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L-F001, a multifunctional ROCK inhibitor prevents paraquat-induced cell death through attenuating ER stress and mitochondrial dysfunction in PC12 cells.

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机构： [1]Department of Neurology, Puai Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430033, China [2]Department of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510080, China [3]International Joint Laboratory (SYSU-PolyU HK) of Novel Anti-Dementia Drugs of Guangdong, Guangzhou 510006, China [4]National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China

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关键词： L-F001 ROCK inhibitor Paraquat Cell death Endoplasmic reticulum stress Mitochondria

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Paraquat (PQ) was demonstrated to induce dopaminergic neuron death and is used as a Parkinson's disease (PD) mimetic. Amounting evidences demonstrated that Rho/ROCK may a novel target for the therapy of PD. Previously we synthesized L-F001 and proved it is a potent ROCK inhibitor with multifunctional effects, including anti-oxidative stress. In this study, we investigated the effects and also the molecular mechanisms of L-F001 in preventing PQ-induced cytotoxicity in PC12 cells. L-F001 effectively prevented PQ-induced apoptotic cell death, which involves the scavenger of ROS and also attenuated the declined of mitochondrial membrane potential and intracellular level of GSH induced by PQ. Moreover, PQ quickly induced alterations of GRP78 and CHOP, two hallmarks of endoplasmic reticulum (ER) stress and subsequently induced dysfunction of the mitochondria (such as the decrease in membrane potential and increase in ROS). These changes all were potently attenuated by L-F001. In summary, L-F001 attenuated PQ-induced apoptosis through modulating mitochondrial dysfunction and ER stress as well as the ROS production elicited by PQ. These data indicated that L-F001 could possibly be used to treat PD and other neurodegenerative disorders with similar pathologic mechanisms. Copyright © 2015 Elsevier Inc. All rights reserved.

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出版当年[2014]版：

大类 | 3 区生物

小类 | 4 区生化与分子生物学 4 区生物物理

最新[2025]版：

大类 | 4 区生物学

小类 | 4 区生化与分子生物学 4 区生物物理

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第一作者机构： [1]Department of Neurology, Puai Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430033, China

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