title: Neuroprotective effect of fasudil on inflammation through PI3K/Akt and Wnt/β-catenin dependent pathways in a mice model of Parkinson's disease.
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.
authors.affiliation: 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.
authors.forename: Yongfei
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University Shanghai 200040, China.
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 200040, China.
authors.forename: Jianying
authors.initials: J
authors.lastname: Xi
authors.affiliation: Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University Shanghai 200040, China.
authors.forename: Baoguo
authors.initials: B
authors.lastname: Xiao
authors.affiliation: Department of Neurology, Institute of Brain Science, Medical School, Shanxi Datong University Datong 037009, Shanxi, China.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Cungen
authors.initials: C
authors.lastname: Ma
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D002470:Cell Survival / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D004789:Enzyme Activation; D005260:Female; D051157:Frizzled Receptors / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology / Q000523:psychology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051155:Wnt1 Protein / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; C495267:CTNNB1 protein, mouse; D016207:Cytokines; D051157:Frizzled Receptors; C489739:Fzd1 protein, mouse; D018836:Inflammation Mediators; D018696:Neuroprotective Agents; D047428:Protein Kinase Inhibitors; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D051176:beta Catenin; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D058534:Class I Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D054460:rho-Associated Kinases; C049347:fasudil
keywords: MPTP; Parkinson’s disease; fasudil; inflammatory response; signaling pathways