title: DA-9801 promotes neurite outgrowth via ERK1/2-CREB pathway in PC12 cells.
abstract: In the present study, we examined the mechanisms underlying the effect of DA-9801 on neurite outgrowth. We found that DA-9801 elicits its effects via the mitogen-activated protein kinase (MEK) extracellular signal-regulated kinase (ERK)1/2-cAMP response element-binding protein (CREB) pathway. DA-9801, an extract from a mixture of Dioscorea japonica and Dioscorea nipponica, was reported to promote neurite outgrowth in PC12 cells. The effects of DA-9801 on cell viability and expression of neuronal markers were evaluated in PC12 cells. To investigate DA-9801 action, specific inhibitors targeting the ERK signaling cascade were used. No cytotoxicity was observed in PC12 cells at DA-9801 concentrations of less than 30 µg/mL. In the presence of nerve growth factor (NGF, 2 ng/mL), DA-9801 promoted neurite outgrowth and increased the relative mRNA levels of neurofilament-L (NF-L), a marker of neuronal differentiation. The Raf-1 inhibitor GW5074 and MEK inhibitor PD98059 significantly attenuated DA-9801-induced neurite outgrowth. Additionally, the MEK1 and MEK2 inhibitor SL327 significantly attenuated the increase in the percentage of neurite-bearing PC12 cells induced by DA-9801 treatment. Conversely, the selective p38 mitogen-activated protein kinase inhibitor SB203580 did not attenuate the DA-9801 treatment-induced increase in the percentage of neurite-bearing PC12 cells. DA-9801 enhanced the phosphorylation of ERK1/2 and CREB in PC12 cells incubated with and without NGF. Pretreatment with PD98059 blocked the DA-9801-induced phosphorylation of ERK1/2 and CREB. In conclusion, DA-9801 induces neurite outgrowth by affecting the ERK1/2-CREB signaling pathway. Insights into the mechanism underlying this effect of DA-9801 may suggest novel potential strategies for the treatment of peripheral neuropathy.
authors.affiliation: Department of Environmental & Health Chemistry, College of Pharmacy, Chung-Ang University.
authors.forename: Jong Hoon
authors.initials: JH
authors.lastname: Won
authors.forename: Kyong Hoon
authors.initials: KH
authors.lastname: Ahn
authors.forename: Moon Jung
authors.initials: MJ
authors.lastname: Back
authors.forename: Hae Chan
authors.initials: HC
authors.lastname: Ha
authors.forename: Ji Min
authors.initials: JM
authors.lastname: Jang
authors.forename: Ha Hyung
authors.initials: HH
authors.lastname: Kim
authors.forename: Sang-Zin
authors.initials: SZ
authors.lastname: Choi
authors.forename: Miwon
authors.initials: M
authors.lastname: Son
authors.forename: Dae Kyong
authors.initials: DK
authors.lastname: Kim
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D016501:Neurites / Q000187:drug effects*; D016900:Neurofilament Proteins / Q000378:metabolism; D016716:PC12 Cells; D028321:Plant Preparations / Q000494:pharmacology*; D019908:Proto-Oncogene Proteins c-raf; D051381:Rats
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; C562027:DA-9801; D016900:Neurofilament Proteins; D028321:Plant Preparations; C044882:neurofilament protein L; D019908:Proto-Oncogene Proteins c-raf; C546782:Raf1 protein, rat; D020930:MAP Kinase Kinase Kinases