PMID- 32568105
OWN - NLM
STAT- MEDLINE
DCOM- 20210819
LR  - 20210819
IS  - 1877-718X (Electronic)
IS  - 1877-7171 (Linking)
VI  - 10
IP  - 3
DP  - 2020
TI  - Fasudil Promotes alpha-Synuclein Clearance in an AAV-Mediated alpha-Synuclein Rat Model 
      of Parkinson's Disease by Autophagy Activation.
PG  - 969-979
LID - 10.3233/JPD-191909 [doi]
AB  - BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative 
      disorder, but the disease-modifying therapies focusing on the core pathological 
      changes are still unavailable. Rho-associated protein kinase (ROCK) has been 
      suggested as a promising target for developing neuroprotective therapies in PD. 
      OBJECTIVE: We aimed to explore the promotion of alpha-synuclein (alpha-syn) clearance in 
      a rat model. METHODS: In a rat model induced by unilateral injection of 
      adeno-associated virus of serotype 9 (AAV9) expressing A53T alpha-syn 
      (AAV9-A53T-alpha-syn) into the right substantia nigra, we aimed to investigate 
      whether Fasudil could promote alpha-syn clearance and thereby attenuate motor 
      impairments and dopaminergic deficits. RESULTS: In our study, treatment with 
      Fasudil (5 mg/kg rat weight/day) for 8 weeks significantly improved the motor 
      deficits in the Cylinder and Rotarod tests. In the in vivo positron emission 
      tomography imaging with the ligand 18F-dihydrotetrabenazine, Fasudil 
      significantly enhanced the dopaminergic imaging in the injected striatum of the 
      rat model (p < 0.05 vs. vehicle group, p < 0.01 vs. left striatum in Fasudil 
      group). The following mechanistic study confirmed that Fasudil could promote the 
      autophagic clearance of alpha-syn by Becline 1 and Akt/mTOR pathways. CONCLUSION: Our 
      study suggested that Fasudil, the ROCK2 inhibitor, could attenuate the anatomical 
      and behavioral lesions in the Parkinsonian rat model by autophagy activation. Our 
      results identify Fasudil as a drug with high translational potential as 
      disease-modifying treatment for PD and other synucleinopathies.
FAU - Yang, Yu-Jie
AU  - Yang YJ
AD  - Department of Neurology & National Clinical Research Center for Aging and 
      Medicine, Huashan Hospital, Fudan University, Shanghai, China.
AD  - Institute of Biomedical Science, Fudan University, Shanghai, China.
FAU - Bu, Lu-Lu
AU  - Bu LL
AD  - Department of Neurology & National Clinical Research Center for Aging and 
      Medicine, Huashan Hospital, Fudan University, Shanghai, China.
AD  - Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 
      Guangzhou, China.
FAU - Shen, Cong
AU  - Shen C
AD  - Department of Neurology & National Clinical Research Center for Aging and 
      Medicine, Huashan Hospital, Fudan University, Shanghai, China.
FAU - Ge, Jing-Jie
AU  - Ge JJ
AD  - PET Center, Fudan University, Shanghai, China.
FAU - He, Shu-Jin
AU  - He SJ
AD  - Department of Neurology & National Clinical Research Center for Aging and 
      Medicine, Huashan Hospital, Fudan University, Shanghai, China.
FAU - Yu, Hui-Ling
AU  - Yu HL
AD  - Department of Neurology & National Clinical Research Center for Aging and 
      Medicine, Huashan Hospital, Fudan University, Shanghai, China.
FAU - Tang, Yi-Lin
AU  - Tang YL
AD  - Department of Neurology & National Clinical Research Center for Aging and 
      Medicine, Huashan Hospital, Fudan University, Shanghai, China.
FAU - Jue, Zhao
AU  - Jue Z
AD  - Department of Neurology & National Clinical Research Center for Aging and 
      Medicine, Huashan Hospital, Fudan University, Shanghai, China.
FAU - Sun, Yi-Min
AU  - Sun YM
AD  - Department of Neurology & National Clinical Research Center for Aging and 
      Medicine, Huashan Hospital, Fudan University, Shanghai, China.
FAU - Yu, Wen-Bo
AU  - Yu WB
AD  - Department of Neurology & National Clinical Research Center for Aging and 
      Medicine, Huashan Hospital, Fudan University, Shanghai, China.
FAU - Zuo, Chuan-Tao
AU  - Zuo CT
AD  - PET Center, Fudan University, Shanghai, China.
FAU - Wu, Jian-Jun
AU  - Wu JJ
AD  - Department of Neurology & National Clinical Research Center for Aging and 
      Medicine, Huashan Hospital, Fudan University, Shanghai, China.
FAU - Wang, Jian
AU  - Wang J
AD  - Department of Neurology & National Clinical Research Center for Aging and 
      Medicine, Huashan Hospital, Fudan University, Shanghai, China.
FAU - Liu, Feng-Tao
AU  - Liu FT
AD  - Department of Neurology & National Clinical Research Center for Aging and 
      Medicine, Huashan Hospital, Fudan University, Shanghai, China.
AD  - Department of Neurology, Huashan Hospital North, Fudan University, Shanghai, 
      China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Netherlands
TA  - J Parkinsons Dis
JT  - Journal of Parkinson's disease
JID - 101567362
RN  - 0 (Snca protein, rat)
RN  - 0 (alpha-Synuclein)
RN  - VTD58H1Z2X (Dopamine)
SB  - IM
MH  - Animals
MH  - Autophagy/physiology
MH  - Disease Models, Animal
MH  - Dopamine/*metabolism
MH  - Dopaminergic Neurons/*metabolism
MH  - Female
MH  - Neurodegenerative Diseases/metabolism
MH  - Parkinson Disease/drug therapy/*metabolism
MH  - Rats, Sprague-Dawley
MH  - Substantia Nigra/metabolism/pathology
MH  - alpha-Synuclein/*metabolism
OTO - NOTNLM
OT  - A53T alpha-synuclein
OT  - Fasudil
OT  - Parkinson's disease
OT  - macroautophagy
OT  - positron emission tomography
OT  - vesicular monoamine transporter 2
EDAT- 2020/06/23 06:00
MHDA- 2021/08/20 06:00
CRDT- 2020/06/23 06:00
PHST- 2020/06/23 06:00 [pubmed]
PHST- 2021/08/20 06:00 [medline]
PHST- 2020/06/23 06:00 [entrez]
AID - JPD191909 [pii]
AID - 10.3233/JPD-191909 [doi]
PST - ppublish
SO  - J Parkinsons Dis. 2020;10(3):969-979. doi: 10.3233/JPD-191909.