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Novel cudraisoflavone J derivatives as potent neuroprotective agents for the treatment of Parkinson?s disease via the activation of Nrf2/ HO-1 signaling

Authors
Lu, QiliGouda, Noha A.Quan, GuofengNada, HossamElkamhawy, AhmedLee, DonghoLee, Chang HoonCho, JungsookLee, Kyeong
Issue Date
15-11월-2022
Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
Keywords
Cudraisoflavone J; Parkinson ?s disease; Nuclear factor erythroid 2-related factor 2; (Nrf2); Heme oxygenase-1; Neuroprotection; PC12 cells
Citation
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v.242
Indexed
SCIE
SCOPUS
Journal Title
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume
242
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/145631
DOI
10.1016/j.ejmech.2022.114692
ISSN
0223-5234
Abstract
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.
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