GSDMD knockdown exacerbates hippocampal damage and seizure susceptibility by crosstalk between pyroptosis and apoptosis in kainic acid-induced temporal lobe epilepsy

作者全名："Lin, Aolei; Guo, Yi; Zhang, Hui; Lin, Peijia; Tao, Kaiyan; Jiang, Li; Xu, Demei; Chen, Bo"

作者地址："[Lin, Aolei] Tianjin Med Univ Gen Hosp, Tianjin Neurol Inst, Dept Neurol, Anshan Rd 154, Tianjin 300052, Peoples R China; [Lin, Aolei; Zhang, Hui; Lin, Peijia; Tao, Kaiyan; Xu, Demei] Chongqing Med Univ, Affiliated Hosp 1, Dept Neurol, Chongqing Key Lab Neurol, 1 Youyi Rd, Chongqing 400016, Peoples R China; [Guo, Yi] Univ Elect Sci & Technol China, Sichuan Prov Peoples Hosp, Dept Neurol, 32 W Sec 2,1st Ring Rd, Chengdu 610072, Sichuan, Peoples R China; [Jiang, Li] Chongqing Med Univ, Affiliated Hosp 1, Dept Rehabil Med, 1 Youyi Rd, Chongqing 400016, Peoples R China; [Chen, Bo] Chongqing Univ, Canc Hosp, Dept Anesthesiol, Chongqing 40030, Peoples R China"

通信作者："Lin, AL (通讯作者)，Tianjin Med Univ Gen Hosp, Tianjin Neurol Inst, Dept Neurol, Anshan Rd 154, Tianjin 300052, Peoples R China.; Lin, AL (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Neurol, Chongqing Key Lab Neurol, 1 Youyi Rd, Chongqing 400016, Peoples R China.; Chen, B (通讯作者)，Chongqing Univ, Canc Hosp, Dept Anesthesiol, Chongqing 40030, Peoples R China."

来源：BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001042122100001

JCR分区：Q1

影响因子：4.2

年份：2023

卷号：1869

期号：5

开始页：　

结束页：　

文献类型：Article

关键词：Pyroptosis; GSDMD; Crosstalk; Apoptosis; Programmed cell death; Temporal lobe epilepsy

摘要："Background: Neuronal loss is a vital pathological feature of temporal lobe epilepsy (TLE). However, the exact mechanism of neuronal loss in TLE is not fully understood. Pyroptosis, a novel form of programmed cell death (PCD), has been considered a contributor to the pathogenesis of TLE. However, recent studies have implicated extensive molecular crosstalk among pyroptosis, apoptosis, and necroptosis in various diseases, and they can be transformed to each other according to different contexts. This study aimed to investigate whether gasdermin D (GSDMD)-mediated pyroptosis is involved in the pathogenesis of TLE and whether crosstalk exists in the process of the modulation of pyroptosis. Methods: The TLE model was established by intra-amygdala injection of kainic acid. The Racine score and local field potential (LFP) recordings were used to assess seizure severity. Western blotting and immunofluorescence were applied to detect the levels and cellular localization of GSDMD. The neuronal loss and type of neuronal death in the bilateral hippocampus were assessed by Nissl staining and flow cytometry analysis. The underlying crosstalk among pyroptosis, apoptosis, and necroptosis was explored by western blot and verified by VX765. Results: GSDMD was significantly upregulated and mainly expressed within the neurons of the hippocampus in the TLE model. Inhibition of pyroptosis by GSDMD knockdown triggered caspase-3-mediated apoptosis, leading to excess neuronal loss and deterioration of epileptic behaviors. Blocking caspase-1 markedly inhibited caspase3-mediated apoptosis and improved epileptic behaviors under GSDMD knockdown. Conclusions: Our results demonstrate that GSDMD-mediated pyroptosis is involved in the pathogenesis of TLE. However, inhibition of GSDMD triggers caspase-1-mediated crosstalk between pyroptosis and apoptosis, which exacerbates neuronal loss and seizure susceptibility. Therefore, the complex crosstalk among different forms of PCD should be considered when a potential molecular target in the single PCD pathway is modulated. On the other hand, along with further studies of molecular crosstalk among the PCD pathways, taking advantage of crosstalk to attenuate neuronal loss may provide new insight for the clinical therapy of TLE."

基金机构："National Natural Science Foundation of China [82101517]; National Science Foundation Project of Chongqing [cstc2019jcyj-msxmX0608, CSTB2022NSCQ-MSX0916]; Natural Science Foundation of Sichuan [2022NSFSC1545]; Tianjin Key Medical Discipline (Specialty) Construction Project; Department of Neurology of the Tianjin Medical University General Hospital"

基金资助正文：This study was supported by a grant from the National Natural Science Foundation of China (No.82101517) . This study was also supported by grants from the National Science Foundation Project of Chongqing (cstc2019jcyj-msxmX0608 and CSTB2022NSCQ-MSX0916) and Natural Science Foundation of Sichuan (2022NSFSC1545) . This study was also supported by Tianjin Key Medical Discipline (Specialty) Construction Project. This project funded all doctors in the Department of Neurology of the Tianjin Medical University General Hospital.