Chen Qiu-Xu, Zhou Ling, Long Tao, Qin Da-Lian, Wang Yi-Ling, Ye Yun, Zhou Xiao-Gang, Wu Jian-Ming, Wu An-Guo
Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, Materia Medica, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou 646000, China.
Department of Pharmacy, Affiliated Hospital of Southwest Medical University, Luzhou 646000, China.
Pharmaceuticals (Basel). 2022 Aug 17;15(8):1014. doi: 10.3390/ph15081014.
Parkinson's disease (PD) is the second most common neurodegenerative disease, and there is still no cure for it. PD is characterized by the degeneration of dopaminergic neurons, and oxidative stress has been considered an important pathological mechanism. Therefore, the discovery of antioxidants to alleviate the oxidative damage of dopaminergic neurons is a promising therapeutic strategy for PD. First, a network pharmacology approach was used, and nine common core targets of galangin and PD were screened, mainly involving cell aging, apoptosis, and cellular responses to hydrogen peroxide and hypoxia. In addition, the Gene Ontology (GO) function and pathway enrichment analysis of the Kyoto Encyclopedia of Genes and Genomes (KEGG) identified apoptosis, PI3K/Akt, and HIF-1 signaling pathways. Furthermore, the molecular docking results revealed a strong affinity between galangin and the NFE2L2/Nrf2 protein. To validate the above predictions, we employed 6-hydroxydopamine (6-OHDA) to induce neuronal death in HT22 cells and (). MTT, cell morphology observation, and Hoechst 33342-PI staining results showed that galangin significantly increased the viability of 6-OHDA-treated HT22 cells. In addition, galangin inhibited 6-OHDA-induced ROS generation and apoptosis in HT22 cells. Mechanistic studies demonstrated that galangin activates the Nrf2/Keap1 signaling pathway, as evidenced by the decreased protein expression of Keap1 and increased protein expression of Nrf2 and HO-1. In the 6-OHDA-induced PD model of , galangin indeed inhibited the degeneration of dopaminergic neurons, improved behavioral ability, and decreased ROS generation. In conclusion, the current study is the first to show that galangin has the capacity to inhibit neuronal degeneration via the Nrf2/Keap1 pathway, suggesting that galangin is a possible PD treatment.
帕金森病（PD）是第二常见的神经退行性疾病，目前仍然无法治愈。PD的特征是多巴胺能神经元变性，氧化应激被认为是一种重要的病理机制。因此，发现抗氧化剂以减轻多巴胺能神经元的氧化损伤是一种有前景的PD治疗策略。首先，采用网络药理学方法，筛选出了高良姜素和PD的9个共同核心靶点，主要涉及细胞衰老、凋亡以及细胞对过氧化氢和缺氧的反应。此外，基因本体论（GO）功能和京都基因与基因组百科全书（KEGG）通路富集分析确定了凋亡、PI3K/Akt和HIF-1信号通路。此外，分子对接结果显示高良姜素与NFE2L2/Nrf2蛋白之间具有很强的亲和力。为了验证上述预测，我们使用6-羟基多巴胺（6-OHDA）诱导HT22细胞神经元死亡以及（）。MTT、细胞形态观察和Hoechst 33342-PI染色结果表明，高良姜素显著提高了6-OHDA处理的HT22细胞的活力。此外，高良姜素抑制了6-OHDA诱导的HT22细胞中ROS的产生和凋亡。机制研究表明，高良姜素激活了Nrf2/Keap1信号通路，Keap1蛋白表达降低以及Nrf2和HO-1蛋白表达增加证明了这一点。在（）的6-OHDA诱导的PD模型中，高良姜素确实抑制了多巴胺能神经元的变性，改善了行为能力，并减少了ROS的产生。总之，当前研究首次表明高良姜素有能力通过Nrf2/Keap1途径抑制神经元变性，这表明高良姜素可能是一种PD治疗药物。
