Isolation and characterization of activators of ERK/MAPK from citrus plants

• Published in: International journal of molecular sciences Vol. 13; no. 2; pp. 1832 - 1845
• Main Authors: Furukawa, Yoshiko, Okuyama, Satoshi, Amakura, Yoshiaki, Watanabe, Sono, Fukata, Takahiro, Nakajima, Mitsunari, Yoshimura, Morio, Yoshida, Takashi
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.02.2012; Molecular Diversity Preservation International (MDPI)
• Subjects: 3,5,6,7,8,3′,4′-heptamethoxyflavone; Animals; Bioassays; Cells, Cultured; Citrus - chemistry; Citrus fruits; Citrus grandis; Embryo, Mammalian; Enzyme Activation - drug effects; ERK1/2; Ethanol; Extracellular Signal-Regulated MAP Kinases - metabolism; Flavonoids; Fruit - chemistry; Kawachi bankan; Kinases; Male; MAP Kinase Signaling System - drug effects; methoxyflavone; Mice; Mice, Inbred C57BL; MK-801; Nervous system; neurons; Neurons - drug effects; Neurons - metabolism; Pharmaceutical sciences; Phosphorylation; Phytochemicals; Plant Extracts - chemistry; Plant Extracts - pharmacology; Proteins; Rats; Rats, Wistar; Signal transduction; Japan; Citrus grandis; methoxyflavone; MK-801; 3,5,6,7,8,3′,4′-heptamethoxyflavone; ERK1/2; Kawachi bankan; neurons
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms13021832

Extracellular signal-regulated kinases 1/2 (ERK1/2), components of the mitogen-activated protein kinase (MAPK) signaling cascade, have been recently shown to be involved in synaptic plasticity and in the development of long-term memory in the central nervous system (CNS). We therefore examined the ability of Citrus compounds to activate ERK1/2 in cultured rat cortical neurons, whose activation might have a protective effect against neurodegenerative neurological disorders. Among the samples tested, extracts prepared from the peels of Citrus grandis (Kawachi bankan) were found to have the greatest ability to activate ERK1/2. The active substances were isolated by chromatographic separation, and one of them was identified to be 3,5,6,7,8,3',4'-heptamethoxyflavone (HMF). HMF significantly induced the phosphorylation of cAMP response element-binding protein (CREB), a downstream target of activated ERK1/2, which appears to be a critical step in the signaling cascade for the structural changes underlying the development of long-term potentiation (LTP). In addition, the administration of HMF into mice treated with NMDA receptor antagonist MK-801 restored the MK-801-induced deterioration of spatial learning performance in the Morris mater-maze task. Taken together, these results suggest that HMF is a neurotrophic agent for treating patients with memory disorders.