AI Article Synopsis
- Parkinson's disease (PD) lacks effective therapies targeting its core pathology, prompting research into Rho-associated protein kinase (ROCK) as a potential treatment avenue.
- In a rat model of PD, treatment with Fasudil was found to improve motor function and increase dopaminergic activity by promoting the clearance of α-synuclein through specific cellular pathways.
- The findings suggest Fasudil's potential as a disease-modifying therapy for PD, emphasizing its ability to enhance autophagy and mitigate both anatomical and behavioral impairments associated with the disorder.
Article 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.
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