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

摘要

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. (C) 2015 Elsevier Inc. All rights reserved.