Department of Pharmacy, Shenzhen Bao'an Traditional Chinese Medical Hospital (Group), Shenzhen, 518000, Guangdong, China.
Department of Cardiology, First Affiliated Hospital of Guangzhou University of Chinese Medicine, No.16, Jichang Road, Guangzhou, 510405, Guangdong, China.
Neurochem Res. 2018 Oct;43(10):1914-1926. doi: 10.1007/s11064-018-2609-5. Epub 2018 Sep 11.
Recent researches have shown that autophagy is associated with the pathogenesis of neurodegenerative disorders, but there is no paper to investigate the effects of autophagy modulation on Parkinson's disease depression (PDD). In addition, glycyrrhizic acid (GA), the major bioactive ingredient of Radix glycyrrhizae, can induce autophagy and ease rotenone-induced Parkinson's disease (PD). However, there is also no paper to study the action and molecular mechanisms of GA on PDD. In this research, we built the injury model of SH-SY5Y cells through 6-hydroxydopamine (6-OHDA) and corticosterone (CORT). Then, our results showed that GA markedly increased the viability and decreased the apoptosis in SH-SY5Y cells after pre-treating with 6-OHDA and CORT. Moreover, GA notably decreased the expressions of α-Syn and p-S1292-LRRK2 proteins, and significantly increased the levels of CREB and BDNF proteins. Previous papers have suggested that CORT contributed to dopaminergic neurodegeneration via the glucocorticoid (GC)/glucocorticoid receptor (GR) interaction, and our results showed that GA reduced GC level and hypothalamic-pituitary-adrenal (HPA) activity in SH-SY5Y cells by regulating GR signaling pathway. Furthermore, mechanism investigations also showed that GA had the ability to up-regulate the conversion of LC3B II/I and the expression of Beclin-1, and induce autophagy in SH-SY5Y cells, which were reversed by the autophagy inhibitor 3-methyladenine (3-MA). Collectively, these findings proved that GA exerted efficient activity against neurotoxicity in SH-SY5Y cells induced by 6-OHDA and CORT via activation of autophagy, which should be developed as an efficient candidate for treating PDD in the future.
最近的研究表明，自噬与神经退行性疾病的发病机制有关，但没有研究探讨自噬调节对帕金森病抑郁（PDD）的影响。此外，甘草酸（GA）是甘草根的主要生物活性成分，可诱导自噬并缓解鱼藤酮诱导的帕金森病（PD）。然而，也没有研究探讨 GA 对 PDD 的作用和分子机制。在这项研究中，我们通过 6-羟多巴胺（6-OHDA）和皮质酮（CORT）构建了 SH-SY5Y 细胞损伤模型。然后，我们的结果表明，GA 在用 6-OHDA 和 CORT 预处理后，显著增加了 SH-SY5Y 细胞的活力并降低了细胞凋亡。此外，GA 明显降低了 α-Syn 和 p-S1292-LRRK2 蛋白的表达，并显著增加了 CREB 和 BDNF 蛋白的水平。先前的研究表明，CORT 通过糖皮质激素（GC）/糖皮质激素受体（GR）相互作用导致多巴胺能神经退行性变，我们的结果表明，GA 通过调节 GR 信号通路降低了 SH-SY5Y 细胞中的 GC 水平和下丘脑-垂体-肾上腺（HPA）活性。此外，机制研究还表明，GA 具有上调 LC3B II/I 的转化和 Beclin-1 表达的能力，并在 SH-SY5Y 细胞中诱导自噬，而自噬抑制剂 3-甲基腺嘌呤（3-MA）则逆转了这一过程。综上所述，这些发现证明 GA 通过激活自噬对 6-OHDA 和 CORT 诱导的 SH-SY5Y 细胞的神经毒性具有有效的作用，有望成为未来治疗 PDD 的有效候选药物。
