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.

Can proline‐rich polypeptide complex mimic the effect of nerve growth factor?

“…The results obtained prompt us to postulate that nNOS activation and stimulation of the NO-dependent soluble GC by PRP and NP trigger the MAPK signaling cascade. Similar mechanisms of action have been observed in other naturally occurring substances, for example, neuropeptide Y [44], genipin [45,46], artemisinin [49], curcuminoids [47,48], and auraptene [50].…”

“…Taking these results into consideration, it is suggested that PRP and NP, similarly to NGF, increase the cGMP production via activation of nNOS and release of NO. This indicates that both PRP and NP can trigger the NO-cGMP signaling pathway, similarly to other naturally occurring substances, for example, neuropeptide Y [44], genipin [45,46], or curcuminoids [47,48].…”

DA-9801 Promotes Neurite Outgrowth <i>via</i> ERK1/2-CREB Pathway in PC12 Cells

“…13,43,44) To further determine whether DA-9801-mediated neurite outgrowth is mediated by the Raf-1/MEK signaling pathway, GW5074 (a Raf-1 kinase inhibitor) and PD98059 (an MEK inhibitor), compounds known to inhibit the ERK1/2 pathway, were used. Compared to the treatment with NGF plus DA-9801 alone, GW5074 and PD98059 significantly at- tenuated the percentage of neurite-bearing PC12 cells (Figs.…”

“…[11][12][13] Additionally, the effectiveness of NGF application as a therapeutic intervention to treat brain injury is limited by the numerous unwanted side effects observed in both animals and patients, reflecting the diversity of cell types that react to NGF, both centrally and peripherally. [14][15][16] To avoid the side effects, development of orally active small molecules that potentiate the expression and activity of NGF is warranted.…”

A natural diarylheptanoid promotes neuronal differentiation via activating ERK and PI3K-Akt dependent pathways

“…Curcuminoids, a group of natural diarylheptanoids found in the dietary spice turmeric of the ginger family (Zingiberaceae), exhibit multi-faceted activities in neurogenesis, neuronal differentiation and neuroprotection (Kim et al, 2008;Dong et al, 2012;Liao et al, 2012;Lu et al, 2014;Nam et al, 2014), and show therapeutic potential in preventing or treating a number of neurological diseases (Hamaguchi et al, 2010;Darvesh et al, 2012;Monroy et al, 2013;Ahmed and Gilani, 2014). Curcuminoids, including curcumin, demethoxycurcumin and bisdemethoxycurcumin, consist of two phenyl groups linked by a linear seven-carbon (heptanone) chain.…”