title: L-F001, a multifunctional ROCK inhibitor prevents paraquat-induced cell death through attenuating ER stress and mitochondrial dysfunction in PC12 cells.
abstract: 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.
authors.affiliation: Department of Neurology, Puai Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430033, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Shen
authors.affiliation: Department of Neurology, Puai Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430033, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510080, China; International Joint Laboratory (SYSU-PolyU HK) of Novel Anti-Dementia Drugs of Guangdong, Guangzhou 510006, China.
authors.forename: Rongbiao
authors.initials: R
authors.lastname: Pi
authors.affiliation: National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China.
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Li
authors.affiliation: National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China. Electronic address: wrk168ok@163.com.
authors.lastname: Rikang Wang
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000737:chemistry / Q000494:pharmacology; D001381:Azepines / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects* / Q000502:physiology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D016716:PC12 Cells; D010269:Paraquat / Q000037:antagonists & inhibitors / Q000633:toxicity*; D020734:Parkinsonian Disorders / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000978:Antiparkinson Agents; D001381:Azepines; C000602526:L-F001 compound; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D054460:rho-Associated Kinases; D005978:Glutathione; D010269:Paraquat
keywords: Cell death; Endoplasmic reticulum stress; L-F001; Mitochondria; Paraquat; ROCK inhibitor