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: Jong Hoon Won, Kyong Hoon Ahn, Moon Jung Back, Hae Chan Ha, Ji Min Jang, Ha Hyung Kim, Sang-Zin Choi, Miwon Son, Dae Kyong Kim
• Journal: Biological & pharmaceutical bulletin (Biol Pharm Bull) Vol. 38 Issue 2 Pg. 169-78 ( 2015) ISSN: 1347-5215 [Electronic] Japan
• PMID: 25482167 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclic AMP Response Element-Binding Protein
• DA-9801
• Neurofilament Proteins
• Plant Preparations
• neurofilament protein L
• Proto-Oncogene Proteins c-raf
• Raf1 protein, rat
• MAP Kinase Kinase Kinases

Topics

• Animals
• Cell Survival (drug effects)
• Cyclic AMP Response Element-Binding Protein (metabolism)
• MAP Kinase Kinase Kinases (metabolism)
• MAP Kinase Signaling System (drug effects)
• Neurites (drug effects)
• Neurofilament Proteins (metabolism)
• PC12 Cells
• Plant Preparations (pharmacology)
• Proto-Oncogene Proteins c-raf
• Rats