Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, China.
Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, China; Department of Chemistry and Life Science, School of Advanced Engineering, Kogakuin University, 2665-1, Nakanomachi, Hachioji, Tokyo, 192-0015, Japan; Nippi Research Institute of Biomatrix, Toride, Ibaraki 302-0017, Japan.
Physiol Behav. 2021 Oct 1;239:113510. doi: 10.1016/j.physbeh.2021.113510. Epub 2021 Jun 25.
Silybum marianum (L.) Gaertn has been widely used to obtain a drug for the treatment of hepatic diseases. Silibinin (silybin), a flavonoid extracted and isolated from the fruit of S. marianumis investigated in our study to explore its motor protective potential on Parkinson's disease (PD) model mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). PD is a neurodegenerative disease that causes a debilitating movement disorder, characterized by a progressive loss of nigrostriatal (substantia nigra and striatum) dopaminergic neurons. Several studies have proven that neurodegeneration is aggravated by neuroinflammation, oxidative stress and/or the presence of α-synuclein (α-syn) aggregation. Essentially no causal therapy for PD exists at present. Our results demonstrate that silibinin significantly attenuates MPTP-induced movement disorder in behavioral tests. Immunohistochemical analysis shows that MPTP injection results in the loss of dopaminergic neurons in the substantia nigra, and the decrease of the striatal tyrosine hydroxylase. However, MPTP-injected mice were protected against dopaminergic neuronal loss by oral administration of silibinin (280 mg/kg) that increased expressions of PTEN-induced putative kinase 1 (PINK1) and Parkin, suggesting mitophagy activation. The neuroprotective mechanism of silibinin involves not only reduction of mitochondrial damage by repressing proinflammatory response and α-syn aggregation, but also enhancement of oxidative defense system. Namely, protection of dopaminergic nerves is due to promotion of mitophagy, leading to clearance of the toxic effects of damaged mitochondria. These findings suggest that silibinin has a potential to be further developed as a therapeutic candidate for PD.
水飞蓟素（奶蓟素），一种从水飞蓟（Silybum marianum）果实中提取和分离的类黄酮，在本研究中用于探索其对 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的帕金森病（PD）模型小鼠的运动保护潜力。PD 是一种神经退行性疾病，导致进行性丧失黑质纹状体（黑质和纹状体）多巴胺能神经元，从而引起致残性运动障碍。多项研究已经证明神经炎症、氧化应激和/或α-突触核蛋白（α-syn）聚集的加剧会加重神经退行性变。目前基本上没有针对 PD 的因果疗法。我们的结果表明，水飞蓟素可显著减轻 MPTP 诱导的行为测试中的运动障碍。免疫组织化学分析表明，MPTP 注射导致黑质多巴胺能神经元丧失，纹状体酪氨酸羟化酶减少。然而，通过口服水飞蓟素（280mg/kg），MPTP 注射的小鼠可免受多巴胺能神经元丧失的影响，这增加了 PTEN 诱导的假定激酶 1（PINK1）和 Parkin 的表达，表明自噬激活。水飞蓟素的神经保护机制不仅涉及通过抑制促炎反应和α-syn 聚集来减少线粒体损伤，还涉及增强氧化防御系统。即，多巴胺能神经的保护是由于促进自噬，从而清除受损线粒体的毒性作用。这些发现表明，水飞蓟素有可能进一步开发为 PD 的治疗候选药物。
