Wu Hao, Liu Xi, Gao Ze-Yu, Lin Ming, Zhao Xin, Sun Yi, Pu Xiao-Ping
National Key Research Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China.
Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Antioxidants (Basel). 2021 Mar 29;10(4):529. doi: 10.3390/antiox10040529.
Neuroinflammation, oxidative stress, and mitochondrial dysfunction are all important pathogenic mechanisms underlying motor dysfunction and dopaminergic neuronal damage observed in patients with Parkinson's disease (PD). However, despite extensive efforts, targeting inflammation and oxidative stress using various approaches has not led to meaningful clinical outcomes, and mitochondrial enhancers have also failed to convincingly achieve disease-modifying effects. We tested our hypothesis that treatment approaches in PD should simultaneously reduce neuroinflammation, oxidative stress, and improve alterations in neuronal energy metabolism using the flavonoid icaritin in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Using matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI), coupled with biochemical analyses and behavioral tests, we demonstrate that icaritin improves PD by attenuating the the NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome activity and stabilizing mitochondrial function, based on our extensive analyses showing the inhibition of NLRP3 inflammasome, reduction of NLRP3-mediated IL-1β secretion, and improvements in the levels of antioxidant molecules. Our data also indicated that icaritin stabilized the levels of proteins related to mitochondrial function, such as voltage-dependent anion channel (VDAC) and ATP synthase subunit beta (ATP5B), as well as those of molecules related to energy metabolism, such as ATP and ADP, ultimately improving mitochondrial dysfunction. By employing molecular docking, we also discovered that icaritin can interact with NLRP3, VDAC, ATP5B, and several blood-brain barrier (BBB)-related proteins. These data provide insights into the promising therapeutic potential of icaritin in PD.
神经炎症、氧化应激和线粒体功能障碍都是帕金森病（PD）患者运动功能障碍和多巴胺能神经元损伤的重要致病机制。然而，尽管付出了巨大努力，采用各种方法针对炎症和氧化应激进行治疗并未带来有意义的临床结果，线粒体增强剂也未能令人信服地实现疾病修饰作用。我们在1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的PD小鼠模型中，使用类黄酮淫羊藿素测试了我们的假设，即PD的治疗方法应同时减轻神经炎症、氧化应激并改善神经元能量代谢的改变。通过基质辅助激光解吸/电离质谱成像（MALDI-MSI），结合生化分析和行为测试，我们证明淫羊藿素通过减弱含NOD样受体家族pyrin结构域蛋白3（NLRP3）炎性小体活性和稳定线粒体功能来改善PD，基于我们广泛的分析显示其抑制NLRP3炎性小体、减少NLRP3介导的IL-1β分泌以及提高抗氧化分子水平。我们的数据还表明，淫羊藿素稳定了与线粒体功能相关的蛋白质水平，如电压依赖性阴离子通道（VDAC）和ATP合酶β亚基（ATP5B），以及与能量代谢相关的分子水平，如ATP和ADP，最终改善线粒体功能障碍。通过分子对接，我们还发现淫羊藿素可以与NLRP3、VDAC、ATP5B以及几种血脑屏障（BBB）相关蛋白相互作用。这些数据为淫羊藿素在PD中的潜在治疗前景提供了见解。
