The Traf2 and NcK interacting kinase inhibitor NCB-0846 suppresses seizure activity involving the decrease of GRIA1
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 modulati...
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KeAi Communications Co., Ltd.
2024-05-01
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| Series: | Genes and Diseases |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352304223002544 |
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| author | Min Wang Yixue Gu Qiubo Li Bangzhe Feng Xinke Lv Hao Zhang Qingxia Kong Zhifang Dong Xin Tian Yanke Zhang |
| author_facet | Min Wang Yixue Gu Qiubo Li Bangzhe Feng Xinke Lv Hao Zhang Qingxia Kong Zhifang Dong Xin Tian Yanke Zhang |
| author_sort | Min Wang |
| collection | DOAJ |
| description | 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. |
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| issn | 2352-3042 |
| language | English |
| last_indexed | 2024-03-07T21:43:12Z |
| publishDate | 2024-05-01 |
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| series | Genes and Diseases |
| spelling | doaj.art-1e4afd6b6fde403e9230c64ff982f95b2024-02-26T04:15:46ZengKeAi Communications Co., Ltd.Genes and Diseases2352-30422024-05-01113100997The Traf2 and NcK interacting kinase inhibitor NCB-0846 suppresses seizure activity involving the decrease of GRIA1Min Wang0Yixue Gu1Qiubo Li2Bangzhe Feng3Xinke Lv4Hao Zhang5Qingxia Kong6Zhifang Dong7Xin Tian8Yanke Zhang9Department of Neurology, Affiliated Hospital of Jining Medical University, Jining, Shandong 272000, ChinaDepartment of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing 400016, ChinaDepartment of Pediatrics, Affiliated Hospital of Jining Medical University, Jining, Shandong 272000, ChinaDepartment of Neurology, Affiliated Hospital of Jining Medical University, Jining, Shandong 272000, ChinaDepartment of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing 400016, ChinaDepartment of Neurosurgery, Affiliated Hospital of Jining Medical University, Jining, Shandong 272000, ChinaDepartment of Neurology, Affiliated Hospital of Jining Medical University, Jining, Shandong 272000, ChinaPediatric 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 400014, China; Corresponding author. 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 400014, China.Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing 400016, China; Corresponding author. Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing 400016, China.Department of Neurology, Affiliated Hospital of Jining Medical University, Jining, Shandong 272000, China; Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China; Corresponding author. Department of Neurology, Affiliated Hospital of Jining Medical University, Jining, Shandong 272000, China.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.http://www.sciencedirect.com/science/article/pii/S2352304223002544EpilepsyNCB-0846RatTLETNIKTraf2-and NcK-interacting kinase |
| spellingShingle | Min Wang Yixue Gu Qiubo Li Bangzhe Feng Xinke Lv Hao Zhang Qingxia Kong Zhifang Dong Xin Tian Yanke Zhang The Traf2 and NcK interacting kinase inhibitor NCB-0846 suppresses seizure activity involving the decrease of GRIA1 Genes and Diseases Epilepsy NCB-0846 Rat TLE TNIK Traf2-and NcK-interacting kinase |
| title | The Traf2 and NcK interacting kinase inhibitor NCB-0846 suppresses seizure activity involving the decrease of GRIA1 |
| title_full | The Traf2 and NcK interacting kinase inhibitor NCB-0846 suppresses seizure activity involving the decrease of GRIA1 |
| title_fullStr | The Traf2 and NcK interacting kinase inhibitor NCB-0846 suppresses seizure activity involving the decrease of GRIA1 |
| title_full_unstemmed | The Traf2 and NcK interacting kinase inhibitor NCB-0846 suppresses seizure activity involving the decrease of GRIA1 |
| title_short | The Traf2 and NcK interacting kinase inhibitor NCB-0846 suppresses seizure activity involving the decrease of GRIA1 |
| title_sort | traf2 and nck interacting kinase inhibitor ncb 0846 suppresses seizure activity involving the decrease of gria1 |
| topic | Epilepsy NCB-0846 Rat TLE TNIK Traf2-and NcK-interacting kinase |
| url | http://www.sciencedirect.com/science/article/pii/S2352304223002544 |
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