title: Induction of neurite outgrowth in PC12 cells by artemisinin through activation of ERK and p38 MAPK signaling pathways.
abstract: Growth of neurite processes is a critical step in neuronal development, regeneration, differentiation, and response to injury. The discovery of compounds that can stimulate neurite formation would be important for developing new therapeutics against both neurodegenerative disorders and trauma-induced neuronal injuries. Semisynthetic derivatives of artemisinin, an active compound in Artemisia annua, have been effectively used in malaria treatment, but they have been shown to possess neurotoxic potential. In this study, we found unexpectedly that artemisinin and its derivatives induced neurite outgrowth of PC12 cells. Artemisinins containing an endoperoxide bridge such as artemisinin and dihydroartemisinin induced growth of neurite processes at concentrations that were slightly cytotoxic, artemisinin having the most potent maximal effect among them. Deoxyartemisinin, which lacks the endoperoxide bridge, was ineffective. Artemisinin-treated cells expressed increased levels of the neuronal marker β(III)-tubulin. Artemisinin upregulated phosphorylation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK), critical signaling molecules in neuronal differentiation. Consistent with activation of the two MAPKs, neurite outgrowth induced by artemisinin was inhibited by the MAPK/ERK kinase inhibitor PD98059 and the p38 MAPK inhibitor SB203580. Artemisinin also induced phosphorylation of cyclic AMP response element-binding protein (CREB) that was almost completely attenuated by PD98059 but not by SB203580. Taken together, our results indicate that artemisinin and its derivatives containing the endoperoxide bridge induced differentiation of PC12 cells toward a neuronal phenotype and suggest that both activation of ERK signaling pathway, which leads to CREB phosphorylation, and activation of p38 MAPK signaling pathway are involved in this process.
authors.affiliation: Department of Immunochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Tsushima-naka, Kita-ku, Okayama, Okayama 700-8530, Japan.
authors.lastname: Sarina
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Yagi
authors.forename: Oki
authors.initials: O
authors.lastname: Nakano
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Ko
authors.initials: K
authors.lastname: Kimura
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Asakawa
authors.forename: Ming
authors.initials: M
authors.lastname: Zhong
authors.forename: Shizuo
authors.initials: S
authors.lastname: Narimatsu
authors.forename: Eiichi
authors.initials: E
authors.lastname: Gohda
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology*; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D004396:Coloring Agents; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003627:Data Interpretation, Statistical; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D020932:Nerve Growth Factor / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects* / Q000502:physiology*; D016716:PC12 Cells; D010766:Phosphorylation; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D013778:Tetrazolium Salts; D013844:Thiazoles; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects*
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004396:Coloring Agents; D017362:Cyclic AMP Response Element-Binding Protein; D013778:Tetrazolium Salts; D013844:Thiazoles; D020932:Nerve Growth Factor; C031327:artemisinin; D000242:Cyclic AMP; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C022616:thiazolyl blue