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.
机构：[1]National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, China[2]Department of Pharmacy, Zhuhai Maternal and Child Health Hospital, Zhuhai 519000, China[3]Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510080, China[4]International Joint Laboratory (SYSU-PolyU HK) of Novel Anti-Dementia Drugs of Guangdong, Guangzhou 510006, China[5]National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Sun Yat-Sen University, Guangzhou 510080, China[6]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其他部门华南肿瘤学国家重点实验室中山大学肿瘤防治中心[7]Department of Neurology, Puai Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430033, China
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.
基金：
Guangdong Provincial International Cooperation Project of Science Technology [2012B050300015, 2013B051000038]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China [81560662]; Natural Science Foundation of Jiangxi ProvinceNatural Science Foundation of Jiangxi Province [20151BDH80081, 20161BAB205195]
语种：
外文
被引次数：
WOS：
PubmedID：
中科院(CAS)分区：
出版当年[2017]版：
大类|3 区医学
小类|4 区生化与分子生物学4 区神经科学
最新[2023]版：
大类|3 区医学
小类|3 区生化与分子生物学3 区神经科学
第一作者：
第一作者机构：[1]National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, China[2]Department of Pharmacy, Zhuhai Maternal and Child Health Hospital, Zhuhai 519000, China[3]Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510080, China[4]International Joint Laboratory (SYSU-PolyU HK) of Novel Anti-Dementia Drugs of Guangdong, Guangzhou 510006, China[5]National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Sun Yat-Sen University, Guangzhou 510080, China
共同第一作者：
通讯作者：
通讯机构：[1]National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, China[7]Department of Neurology, Puai Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430033, China
推荐引用方式(GB/T 7714)：
Luo Liting,Chen Jingkao,Su Dan,et al.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.[J].Neurochemical research.2017,42(2):615-624.doi:10.1007/s11064-016-2117-4.
APA：
Luo, Liting,Chen, Jingkao,Su, Dan,Chen, Meihui,Luo, Bingling...&Wang, Rikang.(2017).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..Neurochemical research,42,(2)
MLA：
Luo, Liting,et al."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.".Neurochemical research 42..2(2017):615-624
