Carbajal Candy, Rodriguez Myosotys, Owens Florida, Stone Nicole, Veeragoni Dileepkumar, Fan Rebecca Z, Tieu Kim, El-Hage Nazira
Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA.
Department of Environmental Health Sciences, Robert Stempel College of Public Health & Social Work, Florida International University, Miami, FL 33199, USA.
Pharmaceutics. 2025 Mar 13;17(3):365. doi: 10.3390/pharmaceutics17030365.
Parkinson's disease (PD) is a rapidly growing neurological disorder in the developed world, affecting millions over the age of 60. The decline in motor functions occurs due to a progressive loss of midbrain dopaminergic neurons, resulting in lowered dopamine levels and impaired muscle function. Studies show defective mitochondrial autophagy (or "mitophagy") links to PD. Rho-associated coiled-coil containing protein kinases (ROCK) 1 and ROCK2 are serine/threonine kinases, and their inhibition can enhance neuroprotection in PD by promoting mitophagy. We examine the effects of ROCK inhibitor SR3677, delivered via macrophage-derived small extracellular vesicles (sEVs) to Parkin Q311X(A) PD mouse models. sEVs with SR3677, administered intranasally, increased mitophagy gene expression, reduced inflammatory factors, and elevated dopamine levels in brain tissues. ROCK2 expression decreased, showing the drug's inhibitory effect. sEV-SR3677 treatment was more effective than treatment with the drug alone, although sham EVs showed lower effects. This suggests that EV-SR3677 not only activates mitochondrial processes but also promotes the degradation of damaged mitochondria through autophagy. Mitochondrial functional assays and oxygen consumption in ex vivo glial cultures revealed that sEV-SR3677 significantly improved mitochondrial respiration compared to that in untreated or SR3677-only treated cells. We demonstrated the efficacy of ROCK2 inhibition on mitochondrial function via sEV-SR3677 in the PD mouse model, necessitating further studies to explore design challenges and mechanisms of sEV-SR3677 as mitochondria-targeted therapy for PD.
帕金森病（PD）在发达国家是一种迅速增长的神经疾病，影响着数百万60岁以上的人群。运动功能的衰退是由于中脑多巴胺能神经元的逐渐丧失，导致多巴胺水平降低和肌肉功能受损。研究表明，缺陷性线粒体自噬（或“线粒体自噬”）与帕金森病有关。含Rho相关卷曲螺旋的蛋白激酶（ROCK）1和ROCK2是丝氨酸/苏氨酸激酶，抑制它们可以通过促进线粒体自噬增强帕金森病中的神经保护作用。我们研究了通过巨噬细胞衍生的小细胞外囊泡（sEVs）递送的ROCK抑制剂SR3677对帕金Q311X（A）帕金森病小鼠模型的影响。经鼻给药含有SR3677的sEVs可增加线粒体自噬基因表达，减少炎症因子，并提高脑组织中的多巴胺水平。ROCK2表达下降，显示出该药物的抑制作用。sEV-SR3677治疗比单独使用该药物治疗更有效，尽管假sEVs的效果较低。这表明EV-SR3677不仅激活线粒体过程，还通过自噬促进受损线粒体的降解。体外神经胶质细胞培养中的线粒体功能测定和氧消耗显示，与未处理或仅用SR3677处理的细胞相比，sEV-SR3677显著改善了线粒体呼吸。我们在帕金森病小鼠模型中证明了通过sEV-SR3677抑制ROCK2对线粒体功能的疗效，需要进一步研究以探索sEV-SR3677作为帕金森病线粒体靶向治疗的设计挑战和机制。
