Induction of neurite outgrowth in PC12 cells by artemisinin through activation of ERK and p38 MAPK signaling pathways

[No Value] Sarina, Yasuyuki Yagi, Oki Nakano, Toshihiro Hashimoto, Ko Kimura, Yoshinori Asakawa, Ming Zhong, Shizuo Narimatsu, Eiichi Gohda

Research output: Contribution to journalArticle

33 Citations (Scopus)

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 βIII-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.

Original languageEnglish
Pages (from-to)61-71
Number of pages11
JournalBrain Research
Volume1490
DOIs
Publication statusPublished - Jan 15 2013

Fingerprint

PC12 Cells
Extracellular Signal-Regulated MAP Kinases
p38 Mitogen-Activated Protein Kinases
Neurites
Cyclic AMP Response Element-Binding Protein
dihydroartemisinin
Phosphorylation
Artemisinins
Wounds and Injuries
Artemisia annua
artemisinine
Neuronal Outgrowth
Tubulin
Protein Kinase Inhibitors
Growth
Mitogen-Activated Protein Kinases
Neurodegenerative Diseases
Malaria
Regeneration
Phosphotransferases

Keywords

  • Artemisinin
  • Cyclic AMP response element-binding protein
  • Extracellular signal-regulated kinase
  • Neurite outgrowth
  • p38 Mitogen-activated protein kinase

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology
  • Developmental Biology
  • Molecular Biology

Cite this

Induction of neurite outgrowth in PC12 cells by artemisinin through activation of ERK and p38 MAPK signaling pathways. / Sarina, [No Value]; Yagi, Yasuyuki; Nakano, Oki; Hashimoto, Toshihiro; Kimura, Ko; Asakawa, Yoshinori; Zhong, Ming; Narimatsu, Shizuo; Gohda, Eiichi.

In: Brain Research, Vol. 1490, 15.01.2013, p. 61-71.

Research output: Contribution to journalArticle

Sarina, NV, Yagi, Y, Nakano, O, Hashimoto, T, Kimura, K, Asakawa, Y, Zhong, M, Narimatsu, S & Gohda, E 2013, 'Induction of neurite outgrowth in PC12 cells by artemisinin through activation of ERK and p38 MAPK signaling pathways', Brain Research, vol. 1490, pp. 61-71. https://doi.org/10.1016/j.brainres.2012.10.059
Sarina, [No Value] ; Yagi, Yasuyuki ; Nakano, Oki ; Hashimoto, Toshihiro ; Kimura, Ko ; Asakawa, Yoshinori ; Zhong, Ming ; Narimatsu, Shizuo ; Gohda, Eiichi. / Induction of neurite outgrowth in PC12 cells by artemisinin through activation of ERK and p38 MAPK signaling pathways. In: Brain Research. 2013 ; Vol. 1490. pp. 61-71.
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