PMID- 30880180 OWN - NLM STAT- MEDLINE DCOM- 20191220 LR - 20191220 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 855 DP - 2019 Jul 15 TI - A novel, highly-water-soluble apigenin derivative provides neuroprotection following ischemia in male rats by regulating the ERK/Nrf2/HO-1 pathway. PG - 208-215 LID - S0014-2999(19)30179-7 [pii] LID - 10.1016/j.ejphar.2019.03.024 [doi] AB - 6"-O-succinylapigenin [apigenin-7-O-(6'-O-succinyl)-glucoside], a novel compound, is identified in chamomile. Although it is highly produced by Bacillus amyloliquefaciens FJ18, its bioactivity remains unknown. The neuroprotective effects and antioxidative mechanism of 6''-O-succcinylapigenin in the middle cerebral artery occlusion model in male rats was investigated in this study. The structure of this compound was determined by spectroscopic data analysis. After 2 h of occlusion and 24 h of reperfusion, magnetic resonance imaging and assessed neurological scores following middle cerebral artery occlusion (MCAO) in male rats to determine the infarction size and neurological deficits, respectively. In addition, we tested protein levels of the nuclear factor E2-related factor 2 (Nrf2), Kelch-like ECH-associated protein1 (Keap1), heme oxygenase-1 (HO-1), and extracellular-signal-regulated kinase (ERK), to investigate the mechanism of antioxidative action of 6''-O-succcinylapigenin. Finally, we employed immunofluorescence to determine the location of Nrf2 and Keap1 in HT22 cells cultured in vitro. Our results revealed that administration of 6''-O-succcinylapigenin induced a decrease in both infarct volume and neurological scores following MCAO, and significantly increased the activity of HO-1 and nuclear Nrf2 in vivo. Similarly, immunofluorescence assays indicated that Nrf2 is highly expressed in the nucleus following treatment with 6''-O-succcinylapigenin in vitro. Our study suggests that 6''-O-succcinylapigenin exerts an anti-ischemic effect by activating the ERK/Nrf2/HO-1 pathway. CI - Copyright (c) 2019. Published by Elsevier B.V. FAU - Zhang, Sen AU - Zhang S AD - Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resources and Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China; Jiangsu Key Laboratory for High Technology Research of TCM Formulae, State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China. FAU - Xu, Sikai AU - Xu S AD - Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resources and Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China; Jiangsu Key Laboratory for High Technology Research of TCM Formulae, State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China. FAU - Duan, Huifang AU - Duan H AD - Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resources and Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China. FAU - Zhu, Zhenhua AU - Zhu Z AD - Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resources and Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China; Jiangsu Key Laboratory for High Technology Research of TCM Formulae, State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China. FAU - Yang, Zihong AU - Yang Z AD - Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resources and Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China; Jiangsu Key Laboratory for High Technology Research of TCM Formulae, State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China. FAU - Cao, Jianan AU - Cao J AD - Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resources and Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China; Jiangsu Key Laboratory for High Technology Research of TCM Formulae, State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China. FAU - Zhao, Yuxiang AU - Zhao Y AD - Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resources and Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China; Jiangsu Key Laboratory for High Technology Research of TCM Formulae, State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China. FAU - Huang, Zhiheng AU - Huang Z AD - Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resources and Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China. FAU - Wu, Qinan AU - Wu Q AD - Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resources and Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China. Electronic address: qnwyjs@163.com. FAU - Duan, Jinao AU - Duan J AD - Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resources and Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China; Jiangsu Key Laboratory for High Technology Research of TCM Formulae, State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China. Electronic address: dja@njutcm.edu.cn. LA - eng PT - Journal Article DEP - 20190314 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - 0 (Antioxidants) RN - 0 (NF-E2-Related Factor 2) RN - 0 (Neuroprotective Agents) RN - 059QF0KO0R (Water) RN - 4Y8F71G49Q (Malondialdehyde) RN - 7V515PI7F6 (Apigenin) RN - EC 1.14.14.18 (Heme Oxygenase (Decyclizing)) RN - EC 1.14.14.18 (Hmox1 protein, rat) RN - EC 1.15.1.1 (Superoxide Dismutase) RN - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases) SB - IM MH - Animals MH - Antioxidants/metabolism MH - Apigenin/*chemistry/*pharmacology/therapeutic use MH - Brain/drug effects/metabolism/pathology MH - Cell Line MH - Cell Survival/drug effects MH - Extracellular Signal-Regulated MAP Kinases/*metabolism MH - Heme Oxygenase (Decyclizing)/*metabolism MH - Humans MH - Infarction, Middle Cerebral Artery/*drug therapy/metabolism/pathology MH - Male MH - Malondialdehyde/metabolism MH - NF-E2-Related Factor 2/*metabolism MH - Neuroprotective Agents/chemistry/pharmacology/therapeutic use MH - Rats MH - Rats, Sprague-Dawley MH - Solubility MH - Superoxide Dismutase/metabolism MH - Water/*chemistry OTO - NOTNLM OT - 6''-O-succcinylapigenin OT - Antioxidant OT - Biotransformation OT - MCAO OT - MRI EDAT- 2019/03/19 06:00 MHDA- 2019/12/21 06:00 CRDT- 2019/03/19 06:00 PHST- 2018/12/09 00:00 [received] PHST- 2019/03/12 00:00 [revised] PHST- 2019/03/14 00:00 [accepted] PHST- 2019/03/19 06:00 [pubmed] PHST- 2019/12/21 06:00 [medline] PHST- 2019/03/19 06:00 [entrez] AID - S0014-2999(19)30179-7 [pii] AID - 10.1016/j.ejphar.2019.03.024 [doi] PST - ppublish SO - Eur J Pharmacol. 2019 Jul 15;855:208-215. doi: 10.1016/j.ejphar.2019.03.024. Epub 2019 Mar 14.