DA-9801 Promotes Neurite Outgrowth via ERK1/2-CREB Pathway in PC12 Cells
- Authors
- Won, Jong Hoon; Ahn, Kyong Hoon; Back, Moon Jung; Ha, Hae Chan; Jang, Ji Min; Kim, Ha Hyung; Choi, Sang-Zin; Son, Miwon; Kim, Dae Kyong
- Issue Date
- Feb-2015
- Publisher
- PHARMACEUTICAL SOC JAPAN
- Keywords
- DA-9801; diabetic peripheral neuropathy; neurite outgrowth; extracellular signal-regulated kinase 1/2; cAMP response element-binding protein (CREB)
- Citation
- BIOLOGICAL & PHARMACEUTICAL BULLETIN, v.38, no.2, pp 169 - 178
- Pages
- 10
- Journal Title
- BIOLOGICAL & PHARMACEUTICAL BULLETIN
- Volume
- 38
- Number
- 2
- Start Page
- 169
- End Page
- 178
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/9912
- DOI
- 10.1248/bpb.b14-00236
- ISSN
- 0918-6158
1347-5215
- 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 mu g/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.
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