title: Nobiletin, a citrus flavonoid, reverses learning impairment associated with N-methyl-D-aspartate receptor antagonism by activation of extracellular signal-regulated kinase signaling.
abstract: Recent studies have indicated that learning-induced activation of extracellular signal-regulated kinase (ERK) signaling via N-methyl-D-aspartate (NMDA) receptors is required for consolidation of the resultant learning. These findings raise an idea that control of ERK signaling may be a potential target for treatment of cognitive dysfunction. Our recent studies have demonstrated that nobiletin, a polymethoxylated flavone from Citrus depressa, enhances cAMP/protein kinase A/ERK signaling in cultured rat hippocampal neurons and PC12D cells. Here, we, for the first time, present the evidence that this natural compound reverses learning impairment associated with NMDA receptor antagonism by activation of ERK in the hippocampus. Treatment with 50 mg/kg nobiletin reversed the NMDA receptor antagonist MK-801 (dizocilpine maleate)-induced learning impairment in mice. Western blot analysis also showed that nobiletin reversed MK-801-induced inhibition of learning-associated ERK activation in the hippocampus of the animals. Furthermore, consistent with these results, in cultured rat hippocampal neurons, nobiletin restored MK-801-induced impairment of NMDA-stimulated phosphorylation of ERK in a concentration-dependent manner. Taken together, the present study suggests that compounds that activate ERK signaling improve cognitive deficits associated with NMDA receptor hypofunction and that nobiletin may give us a new insight into therapeutic drug development for neurological disorders exhibiting cognitive impairment accompanied by a hypofunction of NMDA receptor-ERK signaling.
authors.affiliation: Department of Pharmaceutical Molecular Biology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-6-11-404 Aoba, Aramaki, Aoba-ku, Sendai 980-8579, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Nakajima
authors.forename: Tohru
authors.initials: T
authors.lastname: Yamakuni
authors.forename: Kentaro
authors.initials: K
authors.lastname: Matsuzaki
authors.forename: Norihito
authors.initials: N
authors.lastname: Nakata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Onozuka
authors.forename: Akihito
authors.initials: A
authors.lastname: Yokosuka
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Sashida
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Mimaki
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ohizumi
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D047309:Flavones / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects; D007859:Learning Disabilities / Q000139:chemically induced / Q000188:drug therapy*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D010766:Phosphorylation; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
chemical_list: D047309:Flavones; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; C008661:nobiletin; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases