Rho kinase II interference by small hairpin RNA ameliorates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in mice

• Published in: Molecular medicine reports Vol. 14; no. 6; pp. 4947 - 4956
• Main Authors: Zhang, Qiong, Zhao, Yong-Fei, Xi, Jian-Ying, Yu, Wen-Bo, Xiao, Bao-Guo
• Format: Journal Article
• Language: English
• Published: Greece D.A. Spandidos 01.12.2016; Spandidos Publications; Spandidos Publications UK Ltd
• Subjects: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine - adverse effects; Alzheimer's disease; Animals; Basal ganglia; Behavior, Animal; Biomarkers; Brain diseases; Care and treatment; Central nervous system diseases; Cytokines; Development and progression; Disease Models, Animal; Dopamine receptors; Dopaminergic mechanisms; Dopaminergic Neurons - metabolism; Enzyme Activation; Female; Gene Expression; Gene Expression Regulation; Genetic aspects; Health aspects; Hydroxylase; Inflammation; Interleukin 6; Kinases; Laboratory animals; Mice; Microglia; Microglia - metabolism; Movement disorders; MPTP; neuro-inflammation; Neurodegenerative diseases; Neurons; NF-kappa B - metabolism; Nitric oxide; Nitric-oxide synthase; Parkinson's disease; Parkinsonian Disorders - etiology; Parkinsonian Disorders - metabolism; Parkinsonian Disorders - physiopathology; Phosphotransferases; Polyclonal antibodies; Proteins; Rho kinases; Rho-associated kinase; rho-Associated Kinases - genetics; rho-Associated Kinases - metabolism; Ribonucleic acid; RNA; RNA Interference; RNA, Small Interfering - genetics; RNA-mediated interference; Signal Transduction; Studies; Substantia nigra; TLR2 protein; Toll-like receptors; Tyrosine 3-monooxygenase; United States > US; China
• ISSN: 1791-2997; 1791-3004
• DOI: 10.3892/mmr.2016.5889

Novel therapeutic targets are required for the treatment of Parkinson's disease (PD). Previous studies suggest that the Rho/Rho-associated, coiled-coil-containing protein kinases (ROCKs) signaling pathway may be a promising therapeutic target in PD. To elucidate the importance of ROCKII in the pathogenesis of dopaminergic (DA) neuron loss and to investigate the efficacy of ROCK inhibitors in PD, ROCKII expression in the substantia nigra (SN) of mice was silenced through the injection of a lentivirus-based small hairpin RNA system. Empty lentivirus vectors served as controls. Mice were subsequently challenged with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The expression levels and activity of ROCKII were elevated in tyrosine hydroxylase-positive neurons and in cluster of differentiation (CD) 11b-positive microglia within the SN of MPTP-treated mice, which was accompanied by an increased level of expression of inducible nitric oxide synthase (iNOS) and activation of the Toll-like receptor (TLR)2/nuclear factor (NF)-κB signaling pathway in M1 microglia. ROCKII interference (RI) significantly improved movement disorder and attenuated DA neuron loss induced by MPTP. In addition, RI inhibited the activation of M1 microglia in the SN, exhibiting reduced activity of the TLR2/NF-κB signaling pathway and decreased expression levels of iNOS and inflammatory factors, including interleukin (IL)-1β and IL-6. The results of the present study verify that ROCKII participates in the loss of DA neurons induced by MPTP and suggest that ROCKII inhibition may be a promising therapeutic target for PD.