title: Curcuminoids promote neurite outgrowth in PC12 cells through MAPK/ERK- and PKC-dependent pathways.
abstract: Curcuminoids, the predominant polyphenolic compounds in the rhizome of Curcuma longa Linn., consist of curcumin, demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC). They exhibit multiple desirable characteristics for a neuroprotective agent including antioxidant, anti-inflammatory, and antiamyloid activities. In this work, we report the first investigation of the neurotrophic action and mechanism of curcuminoids in PC12 cells, which respond to nerve growth factor (NGF) and therefore serve as a model system for primary neuronal cells. The percentages of neurite-bearing cells for those treated with 20 μM curcumin, DMC, and BDMC for 72 h reached 21.6 ± 2.0%, 16.3 ± 2.4%, and 19.9 ± 2.5%, respectively, and were significantly higher than that of the negative control (2.0 ± 0.3%, p < 0.05). In parallel, increased expression of the neuronal differentiation markers, growth-associated protein-43 (GAP-43), and neurofilament-L (NF-L) was found in curcuminoid-treated cells. All three curcuminoids (20 μM) activated extracellular signal-regulated protein kinase 1/2 (ERK1/2) and protein kinase C (PKC) signalings, and inhibition of these kinases with the respective pharmacological inhibitors effectively attenuated curcuminoid-induced neurite outgrowth. Furthermore, our results show that both curcumin and DMC, but not BDMC, induced phosphorylation of cAMP response element-binding protein (CREB) and CRE-reporter gene activity significantly (p < 0.05). These inductions were markedly attenuated by the addition of MEK/ERK or PKC inhibitor; as a consequence, ERK- and PKC-dependent pathways may be involved in curcuminoid-mediated neuritogenesis in PC12 cells. Moreover, activation of CREB coupling with CRE-dependent gene transcription may play a vital role for curcumin- or DMC-induced PC12 differentiation.
authors.affiliation: Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien 970, Taiwan.
authors.forename: Kuo-Kai
authors.initials: KK
authors.lastname: Liao
authors.forename: Ming-Jiuan
authors.initials: MJ
authors.lastname: Wu
authors.forename: Pei-Yi
authors.initials: PY
authors.lastname: Chen
authors.forename: Szu-Wei
authors.initials: SW
authors.lastname: Huang
authors.forename: Shu-Jun
authors.initials: SJ
authors.lastname: Chiu
authors.forename: Chi-Tang
authors.initials: CT
authors.lastname: Ho
authors.forename: Jui-Hung
authors.initials: JH
authors.lastname: Yen
mesh_terms: D000818:Animals; D030024:Curcuma / Q000737:chemistry*; D003474:Curcumin / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D016501:Neurites / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D016716:PC12 Cells; D010936:Plant Extracts / Q000494:pharmacology*; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D051381:Rats
chemical_list: D010936:Plant Extracts; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D003474:Curcumin