title: Isolation and characterization of activators of ERK/MAPK from citrus plants.
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.
authors.affiliation: Department of Pharmaceutical Pharmacology, College of Pharmaceutical Sciences, Matsuyama University, 4-2 Bunkyo-cho, Matsuyama, Ehime 790-8578, Japan.
authors.forename: Yoshiko
authors.identifier: 0000-0003-1233-3526
authors.initials: Y
authors.lastname: Furukawa
authors.affiliation: Department of Pharmaceutical Pharmacology, College of Pharmaceutical Sciences, Matsuyama University, 4-2 Bunkyo-cho, Matsuyama, Ehime 790-8578, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okuyama
authors.affiliation: Department of Pharmacognosy, College of Pharmaceutical Sciences, Matsuyama University, 4-2 Bunkyo-cho, Matsuyama, Ehime 790-8578, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Amakura
authors.affiliation: Department of Pharmaceutical Pharmacology, College of Pharmaceutical Sciences, Matsuyama University, 4-2 Bunkyo-cho, Matsuyama, Ehime 790-8578, Japan.
authors.forename: Sono
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Department of Pharmaceutical Pharmacology, College of Pharmaceutical Sciences, Matsuyama University, 4-2 Bunkyo-cho, Matsuyama, Ehime 790-8578, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Fukata
authors.affiliation: Department of Pharmaceutical Pharmacology, College of Pharmaceutical Sciences, Matsuyama University, 4-2 Bunkyo-cho, Matsuyama, Ehime 790-8578, Japan.
authors.forename: Mitsunari
authors.initials: M
authors.lastname: Nakajima
authors.affiliation: Department of Pharmacognosy, College of Pharmaceutical Sciences, Matsuyama University, 4-2 Bunkyo-cho, Matsuyama, Ehime 790-8578, Japan.
authors.forename: Morio
authors.initials: M
authors.lastname: Yoshimura
authors.affiliation: Department of Pharmacognosy, College of Pharmaceutical Sciences, Matsuyama University, 4-2 Bunkyo-cho, Matsuyama, Ehime 790-8578, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002957:Citrus / Q000737:chemistry*; D004622:Embryo, Mammalian; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005638:Fruit / Q000737:chemistry; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010936:Plant Extracts / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D010936:Plant Extracts; D048049:Extracellular Signal-Regulated MAP Kinases