HET0016 inhibits neuronal pyroptosis in the immature brain post-TBI via the p38 MAPK signaling pathway

作者全名："Chen, Xiaoli; Ning, Yalei; Wang, Bo; Qin, Jun; Li, Changhong; Gao, Ruobing; Ma, Zhihui; Zhou, Yuanguo; Li, Ping; Zhao, Yan; Peng, Yan; Chen, Xing; Yang, Nan; Shu, Shiyu"

作者地址："[Chen, Xiaoli; Qin, Jun; Shu, Shiyu] Chongqing Med Univ, Dept Anesthesiol, Affiliated Hosp 2, Chongqing 400010, Peoples R China; [Ning, Yalei; Wang, Bo; Li, Changhong; Gao, Ruobing; Zhou, Yuanguo; Li, Ping; Zhao, Yan; Peng, Yan; Chen, Xing; Yang, Nan] Army Med Univ, State Key Lab Trauma Burns & Combined Injury, Dept Army Occupat Dis, Res Inst Surg,Daping Hosp, Chongqing 400042, Peoples R China; [Ning, Yalei; Zhou, Yuanguo; Li, Ping; Zhao, Yan] Army Med Univ, Inst Brain & Intelligence, Chongqing 400038, Peoples R China"

通信作者："Shu, SY (通讯作者)，Chongqing Med Univ, Dept Anesthesiol, Affiliated Hosp 2, Chongqing 400010, Peoples R China."

来源：NEUROPHARMACOLOGY

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:001066076500001

JCR分区：Q1

影响因子：4.6

年份：2023

卷号：239

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：20-Hydroxyeicosatetraenoicacid (20-HETE); N-hydroxy-N-4-Butyl-2; methylphenylformamidine (HET0016); Pyroptosis; Traumatic brain injury (TBI); Immature brain

摘要："Traumatic brain injury (TBI) is a serious health threat worldwide, especially for the younger demographic. Our previous study demonstrated that HET0016 (a specific inhibitor of 20-hydroxyeicosatetraenoic acid synthesis) can decrease the lesion volume in the immature brain post-TBI; however, its mechanism of action and its association with pyroptosis post-TBI are unclear. In this study, we established a controlled cortical impact (CCI) injury rat model (postnatal day 9-10) and observed that increased expression of indicators for pyroptosis, including NLR family pyrin domain containing 3 (NLRP3), caspase-1 and gasdermin D (GSDMD) proteins and interleukin (IL)-18/IL-1 & beta; mRNA during the acute phase of TBI, especially on post-injury day (PID) 1. Additionally, we found that caspase-1 was primarily expressed in the neurons and microglia. HET0016 (1 mg/kg/d, ip, 3 consecutive days since TBI) reduced the lesion volume; neuronal death; expression of NLRP3, caspase-1, and GSDMD; and expression of IL-18/IL-1 & beta; mRNA. Bioinformatics analysis suggested involvement of mitogenactivated protein kinase (MAPK) signaling pathway in the HET0016-mediated neuroprotective role against TBI in the immature brain. Western blot analysis revealed reduced expression of p-p38 MAPK and nuclear factorkappa B (NF-& kappa;B) p65 in the neurons and microglia upon HET0016 treatment in TBI rats. In cultured primary cortical neurons subjected to oxygen-glucose deprivation/re-oxygenation (OGD) + (lipopolysaccharide) LPS, HET0016-induced the reduction of p-p38 MAPK, NLRP3, cleaved-caspase-1, GSDMD, IL-18, and IL-1 & beta; was reversed by co-treatment with p38 MAPK activator as well as NLRP3 agonist. Therefore, we conclude that pyroptosis is involved in neuronal death in the immature brains post-TBI and that HET0016 administration can alleviate neuronal pyroptosis possibly via inhibiting the phosphorylation of p38 MAPK."

基金机构："National Natural Science Foundation of China [NSFC 82071377]; Chongqing Science and Technology Commission grants of China [cstc2015jcyjA10095]; Chongqing medical scientific research project (Joint project of Chongqing Health Commission and Science and Technology Bureau) [2022GDRC002]; sixth batch of Young and Middleaged High-level Medical Talents Training Project of Chongqing Municipal Health Commission and Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China"

基金资助正文："This research was funded by the National Natural Science Foundation of China (NSFC 82071377; http://www.nsfc.gov.cn), Chongqing Science and Technology Commission grants of China (No. cstc2015jcyjA10095), and Chongqing medical scientific research project (Joint project of Chongqing Health Commission and Science and Technology Bureau) (No. 2022GDRC002). The study was partly supported by the sixth batch of Young and Middleaged High-level Medical Talents Training Project of Chongqing Municipal Health Commission and Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China."