Abstract
The activation of extracellular signal-regulated kinases (ERK) leads to a number of cellular changes associated with the development of long-term memory. Using cultured cortical neurons, we previously showed that the n-hexane extract prepared from the peels of Citrus grandis (Kawachi bankan) induces the activation of ERK1/2 and that one of the compounds with this ability in the extract is 3,5,6,7,8,3′,4′-heptamethoxyflavone (HMF), a Citrus polymethoxyflavone. In fact, we found that HMF has the ability to rescue mice from drug-induced learning impairment. This hexane extract contains auraptene (AUR), a coumarin derivative with a monoterpene unit, together with HMF. The present study was designed to investigate the effect of AUR in vitro. Our results show that 1) AUR had the ability to induce the activation of ERK1/2 in not only cortical neurons but also the rat pheochromocytoma cell line (PC12 cells), which is a model system for studies on neuronal proliferation and differentiation; and 2) AUR had the ability to promote neurite outgrowth from PC12 cells.
Highlights
Extracellular signal-regulated kinases 1/2 (ERK1/2) are components of the mitogen-activated protein kinase (MAPK) signaling cascade
We previously showed that an n-hexane extract (225 mg) of Citrus grandis yields AUR (39 mg), HMF (8.5 mg), TGN (2.7 mg), and NBT (1.1 mg) and that HMF, TGN, and NBT have the ability to cause the phosphorylation of ERK1/2 in cultured cortical neurons [3]
These results show that AUR as well as HMF and Brain-derived neurotrophic factor (BDNF) had the ability to phosphorylate ERK1/2
Summary
Extracellular signal-regulated kinases 1/2 (ERK1/2) are components of the mitogen-activated protein kinase (MAPK) signaling cascade. We sought to determine whether AUR, like HMF, would have the ability to activate ERK1/2 in neuronal cells. We successfully showed that AUR could activate (namely phosphorylate) ERK1/2 in cultured cortical neurons and rat PC12 pheochromocytoma cells. We found that AUR effectively activated ERK1/2 in PC12 cells. These cells are a useful model system for the study of neuronal differentiation. NGF induces rapid tyrosine phophorylation of TrkA and consequent phosphorylation/activation of signal transduction substrates including ERK1/2 [15,16]. The activation of ERK1/2 by NGF can cause the neurite outgrowth from PC12 cells. It is noteworthy that this is the first report on the neurotrophic action of AUR
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