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 neuro-protective 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.

中文翻译：

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Fasudil 通过自噬激活促进 AAV 介导的帕金森病 α-突触核蛋白大鼠模型中的 α-突触核蛋白清除。

背景：帕金森病（PD）是第二常见的神经退行性疾病，但针对核心病理变化的疾病修饰疗法仍不可用。Rho 相关蛋白激酶 (ROCK) 已被认为是开发 PD 神经保护疗法的有希望的靶点。目的：我们旨在探索在大鼠模型中促进α-突触核蛋白（α-syn）清除。方法：在大鼠右侧黑质注射表达 A53T α-syn（AAV9-A53T-α-syn）的血清型 9 腺相关病毒（AAV9）诱导的大鼠模型中，我们旨在研究 Fasudil 是否能促进 α -syn 清除，从而减轻运动障碍和多巴胺能缺陷。结果：在我们的研究中，用 Fasudil（5 毫克/公斤大鼠体重/天）治疗 8 周显着改善了圆柱和旋转棒测试中的运动缺陷。在配体 18F-二氢丁苯那嗪的体内正电子发射断层扫描成像中，法舒地尔显着增强了大鼠模型注射纹状体的多巴胺能成像（与载体组相比，p < 0.05，与法舒地尔组的左侧纹状体相比，p < 0.01）。以下机理研究证实，Fasudil 可以通过 Becline 1 和 Akt/mTOR 通路促进 α-Syn 的自噬清除。结论：我们的研究表明，ROCK2 抑制剂 Fasudil 可以通过自噬激活减轻帕金森大鼠模型的解剖和行为损伤。