DJ-1 regulating PI3K-Nrf2 signaling plays a significant role in bibenzyl compound 20C-mediated neuroprotection against rotenone-induced oxidative insult

• Published in: Toxicology letters Vol. 271; pp. 74 - 83
• Main Authors: Zhang, Xiao-Ling, Yuan, Yu-He, Shao, Qian-Hang, Wang, Zhen-Zhen, Zhu, Cheng-Gen, Shi, Jian-Gong, Ma, Kai-Li, Yan, Xu, Chen, Nai-Hong
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 05.04.2017
• Subjects: 20C; Akt; Animals; Antioxidants - pharmacology; Benzhydryl Compounds - pharmacology; Bibenzyls - pharmacology; DJ-1; Glycogen Synthase Kinase 3 beta - metabolism; Heme Oxygenase (Decyclizing) - metabolism; Heme Oxygenase-1 - metabolism; Humans; Neurons - drug effects; Neurons - enzymology; Neurons - pathology; Neuroprotective Agents - pharmacology; NF-E2-Related Factor 2 - metabolism; Nuclear factor erythroid 2-related factor (Nrf2); Oxidants - toxicity; Oxidative stress; Oxidative Stress - drug effects; Parkinson’s disease (PD); PC12 Cells; Phenols - pharmacology; Phosphatidylinositol 3-Kinase - antagonists & inhibitors; Phosphatidylinositol 3-Kinase - metabolism; Protein Deglycase DJ-1 - genetics; Protein Deglycase DJ-1 - metabolism; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - metabolism; Rats; RNA Interference; Rotenone - toxicity; Signal Transduction - drug effects; Transfection; NQO1; Oxidative stress; 20C; Nuclear factor erythroid 2-related factor (Nrf2); SNpc; HO-1; DJ-1; MDA; Akt; GSK3β; LDH; TCMs; ARE; PI3K; PD; Nrf2; ROS; Parkinson’s disease (PD); 8-OHdG
• ISSN: 0378-4274; 1879-3169
• DOI: 10.1016/j.toxlet.2017.02.022

[Display omitted] •20C protects PC12 and SH-SY5Y cells against rotenone-induced oxidative injury.•DJ-1 is necessary for 20C-mediated neuroprotection.•20C activates PI3K/Akt signaling and then promotes Nrf2 nuclear translocation.•20C may be developed as a novel candidate for alleviating the consequences of PD. Oxidative stress is thought to be involved in the development of Parkinson’s disease (PD). We previously reported that 20C, a bibenzyl compound isolated from Gastrodia elata, possesses antioxidative properties, but its in-depth molecular mechanisms against rotenone-induced neurotoxicity remains unknown. Recent studies indicate that without intact DJ-1, nuclear factor erythroid 2-related factor (Nrf2) protein becomes unstable, and the activity of Nrf2-mediated downstream antioxidant enzymes are thereby suppressed. In this study, we showed that 20C clearly protected PC12 and SH-SY5Y cells against rotenone-induced oxidative injury. Furthermore, 20C markedly up-regulated the levels of DJ-1, which in turn activated phosphoinositide-3-kinase (PI3K)/Akt signaling and inhibited glycogen synthase kinase 3β (GSK3β) activation, eventually promoted the nuclear translocation of Nrf2 and induced the expression of hemeoxygenase-1 (HO-1). The antioxidant effects of 20C could be partially blocked by ShRNA-mediated knockdown of DJ-1 and inhibition of the PI3K/Akt pathways with Akt1/2 kinase inhibitor, respectively. Conclusively, our findings confirm that DJ-1 is necessary for 20C-mediated protection against rotenone-induced oxidative damage, at least in part, by activating PI3K/Akt signaling, and subsequently enhancing the nuclear accumulation of Nrf2. The findings from our investigation suggest that 20C should be developed as a novel candidate for alleviating the consequences of PD in the future.