Yina Jia1, Sen Long2, Nan Jiang3, Zhe Shan4, Yingmei Lu5, Feng Han3, Jianqiang Yu6, Lili Feng7. 1. Department of Pharmacology, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region, 750004, China. 2. Department of Pharmacy, Hangzhou Seventh People's Hospital, Mental Health Center Zhejiang University School of Medicine, Hangzhou, 310013, China. 3. Key Laboratory of Cardiovascular & Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China. 4. Institute of Translational Medicine, Zhejiang University, Hangzhou, 310058, China. 5. Department of Neurobiology, Nanjing Medical University, Nanjing, 211166, China. 6. Department of Pharmacology, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region, 750004, China. Electronic address: YujqLab@163.com. 7. Key Laboratory of Cardiovascular & Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China. Electronic address: fenglili0311@hotmail.com.
Abstract
BACKGROUND: The novel antidepressant drug agomelatine has been observed to cause adverse effect of hepatotoxicity in clinical applications. This study was designed to explore protective agents and investigated the underlying mechanism on L02 cells. METHOD: L02 cells were treated with agomelatine and oxymatrine (OMT) and cell apoptosis were analyzed through flow cytometric analysis, CCK-8 assay and TUNEL assay. In a separate experiment, the expressions of ER stress-related proteins were determined by western blot. In addition, MG132, chloroquine (CQ) and bafilomycinA1(BafA1) were used to investigate the potential pathway participating in CHOP degradation. RESULTS: OMT significantly rescued agomelatine-induced hepatocyte apoptosis. Agomelatine treatment resulted in accumulation of CHOP protein in L02 cells, and this phenomenon could be significantly reduced by OMT, whereas abolished by MG132 treatment. CONCLUSION: We have demonstrated for the first time that OMT ameliorates the hepatocyte toxicity induced by agomelatine through decreasing CHOP on protein level. The underlying mechanism was proved to involve the molecular events that OMT promotes CHOP degradation via proteasome pathway. Overall, these results suggest that using OMT in combination with agomelatine may provide a safety strategy for clinical depression treatment.
BACKGROUND: The novel antidepressant drug agomelatine has been observed to cause adverse effect of hepatotoxicity in clinical applications. This study was designed to explore protective agents and investigated the underlying mechanism on L02 cells. METHOD: L02 cells were treated with agomelatine and oxymatrine (OMT) and cell apoptosis were analyzed through flow cytometric analysis, CCK-8 assay and TUNEL assay. In a separate experiment, the expressions of ER stress-related proteins were determined by western blot. In addition, MG132, chloroquine (CQ) and bafilomycinA1(BafA1) were used to investigate the potential pathway participating in CHOP degradation. RESULTS: OMT significantly rescued agomelatine-induced hepatocyte apoptosis. Agomelatine treatment resulted in accumulation of CHOP protein in L02 cells, and this phenomenon could be significantly reduced by OMT, whereas abolished by MG132 treatment. CONCLUSION: We have demonstrated for the first time that OMT ameliorates the hepatocyte toxicity induced by agomelatine through decreasing CHOP on protein level. The underlying mechanism was proved to involve the molecular events that OMT promotes CHOP degradation via proteasome pathway. Overall, these results suggest that using OMT in combination with agomelatine may provide a safety strategy for clinical depression treatment.
Authors: Murali Ganesan; Saumi Mathews; Edward Makarov; Armen Petrosyan; Kusum K Kharbanda; Srivatsan Kidambi; Larisa Y Poluektova; Carol A Casey; Natalia A Osna Journal: Am J Physiol Gastrointest Liver Physiol Date: 2020-08-05 Impact factor: 4.052