title: L-F001, a Multifunction ROCK Inhibitor Prevents 6-OHDA Induced Cell Death Through Activating Akt/GSK-3beta and Nrf2/HO-1 Signaling Pathway in PC12 Cells and Attenuates MPTP-Induced Dopamine Neuron Toxicity in Mice.
abstract: Amounting evidences demonstrated that Rho/Rho-associated kinase (ROCK) might be a novel target for the therapy of Parkinson's disease (PD). Recently, we synthesized L-F001 and revealed it was a potent ROCK inhibitor with multifunctional effects. Here we investigated the effects of L-F001 in PD models. We found that L-F001 potently attenuated 6-OHDA-induced cytotoxicity in PC12 cells and significantly decreased intracellular reactive oxygen species (ROS), prevented the 6-OHDA-induced decline of mitochondrial membrane potential and intracellular GSH levels. In addition, L-F001 increased Akt and GSK-3beta phosphorylation and induced the nuclear Nrf2 and HO-1 expression in a time- and concentration-dependent manner. Moreover, L-F001 restored the levels of p-Akt and p-GSK-3beta (Ser9) as well as HO-1 expression reduced by 6-OHDA. Those effects were blocked by the specific PI3K inhibitor, LY294002, indicating the involvement of Akt/GSK-3beta pathway in the neuroprotective effect of L-F001. In addition, L-F001 significantly attenuated the tyrosinehydroxylase immunoreactive cell loss in 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-induced mice PD model. Together, our findings suggest that L-F001 prevents 6-OHDA-induced cell death through activating Akt/GSK-3beta and Nrf2/HO-1 signaling pathway and attenuates MPTP-induced dopaminergic neuron toxicity in mice. L-F001 might be a promising drug candidate for PD.
authors.affiliation: National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330006, China.|Department of Pharmacy, Zhuhai Maternal and Child Health Hospital, Zhuhai, 519000, China.|Department of Pharmacology and 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.|National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Sun Yat-Sen University, Guangzhou, 510080, China.
authors.forename: Liting
authors.initials: L
authors.lastname: Luo
authors.affiliation: Department of Pharmacology and 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.|National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Sun Yat-Sen University, Guangzhou, 510080, China.
authors.forename: Jingkao
authors.initials: J
authors.lastname: Chen
authors.affiliation: National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330006, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Su
authors.affiliation: Department of Pharmacology and 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.|National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Sun Yat-Sen University, Guangzhou, 510080, China.
authors.forename: Meihui
authors.initials: M
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng East Road, Guangzhou, 510060, China.
authors.forename: Bingling
authors.initials: B
authors.lastname: Luo
authors.affiliation: Department of Pharmacology and 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.|National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Sun Yat-Sen University, Guangzhou, 510080, China.
authors.forename: Rongbiao
authors.initials: R
authors.lastname: Pi
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 Neurology, Puai Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430033, China. shenwei19711227@163.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Shen
authors.affiliation: National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330006, China. wrk168ok@163.com.
authors.forename: Rikang
authors.initials: R
authors.lastname: Wang
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D016627:Oxidopamine / Q000633:toxicity; D016716:PC12 Cells; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors
chemical_list: D001381:Azepines; C000602526:L-F001 compound; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; C495636:Nfe2l2 protein, mouse; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D016627:Oxidopamine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D054460:rho-Associated Kinases
keywords: 6-OHDA; GSK-3beta; L-F001; MPTP; Nrf2 pathway; Parkinson’s disease