A novel GSK-3 beta inhibitor YQ138 prevents neuronal injury induced by glutamate and brain ischemia through activation of the Nrf2 signaling pathway
文献类型：期刊论文
| 作者 | Pang, Tao1,4; Wang, Yun-jie1,4; Gao, Yuan-xue1,4; Xu, Yuan1,4; Li, Qiu2; Zhou, Yu-bo3 ; Xu, Lei3; Huang, Zhang-jian5; Liao, Hong1,4; Zhang, Lu-yong1,4
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| 刊名 | ACTA PHARMACOLOGICA SINICA
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| 出版日期 | 2016-06 |
| 卷号 | 37期号:6页码:741-752 |
| 关键词 | GSK-3 beta inhibitor YQ138 cerebellar granule cells glutamate excitotoxicity OGD middle cerebral artery occlusion brain ischemia neuroprotection Nrf2 |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/aps.2016.3 |
| 文献子类 | Article |
| 英文摘要 | Aim: To discover neuroprotective compounds and to characterize the discovered active compound YQ138 as a novel GSK-3 beta inhibitor. Methods: Primary rat cerebellar granule cells (CGCs) were treated with glutamate, and cell viability was analyzed with MTT assay, which was used as in vitro model for screening neuroprotective compounds. Active compound was further tested in OGD- or serum deprivation-induced neuronal injury models. The expression levels of GSK-3 beta downstream proteins (Nrf2, HO-1, NQO1, Tau and beta-catenin) were detected with Western blotting. For evaluating the neuroprotective effects in vivo, adult male rats were subjected to transient middle cerebral artery occlusion (tMCAO), then treated with YQ138 (10 mg/kg, iv) at 2, 4 and 6 h after ischemia onset. Results: From a compound library consisting of about 2000 potential kinase inhibitors, YQ138 was found to exert neuroprotective effects: pretreatment with YQ138 (0.1-40 mu mol/L) dose-dependently inhibited glutamate-induced neuronal death. Furthermore, pretreatment with YQ138 (10 mu mol/L) significantly inhibited OGD- or serum deprivation-induced neuronal death. Among a panel of seven kinases tested, YQ138 selectively inhibited the activity of GSK-3 beta (IC50=0.52 nmol/L). Furthermore, YQ138 dose-dependently increased the expression of beta-catenin, and decreased the phosphorylation of Tau in CGCs. Moreover, YQ138 significantly increased the expression of GSK-3 beta downstream antioxidative proteins Nrf2, HO-1, NQO1, GSH and SOD in CGCs. In rats with tMCAO, administration of YQ138 significantly decreased infarct volume, improved the neurological deficit, and increased the expression of Nrf2 and HO-1 and the activities of SOD and GSH in the cerebral cortex. Conclusion: A novel GSK-3 beta inhibitor YQ138 effectively suppresses brain ischemic injury in vitro and in vivo. |
| WOS关键词 | GLYCOGEN-SYNTHASE KINASE-3 ; TRANSCRIPTION FACTOR NRF2 ; FOCAL CEREBRAL-ISCHEMIA ; ALZHEIMERS-DISEASE ; OXIDATIVE STRESS ; NEURODEGENERATIVE DISORDERS ; INDUCED NEUROTOXICITY ; HEME OXYGENASE ; VALPROIC ACID ; BETA-CATENIN |
| 资助项目 | National Natural Science Foundation of China[21402241] ; Natural Science Foundation of Jiangsu Province[BK20130653] ; Program for Jiangsu Province "Shuang Chuang" Team[00000000] ; Natural Science Foundation of Zhejiang[LY14H300003] ; Postdoctoral Science Foundation of China[2014M550256] ; Open Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University[SKLNMKF201407] ; Fundamental Research Funds for the Central Universities[JKZD2013006] ; Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry, China[00000000] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| CSCD记录号 | CSCD:5722049 |
| WOS记录号 | WOS:000377281000003 |
| 出版者 | ACTA PHARMACOLOGICA SINICA |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276021]  |
| 专题 | 国家新药筛选中心 中科院受体结构与功能重点实验室 新药研究国家重点实验室 药物安全性评价中心 |
| 通讯作者 | Ye, Qing; Li, Jia |
| 作者单位 | 1.China Pharmaceut Univ, State Key Lab Nat Med, Nanjing 210009, Jiangsu, Peoples R China; 2.Zhejiang Univ Technol, State Key Lab Breeding Base Green Chem Synth Tech, Hangzhou 310032, Zhejiang, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 4.China Pharmaceut Univ, Jiangsu Key Lab Drug Screening, Nanjing 210009, Jiangsu, Peoples R China; 5.China Pharmaceut Univ, Jiangsu Key Lab Drug Discovery Metab Dis, Nanjing 210009, Jiangsu, Peoples R China |
| 推荐引用方式 GB/T 7714 | Pang, Tao,Wang, Yun-jie,Gao, Yuan-xue,et al. A novel GSK-3 beta inhibitor YQ138 prevents neuronal injury induced by glutamate and brain ischemia through activation of the Nrf2 signaling pathway[J]. ACTA PHARMACOLOGICA SINICA,2016,37(6):741-752. |
| APA | Pang, Tao.,Wang, Yun-jie.,Gao, Yuan-xue.,Xu, Yuan.,Li, Qiu.,...&Li, Jia.(2016).A novel GSK-3 beta inhibitor YQ138 prevents neuronal injury induced by glutamate and brain ischemia through activation of the Nrf2 signaling pathway.ACTA PHARMACOLOGICA SINICA,37(6),741-752. |
| MLA | Pang, Tao,et al."A novel GSK-3 beta inhibitor YQ138 prevents neuronal injury induced by glutamate and brain ischemia through activation of the Nrf2 signaling pathway".ACTA PHARMACOLOGICA SINICA 37.6(2016):741-752. |
入库方式： OAI收割
来源：上海药物研究所
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