title: P90RSK and Nrf2 Activation via MEK1/2-ERK1/2 Pathways Mediated by Notoginsenoside R2 to Prevent 6-Hydroxydopamine-Induced Apoptotic Death in SH-SY5Y Cells.
abstract: 6-Hydroxydopamine (6-OHDA) is known to contribute to neuronal death in Parkinson's disease. In this study, we found that the preincubation of SH-SY5Y cells for 24 h with 20  μ M notoginsenoside R2 (NGR2), which is a newly isolated notoginsenoside from Panax notoginseng, showed neuroprotective effects against 6-OHDA-induced oxidative stress and apoptosis. NGR2 incubation successively resulted in the activation of P90RSK, inactivation of BAD, and inhibition of 6-OHDA-induced mitochondrial membrane depolarization, thus preventing the mitochondrial apoptosis pathway. NGR2 incubation also led to the activation of Nrf2 and subsequent activity enhancement of phase II detoxifying enzymes, thus suppressing 6-OHDA-induced oxidative stress, and these effects could be removed by Nrf2 siRNA. We also found that the upstream activators of P90RSK and Nrf2 were the MEK1/2-ERK1/2 pathways but not the JNK, P38, or PI3K/Akt pathways. Interestingly, NGR2 incubation could also activate MEK1/2 and ERK1/2. Most importantly, NGR2-mediated P90RSK and Nrf2 activation, respective downstream target activation, and neuroprotection were reversed by the genetic silencing of MEK1/2 and ERK1/2 by using siRNA and PD98059 application. These results suggested that the neuroprotection elicited by NGR2 against 6-OHDA-induced neurotoxicity was associated with NGR2-mediated P90RSK and Nrf2 activation through MEK1/2-ERK1/2 pathways.
authors.affiliation: Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 151, Malianwa North Road, Haidian District, Beijing 100193, China.
authors.forename: Xiang-Bao
authors.initials: XB
authors.lastname: Meng
authors.forename: Gui-Bo
authors.initials: GB
authors.lastname: Sun
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.forename: Meng
authors.initials: M
authors.lastname: Qin
authors.forename: Xiao-Bo
authors.initials: XB
authors.lastname: Sun