title: Inhibition of Rho-kinase by Fasudil protects dopamine neurons and attenuates inflammatory response in an intranasal lipopolysaccharide-mediated Parkinson's model.
abstract: Microglia activation and inflammatory factors in brain microenvironment are associated with degeneration of neurons in the substantia nigra (SN) of Parkinson's disease (PD) patients and various PD models. There is increasing evidence that the Rho/ROCK (Rho kinase) signalling pathway may play a critical role in the inflammatory response, and ROCK inhibitor has been reported to have neuroprotective effects. In this study, we examined the neuroprotective potential and possible mechanism of ROCK inhibitor Fasudil in an intranasal lipopolysaccharide (LPS)-induced PD model. ROCK was activated with LPS stimulation and inhibited by Fasudil treatment in this PD model. Behavioural tests demonstrated a clear improvement in motor performance after Fasudil treatment. Furthermore, Fasudil resulted in a significant attenuation of dopamine cell loss, α-synuclein accumulation and inflammatory response with the reversion of inflammatory M1 to anti-inflammatory M2 microglia, decreased NF-кB activation, and IL-12 and TNF-α generation in the SN and olfactory bulb in this model. This study establishes a role for Fasudil in protecting against LPS-mediated dopamine degeneration and provides a therapeutic strategy for the treatment of PD.
authors.affiliation: Department of Neurology, Shanghai Ninth People's Hospital Affiliated Shanghai Jiaotong University School of Medicine, Shanghai, China.|Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: He
authors.affiliation: Department of Neurology, Institute of Brain Science, Medical School, Shanxi Datong University, Datong, China.
authors.forename: Yan-hua
authors.initials: YH
authors.lastname: Li
authors.affiliation: Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
authors.forename: Si-si
authors.initials: SS
authors.lastname: Guo
authors.affiliation: Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Lin
authors.affiliation: Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, 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, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Neurology, Institute of Brain Science, Medical School, Shanxi Datong University, Datong, China.|'2011'Collaborative Innovation Center/Research Center of Neurobiology, Shanxi University of Traditional Chinese Medicine, Taiyuan, China.
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.
authors.forename: Bao-Guo
authors.initials: BG
authors.lastname: Xiao
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000281:Administration, Intranasal; D000818:Animals; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism; D004660:Encephalitis / Q000201:enzymology* / Q000209:etiology / Q000517:prevention & control*; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D009043:Motor Activity / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D009830:Olfactory Bulb / Q000187:drug effects / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000150:complications*; D015398:Signal Transduction / Q000187:drug effects; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D018696:Neuroprotective Agents; D051844:alpha-Synuclein; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; C049347:fasudil
keywords: LPS; Parkinson's disease; ROCK; fasudil; intranasal; mouse models