Xiao-ling ZHANG,Yu-he YUAN,Nai-hong CHEN,2

(1.State Key Laboratory of Bioactive Substances and Functions of Natural Medicines,Institute of Materia Medica&Neuroscience Center,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China;2.College of Pharmacy,Hunan University of Chinese Medicine,Changsha 410208,China)

T2-33

20C，a new bibenzyl compound,plays a significant role in rotenone-induced oxidative insult

Xiao-ling ZHANG1,Yu-he YUAN1,Nai-hong CHEN1,2

(1.State Key Laboratory of Bioactive Substances and Functions of Natural Medicines,Institute of Materia Medica&Neuroscience Center,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China;2.College of Pharmacy,Hunan University of Chinese Medicine,Changsha 410208,China)

20C,a bibenzyl compound isolated from Gastrodia elata,possesses antioxidative properties in PC12 cells,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.Therefore,increasing the nuclear translocation of Nrf2 by DJ-1 may present a helpful means for the prevention and treatment of chronic diseases related to oxidative stress.Our results showed that 20C clearly protected PC12 and SH-SY5Y cells against rotenone-induced oxidative injury in a concentration-dependent manner.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 promoting Nrf2 nuclear translocation and inducing the expression of Nrf2-mediated downstream antioxidative enzymes such as HO-1.The antioxidative 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 in PC12 and SH-SY5Y cells,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 preventing or alleviating the consequences of PD in the future.

20C;Parkinson disease;DJ-1;Akt;oxidative stress;nuclear factor erythroid 2-related factor(Nrf2)

The project supported by National Natural Science Foundation of China(U1402221,81573640,81603316);Beijing Natural Science Foundation(7161011);CAMS Innovation Fund for Medical Sciences(CIFMS)(2016-I2M-1-004);Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study(BZ0150);Key Research and Development Project of Hunan Province(2015SK2029-1);and Scientific Research Foundation of the Higher Education Institutions of Hunan Province(15K091)

Nai-hong CHEN,Tel:(010)63165177,Fax:(010)63165177,E-mail:chennh@imm.ac.cn