title: Multitarget intervention of Fasudil in the neuroprotection of dopaminergic neurons in MPTP-mouse model of Parkinson's disease.
abstract: Recent studies have demonstrated that activation of the Rho-associated kinase (ROCK) pathway participates in the dopaminergic neuron degeneration and possibly in Parkinson's disease (PD). In the current study, we tried to observe the therapeutic potential of ROCK inhibitor Fasudil against dopaminergic neuron injury in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mouse model of PD, and explore possible molecular mechanisms by enzyme-linked immunosorbent assay (ELISA), western blot and immunofluorescent assays. The results showed that MPTP-PD mice presented motor deficits, dopaminergic neuron loss, activation of inflammatory response and oxidative stress as well as ROCK and glycogen synthase kinase 3β (GSK-3β) signaling pathways. The administration of Fasudil exhibited neuroprotective effects against the dopaminergic neurons and improved the motor function recovery in the MPTP-PD mice, accompanied by the suppression of inflammatory responses (IL-1β, TNF-α, NF-κB-p65 and TLR-2), and oxidative stress (iNOS and gp91Phox), which might be associated with the inhibition of ROCK and GSK-3β activity. Simultaneously, the administration of Fasudil resulted in the shift from inflammatory M1 to anti-inflammatory/neurorepair M2 microglia. Additionally, Fasudil intervention enhanced the expression of anti-oxidative factors such as NF-E2-related factor 2 (Nrf2), Hmox as well as neurotrophic factor including GDNF. Our observations defined the neuroprotective effects of Fasudil in MPTP-PD mice, and we found a series of novel effector molecules and pathways for explaining the neuroprotective effects against dopaminergic neurons. However, a lot of investigations are warranted to further elucidate the crosstalk among Fasudil, oxidative stress, inflammatory response, GDNF and ROCK/NF-kB/Nrf2 pathways in the therapeutic potential of PD.
authors.affiliation: Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China; Department of Neurology, Jinshan Hospital, Fudan University, Shanghai, China. Electronic address: zhaoyongfei1535@163.com.
authors.forename: Yong-fei
authors.initials: YF
authors.lastname: Zhao
authors.affiliation: Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China. Electronic address: zhpoor@163.com.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China. Electronic address: jianyingxi@yeah.net.
authors.forename: Jian-ying
authors.initials: JY
authors.lastname: Xi
authors.affiliation: Department of Neurology, Institute of Brain Science, Medical School, Shanxi Datong University, Datong, China. Electronic address: lyanhual@126.com.
authors.forename: Yan-hua
authors.initials: YH
authors.lastname: Li
authors.affiliation: Department of Neurology, Institute of Brain Science, Medical School, Shanxi Datong University, Datong, China; "2011" Collaborative Innovation Center/Department of Encephalopathy and National Major Clinical Department of Ministry of Health, Third Hospital, Department of Neurology, Shanxi University of Traditional Chinese Medicine, Taiyuan, China. Electronic address: mhcungen@163.com.
authors.forename: Cun-gen
authors.initials: CG
authors.lastname: Ma
authors.affiliation: Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China. Electronic address: bgxiao@shmu.edu.cn.
authors.forename: Bao-guo
authors.initials: BG
authors.lastname: Xiao
mesh_terms: D000818:Animals; D005260:Female; D051379:Mice; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000704:Analysis of Variance; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D020267:MPTP Poisoning / Q000473:pathology / Q000517:prevention & control; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D018696:Neuroprotective Agents / Q000627:therapeutic use; D011597:Psychomotor Performance / Q000187:drug effects; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism
chemical_list: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C488842:Cybb protein, mouse; D016207:Cytokines; C049347:fasudil; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D018696:Neuroprotective Agents; C498144:Rela protein, mouse; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D051996:Transcription Factor RelA; D014446:Tyrosine 3-Monooxygenase; D051267:NF-E2-Related Factor 2
keywords: 1-Methyl-4-phenyl-1,-2,3,6-tetrahydropyridine (MPTP); Dopaminergic neurons; Fasudil; Neuroprotection; Parkinson's disease (PD); Rho kinase inhibitor