Affiliations: [a] Department of Neurology & National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China
| [b] Institute of Biomedical Science, Fudan University, Shanghai, China
| [c] PET Center, Fudan University, Shanghai, China
| [d] Department of Neurology, Huashan Hospital North, Fudan University, Shanghai, China
| [e] Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
Correspondence:
[*]
Correspondence to: Feng-Tao Liu or Jian Wang, Department of Neurology, Huashan Hospital Affiliated to Fudan University, 12 Wulumuqi Middle Road, Shanghai, 200040. P.R. China. Tel.: +86 13917604896; Fax: +86 21 52888163; E-mails: liufengtao@fudan.edu.cn or wangjian336@hotmail.com.
Note: [1] These authors contributed equally to this work.
Abstract: 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 α-synuclein (α-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 α-syn (AAV9-A53T-α-syn) into the right substantia nigra, we aimed to investigate whether Fasudil could promote α-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 α-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.
