Lopez-Lopez Andrea, Valenzuela Rita, Rodriguez-Perez Ana Isabel, Guerra María J, Labandeira-Garcia Jose Luis, Muñoz Ana
Research Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.
Networking Research Center on Neurodegenerative Diseases (CIBERNED), 28029 Madrid, Spain.
Antioxidants (Basel). 2023 Jul 19;12(7):1454. doi: 10.3390/antiox12071454.
Statins have been proposed for L-DOPA-induced dyskinesia (LID) treatment. Statin anti-dyskinetic effects were related to the inhibition of the Ras-ERK pathway. However, the mechanisms responsible for the anti-LID effect are unclear. Changes in cholesterol homeostasis and oxidative stress- and inflammation-related mechanisms such as angiotensin II and Rho-kinase (ROCK) inhibition may be involved. The nigra and striatum of dyskinetic rats showed increased levels of cholesterol, ROCK, and the inflammatory marker IL-1β, which were reduced by the angiotensin type-1 receptor (AT1) antagonist candesartan, simvastatin, and the ROCK inhibitor fasudil. As observed for LID, angiotensin II-induced, via AT1, increased levels of cholesterol and ROCK in the rat nigra and striatum. In cultured dopaminergic neurons, angiotensin II increased cholesterol biosynthesis and cholesterol efflux without changes in cholesterol uptake. In astrocytes, angiotensin induced an increase in cholesterol uptake, decrease in biosynthesis, and no change in cholesterol efflux, suggesting a neuronal accumulation of cholesterol that is reduced via transfer to astrocytes. Our data suggest mutual interactions between angiotensin/AT1, cholesterol, and ROCK pathways in LID, which are attenuated by the corresponding inhibitors. Interestingly, these three drugs have also been suggested as neuroprotective treatments against Parkinson's disease. Therefore, they may reduce dyskinesia and the progression of the disease using common mechanisms.
他汀类药物已被提议用于治疗左旋多巴诱导的异动症（LID）。他汀类药物的抗异动症作用与抑制Ras-ERK通路有关。然而，其抗LID作用的机制尚不清楚。胆固醇稳态的变化以及与氧化应激和炎症相关的机制，如血管紧张素II和Rho激酶（ROCK）的抑制作用可能都参与其中。异动症大鼠的黑质和纹状体中胆固醇、ROCK和炎症标志物白细胞介素-1β的水平升高，而血管紧张素1型受体（AT1）拮抗剂坎地沙坦、辛伐他汀和ROCK抑制剂法舒地尔可降低这些水平。正如在LID中观察到的那样，血管紧张素II通过AT1诱导大鼠黑质和纹状体中胆固醇和ROCK水平升高。在培养的多巴胺能神经元中，血管紧张素II增加了胆固醇的生物合成和胆固醇流出，而胆固醇摄取没有变化。在星形胶质细胞中，血管紧张素诱导胆固醇摄取增加、生物合成减少，胆固醇流出没有变化，这表明神经元中胆固醇的积累通过转移到星形胶质细胞而减少。我们的数据表明，在LID中血管紧张素/AT1、胆固醇和ROCK通路之间存在相互作用，而相应的抑制剂可减弱这种相互作用。有趣的是，这三种药物也被认为是针对帕金森病的神经保护治疗药物。因此，它们可能通过共同机制减少异动症和疾病的进展。
