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

Min Wang; Yixue Gu; Qiubo Li; Bangzhe Feng; Xinke Lv; Hao Zhang; Qingxia Kong; Zhifang Dong; Xin Tian; Yanke Zhang

doi:10.1016/j.gendis.2023.03.036

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

Full-length article | 更新时间：2024-02-04

- The Traf2 and NcK interacting kinase inhibitor NCB-0846 suppresses seizure activity involving the decrease of GRIA1
- Genes & Diseases Vol. 11, Issue 3, (2024)
- 作者机构：
  
  1. Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Children's Hospital of Chongqing Medical University,Chongqing,China,400014
  2. Department of Neurology, Affiliated Hospital of Jining Medical University,Shandong,Jining,China,272000
  3. Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences,Shanghai,China,200031
  4. Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology,Chongqing,China,400016
  5. Department of Neurosurgery, Affiliated Hospital of Jining Medical University,Shandong,Jining,China,272000
  6. Department of Pediatrics, Affiliated Hospital of Jining Medical University,Shandong,Jining,China,272000
- 作者简介：
- 基金信息：
- DOI：10.1016/j.gendis.2023.03.036
  CLC：
- Published：2024，
  
  Published Online：1 May 2024，
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Min Wang, Yixue Gu, Qiubo Li, et al. The Traf2 and NcK interacting kinase inhibitor NCB-0846 suppresses seizure activity involving the decrease of GRIA1. [J]. Genes & Diseases 11(3).(2024)
DOI：

Min Wang, Yixue Gu, Qiubo Li, et al. The Traf2 and NcK interacting kinase inhibitor NCB-0846 suppresses seizure activity involving the decrease of GRIA1. [J]. Genes & Diseases 11(3).(2024) DOI： 10.1016/j.gendis.2023.03.036.

摘要

Abstract

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 interactors 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-0846 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.

关键词

Keywords

EpilepsyNCB-0846RatTLETNIKTraf2-and NcK-interacting kinase

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