，Chongqing Technol & Business Univ, Coll Environm & Resources, Chongqing 400067, Peoples R China.; Pan, Y (通讯作者)，Chongqing Med Univ, Childrens Hosp, Dept Gastroenterol, Chongqing 400030, Peoples R China.

来源：EXPERIMENTAL NEUROLOGY

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:001253191900001

JCR分区：Q1

影响因子：4.6

年份：2024

卷号：379

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Intracerebral hemorrhage; Isoquercitrin; Piezo1; NLRP3; Mechanotransduction; Neural injury

摘要：In intracerebral hemorrhage (ICH), the mechanical brain injury is a considerable and indispensable factor determining the neurological functions and poor outcomes. Previous studies indicate the mechanically gated ion channel-Piezo1 can transduce mechanical effects following ICH. Isoquercitrin (ISQ) is a well-studied ion channel inhibitor. Furthermore, whether the following Piezo1-mediated neurological impairment can be ameliorated by ISQ remains unclear. Herein, we constructed the hydrostatic pressure model and ICH rat model. Firstly, we found that Piezo1 agonists Yoda1 and Jedi1 facilitated extracellular calcium influx dramatically, but ISQ could depress intracellular Ca2+ overload under hydrostatic pressure in primary neurons. Then we detected the expression profile of Piezo1, NLRP3 and NF-kappa B p-p65 after ICH, and found that the expression of Piezo1 was much earlier than NLRP3 and NF-kappa B p-p65. Furthermore, by western blot and immunofluorescence, ISQ decreased the expression of Piezo1 and NLRP3 dramatically like GsMTx4, but Nigericin as a NLRP3 agonist failed to affect Piezo1. Besides, both ISQ and interfering Piezo1 suppressed the upregulated caspase-1, NF-kappa B p-p65, p-I kappa B alpha, Tunel-positive cells and inflammatory factors (IL-1 beta, IL-6 and TNF-alpha) in ICH. At last, the hydrostatic pressure or hematoma induced disturbed neural viability, disordered neural cytomorphology, and increased neurobehavioral and cognitive deficits, but they were improved by ISQ and GsMTx4 strongly. Therefore, ISQ could alleviate neurological injuries induced by Piezo1 via NLRP3 pathway. These observations indicated that Piezos might be the new therapeutic targets, and blocking Piezos/NLRP3 pathway by ISQ could be an auspicious strategy for the treatment of ICH.

基金机构：National Natural Science Foundation of China [11902060]; Chongqing Research Program of Basic Research and Frontier Technology [cstc2020jcyj- msxmX0844, cstc2020jcyjmsxmX0250, cstc2020jcyj-msxmX0711]; Chongqing Municipal Education Commission [KJQN201900814, KJQN202100837]; Opening Research Platform of Chongqing Technology and Business University [KFJJ2022016]; Scientific Research Foundation for Advanced Talents, Chongqing Technology and Business University [1956038]

基金资助正文：This work was supported by the National Natural Science Foundation of China (Grant Nos. 11902060) , the Chongqing Research Program of Basic Research and Frontier Technology (Grant Nos. cstc2020jcyj- msxmX0844, cstc2020jcyjmsxmX0250 and cstc2020jcyj-msxmX0711) , the Chongqing Municipal Education Commission (Grant No. KJQN201900814 and KJQN202100837) , the Opening Research Platform of Chongqing Technology and Business University (KFJJ2022016) and the Scientific Research Foundation for Advanced Talents, Chongqing Technology and Business University (No. 1956038) .