College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, 32 Dongguk-ro, Ilsandong-gu, Goyang, Gyeonggi, 10326, Republic of Korea.
College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, 32 Dongguk-ro, Ilsandong-gu, Goyang, Gyeonggi, 10326, Republic of Korea; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Badr University in Cairo, 11829, Egypt.
Eur J Med Chem. 2022 Nov 15;242:114692. doi: 10.1016/j.ejmech.2022.114692. Epub 2022 Aug 18.
Parkinson's disease (PD) is a neurodegenerative disorder that causes uncontrollable movements. Although many breakthroughs in PD therapy have been accomplished, there is currently no cure for PD, and only trials to relieve symptoms have been evaluated. Recently, we reported the total synthesis of cudraisoflavone J and its chiral isomers [Lu et al., J. Nat. Prod. 2021, 84, 1359]. In this study, we designed and synthesized a series of novel cudraisoflavone J derivatives and evaluated their neuroprotective activities in neurotoxin-treated PC12 cells. Among these compounds, difluoro-substituted derivative (13m) and prenylated derivative (24) provided significant protection to PC12 cells against toxicity induced by 6-hydroxydopamine (6-OHDA) or rotenone. Both derivatives inhibited 6-OHDA- or rotenone-induced production of reactive oxygen species and partially attenuated lipid peroxidation in rat brain homogenates, indicating their antioxidant properties. They also increased the expression of the antioxidant enzyme, heme oxygenase (HO)-1, and enhanced the nuclear translocation of Nrf2, the transcription factor that regulates the expression of antioxidant proteins. The neuroprotective effects of 13m and 24 were eliminated by Zn(II)-protoporphyrin IX, an HO-1 inhibitor, demonstrating the critical role of HO-1 in their actions. Moreover, upregulation of HO-1 was abolished by nuclear factor erythroid 2-related factor (Nrf2) knockdown, verifying that Nrf2 is an upstream regulator of HO-1. Compounds 13m and 24 triggered phosphorylation of ERK1/2, JNK, and Akt. Most importantly, 13m- and 24-induced enhancement of Nrf2 translocation and HO-1 expression was reversed by U0126 (an ERK inhibitor), SP600125 (a JNK inhibitor), and LY294002 (an Akt inhibitor). Collectively, our results show that compounds 13m and 24 exert neuroprotective and antioxidant effects through the Nrf2/HO-1 pathway mediated by phosphorylation of ERK1/2, JNK, or Akt in PC12 cells. Based on our findings, both derivatives could serve as potential therapeutic candidates for the neuroprotective treatment of PD.
帕金森病（PD）是一种神经退行性疾病，会导致无法控制的运动。尽管 PD 治疗方面取得了许多突破，但目前尚无治愈 PD 的方法，仅对缓解症状进行了评估。最近，我们报道了 cudraisoflavone J 及其手性异构体的全合成[Lu 等人，J. Nat. Prod. 2021, 84, 1359]。在这项研究中，我们设计并合成了一系列新型 cudraisoflavone J 衍生物，并在神经毒素处理的 PC12 细胞中评估了它们的神经保护活性。在这些化合物中，二氟取代衍生物（13m）和香叶基化衍生物（24）对 6-羟多巴胺（6-OHDA）或鱼藤酮诱导的 PC12 细胞毒性具有显著的保护作用。这两种衍生物均抑制 6-OHDA 或鱼藤酮诱导的活性氧产生，并部分减轻大鼠脑匀浆中的脂质过氧化，表明它们具有抗氧化特性。它们还增加了抗氧化酶血红素加氧酶（HO）-1 的表达，并增强了核转录因子 Nrf2 的核转位，Nrf2 是调节抗氧化蛋白表达的转录因子。HO-1 抑制剂 Zn(II)-原卟啉 IX 消除了 13m 和 24 的神经保护作用，表明 HO-1 在其作用中起关键作用。此外，核因子红细胞 2 相关因子（Nrf2）敲低消除了 HO-1 的上调，证实了 Nrf2 是 HO-1 的上游调节剂。化合物 13m 和 24 触发 ERK1/2、JNK 和 Akt 的磷酸化。最重要的是，U0126（ERK 抑制剂）、SP600125（JNK 抑制剂）和 LY294002（Akt 抑制剂）逆转了 13m 和 24 诱导的 Nrf2 易位和 HO-1 表达的增强。总的来说，我们的结果表明，化合物 13m 和 24 通过 ERK1/2、JNK 或 Akt 的磷酸化在 PC12 细胞中介导 Nrf2/HO-1 通路发挥神经保护和抗氧化作用。基于我们的发现，这两种衍生物都可以作为 PD 神经保护治疗的潜在治疗候选物。
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