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Int. J. Mol. Sci. 2012, 13(2), 1832-1845; doi:10.3390/ijms13021832
Article

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

1,* , 1
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1 Department of Pharmaceutical Pharmacology, College of Pharmaceutical Sciences, Matsuyama University, 4-2 Bunkyo-cho, Matsuyama, Ehime 790-8578, Japan 2 Department of Pharmacognosy, College of Pharmaceutical Sciences, Matsuyama University, 4-2 Bunkyo-cho, Matsuyama, Ehime 790-8578, Japan
* Author to whom correspondence should be addressed.
Received: 5 January 2012 / Revised: 24 January 2012 / Accepted: 31 January 2012 / Published: 9 February 2012
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Abstract

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.
Keywords: methoxyflavone; 3,5,6,7,8,3′,4′-heptamethoxyflavone; ERK1/2; Citrus grandis; Kawachi bankan; neurons; MK-801 methoxyflavone; 3,5,6,7,8,3′,4′-heptamethoxyflavone; ERK1/2; Citrus grandis; Kawachi bankan; neurons; MK-801
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).
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Furukawa, Y.; Okuyama, S.; Amakura, Y.; Watanabe, S.; Fukata, T.; Nakajima, M.; Yoshimura, M.; Yoshida, T. Isolation and Characterization of Activators of ERK/MAPK from Citrus Plants. Int. J. Mol. Sci. 2012, 13, 1832-1845.

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