The Traf2 and NcK interacting kinase inhibitor NCB-0846 suppresses seizure activity involving the decrease of GRIA1

作者全名："Wang, Min; Gu, Yixue; Li, Qiubo; Feng, Bangzhe; Lv, Xinke; Zhang, Hao; Kong, Qingxia; Dong, Zhifang; Tian, Xin; Zhang, Yanke"

作者地址："[Wang, Min; Feng, Bangzhe; Kong, Qingxia; Zhang, Yanke] Jining Med Univ, Dept Neurol, Affiliated Hosp, Jining 272000, Shandong, Peoples R China; [Gu, Yixue; Lv, Xinke; Tian, Xin] Chongqing Med Univ, Affiliated Hosp 1, Dept Neurol, Chongqing Key Lab Neurol, Chongqing 400016, Peoples R China; [Li, Qiubo] Jining Med Univ, Dept Pediat, Affiliated Hosp, Jining 272000, Shandong, Peoples R China; [Zhang, Hao] Jining Med Univ, Dept Neurosurg, Affiliated Hosp, Jining 272000, Shandong, Peoples R China; [Dong, Zhifang] Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Chongqing Key Lab Translat Med Res Cognit Dev & Le, Minist Educ,Key Lab Child Dev & Disorders,Children, Chongqing 400014, Peoples R China; [Zhang, Yanke] Chinese Acad Sci, Ctr Excellence Brain Sci & Intelligence Technol, Shanghai 200031, Peoples R China"

通信作者："Zhang, YK (通讯作者)，Jining Med Univ, Dept Neurol, Affiliated Hosp, Jining 272000, Shandong, Peoples R China.; Tian, X (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Neurol, Chongqing Key Lab Neurol, Chongqing 400016, Peoples R China.; Dong, ZF (通讯作者)，Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Chongqing Key Lab Translat Med Res Cognit Dev & Le, Minist Educ,Key Lab Child Dev & Disorders,Children, Chongqing 400014, Peoples R China."

来源：GENES & DISEASES

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001150231700001

JCR分区：Q1

影响因子：6.8

年份：2024

卷号：11

期号：3

开始页：　

结束页：　

文献类型：Article

关键词：Epilepsy; NCB-0846; Rat; TLE; TNIK; Traf2-and NcK-interacting kinase

摘要："Epilepsy, one of the most common neurological disorders, is characterized by spontaneous recurrent seizures. Temporal lobe epilepsy (TLE) is one of the most common medically intractable seizure disorders. Traf2-and NcK-interacting kinase (TNIK) has recently attracted attention as a critical modulation target of many neurological and psychiatric disorders, but its role in epilepsy remains unclear. In this study, we hypothesized the involvement of TNIK in epilepsy and investigated TNIK expression in patients with intractable TLE and in a pilocarpine-induced rat model of epilepsy by western blotting, immunofluorescence, and immunohistochemistry. A pentylenetetrazole (PTZ)-induced epilepsy rat model was used to determine the effect of the TNIK inhibitor NCB-0846 on behavioral manifestations of epilepsy. Coimmunoprecipitation (Co-IP)/mass spectrometry (MS) was used to identify the potential mechanism. Through Co-IP, we detected and confirmed the main potential TNIK interactors. Subcellular fractionation was used to establish the effect of NCB-0846 on the expression of the main inter -actors in postsynaptic density (PSD) fractions. We found that TNIK was primarily located in neurons and decreased significantly in epilepsy model rats and TLE patients compared with controls. NCB-084 6 delayed kindling progression and decreased seizure severity. Co-IP/MS identified 63 candidate TNIK interactors in rat hippocampi, notably CaMKII. Co-IP showed that TNIK might correlate with endogenous GRIA1, SYN2, PSD-95, CaMKIV, GABRG1, and GABRG2. In addition, the significant decrease in GRIA1 in hippocampal total lysate and PSDs after NCB-0846 treatment might help modify the progression of PTZ kindling. Our results suggest that TNIK contributes to epileptic pathology and is a potential antiepileptic drug target. 2023 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. This is an open access article under the CC BY license (http://creativecommons.org/ licenses/by/4.0/)."

基金机构："National Natural Science Foundation of China [81901324, 82001378, 82071395]; China Postdoctoral Science Foundation [2021M693246]; Chongqing Health Commission (Chongqing, China) [2023QNXM009]; Science and Technology Research Program of Chongqing Education Commission of China [KJQN202200435]; Chongqing Talents: Exceptional Young Talents Project (Chongqing, China) [CQYC202005014]; Natural Science Foundation of Chongqing, China [cstc2021ycjh-bgzxm0035, CSTB2022NSCQ-LZX0038]; Key Research and Development Projects of Jining City, Shandong, China [2021YXNS057]; Science and Technology Bureau (Chongqing, China) [2023QNXM009]"

基金资助正文："This work was supported by grants from the National Natural Science Foundation of China (No. 81901324, 82001378, 82071395) , China Postdoctoral Science Foundation (No. 2021M693246) , joint project of Chongqing Health Commission and Science and Technology Bureau (Chongqing, China) (No. 2023QNXM009) , Science and Technology Research Program of Chongqing Education Commission of China (No. KJQN202200435) , Chongqing Talents: Exceptional Young Talents Project (Chongqing, China) (No. CQYC202005014) , Natural Science Foundation of Chongqing, China (No. cstc2021ycjh-bgzxm0035, CSTB2022NSCQ-LZX0038) , and Key Research and Development Projects of Jining City, Shandong, China (No. 2021YXNS057) ."