Fasudil Promotes α-Synuclein Clearance in an AAV-Mediated α-Synuclein Rat Model of Parkinson's Disease by Autophagy Activation

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 F-18-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.