title: Docosahexaenoic acid induces ERK1/2 activation and neuritogenesis via intracellular reactive oxygen species production in human neuroblastoma SH-SY5Y cells.
abstract: Docosahexaenoic acid (22: 6n-3; DHA) is a long chain polyunsaturated fatty acid that exists highly enriched in fish oil, and it is one of the low molecular weight food chemicals which can pass a blood brain barrier. A preliminary survey of several fatty acids for expression of growth-associated protein-43 (GAP-43), a marker of axonal growth, identified DHA as one of the most potent inducers. The human neuroblastoma SH-SY5Y cells exposed to DHA showed significant and dose-dependent increases in the percentage of cells with longer neurites. To elucidate signaling mechanisms involved in DHA-enhanced basal neuritogenesis, we examined the role of extracellular signal-regulated kinase (ERK)1/2 and intracellular reactive oxygen species (ROS) production using SH-SY5Y cells. From immunoblotting experiments, we observed that DHA induced the ROS production, protein tyrosine phosphatase inhibition, mitogen-activated protein kinase (MAPK)/ERK kinase (MEK) phosphorylation, and sequentially ERK1/2 phosphorylation, the last of which was significantly reduced by MEK inhibitor U0126. Both antioxidants and MEK inhibitor affected DHA-induced GAP-43 expression, whereas the specific PI3K inhibitor LY294002 did not. We found that total protein tyrosine phosphatase activity was also downregulated by DHA treatment, which was counteracted by antioxidant pretreatment. These results suggest that the ROS-dependent ERK pathway, rather than PI3K, plays an important role during DHA-enhanced neurite outgrowth.
authors.affiliation: Department of Biofunctional Chemistry, Division of Bioscience, Graduate School of Natural Science and Technology, Okayama University, Okayama 700-8530, Japan.
authors.forename: Haitao
authors.initials: H
authors.lastname: Wu
authors.forename: Sanae
authors.initials: S
authors.lastname: Ichikawa
authors.forename: Chiharu
authors.initials: C
authors.lastname: Tani
authors.forename: Beiwei
authors.initials: B
authors.lastname: Zhu
authors.forename: Mikiro
authors.initials: M
authors.lastname: Tada
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Shimoishi
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Murata
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Nakamura
mesh_terms: D045744:Cell Line, Tumor; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004789:Enzyme Activation; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016501:Neurites / Q000187:drug effects / Q000502:physiology*; D009447:Neuroblastoma / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D004281:Docosahexaenoic Acids; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3