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Isolation and Characterization of Activators of ERK/MAPK from Citrus Plants

Author(s): Yoshiko Furukawa | Satoshi Okuyama | Yoshiaki Amakura | Sono Watanabe | Takahiro Fukata | Mitsunari Nakajima | Morio Yoshimura | Takashi Yoshida

Journal: International Journal of Molecular Sciences
ISSN 1422-0067

Volume: 13;
Issue: 2;
Start page: 1832;
Date: 2012;
Original page

Keywords: methoxyflavone | 3 | 5 | 6 | 7 | 8 | 3′ | 4′-heptamethoxyflavone | ERK1/2 | Citrus grandis | Kawachi bankan | neurons | MK-801

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.
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