Dept. of Biological Chemistry Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, 91904, Israel.
Cell Death Dis. 2022 Mar 11;13(3):227. doi: 10.1038/s41419-022-04667-2.
Parkinson's disease (PD) is characterized by a gradual degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNpC). Levodopa, the standard PD treatment, provides the missing dopamine in SNpC, but ultimately after a honeymoon with levodopa treatment the neurodegenerative process and the progression of the disease continue. Aimed at prolonging the life of dopaminergic cells, we prepared the levodopa precursors SuperDopa (SD) and SueprDopamide (SDA), in which levodopa is merged with the antioxidant N-acetylcysteine (NAC) into a single molecule. Rotenone is a mitochondrial complex inhibitor often used as experimental model of PD. In vivo, SD and SDA treatment show a significant relief of motor disabilities in rotenone-injected rats. SD and SDA also lower rotenone-induced-α-synuclein (α-syn) expression in human SH-SY5Y cells, and α-syn oligomerization in α-syn-overexpressing-HEK293 cells. In the neuronal SH-SY5Y cells, SD and SDA reverse oxidative stress-induced phosphorylation of cJun-N-terminal kinase (JNK) and p38-mitogen-activated kinase (p38). Attenuation of the MAPK-inflammatory/apoptotic pathway in SH-SY5Y cells concurrent with protection of rotenone-triggered motor impairment in rats, is a manifestation of the combined antioxidant/anti-inflammatory activity of SD and SDA together with levodopa release. The concept of joined therapies into a single molecule, where levodopa precursors confer antioxidant activity by enabling NAC delivery across the BBB, provides a potential disease-modifying treatment for slowing PD progression.
帕金森病（PD）的特征是黑质致密部（SNpC）中的多巴胺能神经元逐渐退化。左旋多巴是 PD 的标准治疗药物，可提供 SNpC 中缺失的多巴胺，但最终在与左旋多巴治疗的蜜月期过后，神经退行性过程和疾病的进展仍会继续。为了延长多巴胺能细胞的寿命，我们制备了左旋多巴前体 SuperDopa（SD）和 SuperDopamide（SDA），其中左旋多巴与抗氧化剂 N-乙酰半胱氨酸（NAC）融合成一个分子。鱼藤酮是一种常用作 PD 实验模型的线粒体复合物抑制剂。在体内，SD 和 SDA 治疗可显著缓解鱼藤酮注射大鼠的运动障碍。SD 和 SDA 还降低了鱼藤酮诱导的人 SH-SY5Y 细胞中的α-突触核蛋白（α-syn）表达和α-syn 寡聚体在α-syn 过表达-HEK293 细胞中的表达。在神经元 SH-SY5Y 细胞中，SD 和 SDA 逆转了氧化应激诱导的 cJun-N 末端激酶（JNK）和丝裂原活化蛋白激酶（p38）磷酸化。SH-SY5Y 细胞中 MAPK-炎症/凋亡途径的衰减伴随着对大鼠鱼藤酮触发运动障碍的保护，这是 SD 和 SDA 与左旋多巴释放的联合抗氧化/抗炎活性的表现。将联合疗法纳入单个分子的概念，其中左旋多巴前体通过使 NAC 穿过血脑屏障得以递送而赋予抗氧化活性，为减缓 PD 进展提供了一种潜在的疾病修饰治疗方法。
