Yongfei Zhao1, Qiong Zhang2, Jianying Xi2, Baoguo Xiao2, Yanhua Li3, Cungen Ma4. 1. Department of Neurology, Jinshan Hospital, Fudan University Shanghai 200540, China ; Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University Shanghai 200040, China. 2. Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University Shanghai 200040, China. 3. Department of Neurology, Institute of Brain Science, Medical School, Shanxi Datong University Datong 037009, Shanxi, China. 4. Department of Neurology, Institute of Brain Science, Medical School, Shanxi Datong University Datong 037009, Shanxi, 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 030000, China.
Abstract
OBJECTIVE: Fasudil, a Rho kinase inhibitor, has neuroprotection in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-based Parkinson's disease (PD). This study aims to investigate the mechanism underlying the neuroprotection of fasudil in the PD mice model. METHODS: Female MPTP-intoxication C57BL/6 mice were treated with normal saline or fasudil on day 15 after first administration of MPTP. Pole test was used for the behavioral analysis of mice. Expression of interleukin-1β (IL-1β) and tumor necrosis factor alpha (TNF-α) in brain tissue were detected by ELISA. Expression of tyrosine hydroxylase (TH), p-MYPT1, p-nuclear transcription factor NF-κB, toll-like receptor 2 (TLR2), arginase1, inducible nitric oxide synthase (iNOS), bromodeoxyuridine (BrdU), glial cell line-derived neurotrophic factor (GDNF), p-GSK-3b, p110-PI3K, p-Akt, WNT1, Fzd1 and β-catenin were determined by western blot and immunofluorescence analysis. RESULTS: Fasudil enhanced the number of TH neurons which was decreased by MPTP treatment. Behavioral test showed that the motor performance of mice was improved after fasudil treatment. The expression of IL-1β, TNF-α, TLR2 and p-NF-κB and iNOS were lower after fasudil treatment (P<0.05) while the expression of arginase1 was increased (P<0.05). Further, we could observe the increase of GDNF expression in the microglial cells. The expression of p110-PI3K, p-Akt, WNT1, Fzd1 and β-catenin were increased after fasudil administration (P<0.05) in MPTP-based mice model. CONCLUSIONS: Maybe fasudil protect dopamine neurons from loss in the MPTP mice model of PD through inflammatory inhibition via activation of PI3K/p-Akt and WNT1/Fzd1/β-catenin cell signaling pathways.
OBJECTIVE:Fasudil, a Rho kinase inhibitor, has neuroprotection in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-based Parkinson's disease (PD). This study aims to investigate the mechanism underlying the neuroprotection of fasudil in the PDmice model. METHODS: Female MPTP-intoxication C57BL/6 mice were treated with normal saline or fasudil on day 15 after first administration of MPTP. Pole test was used for the behavioral analysis of mice. Expression of interleukin-1β (IL-1β) and tumor necrosis factor alpha (TNF-α) in brain tissue were detected by ELISA. Expression of tyrosine hydroxylase (TH), p-MYPT1, p-nuclear transcription factor NF-κB, toll-like receptor 2 (TLR2), arginase1, inducible nitric oxide synthase (iNOS), bromodeoxyuridine (BrdU), glial cell line-derived neurotrophic factor (GDNF), p-GSK-3b, p110-PI3K, p-Akt, WNT1, Fzd1 and β-catenin were determined by western blot and immunofluorescence analysis. RESULTS:Fasudil enhanced the number of TH neurons which was decreased by MPTP treatment. Behavioral test showed that the motor performance of mice was improved after fasudil treatment. The expression of IL-1β, TNF-α, TLR2 and p-NF-κB and iNOS were lower after fasudil treatment (P<0.05) while the expression of arginase1 was increased (P<0.05). Further, we could observe the increase of GDNF expression in the microglial cells. The expression of p110-PI3K, p-Akt, WNT1, Fzd1 and β-catenin were increased after fasudil administration (P<0.05) in MPTP-based mice model. CONCLUSIONS: Maybe fasudil protect dopamine neurons from loss in the MPTPmice model of PD through inflammatory inhibition via activation of PI3K/p-Akt and WNT1/Fzd1/β-catenin cell signaling pathways.
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