Nobiletin, a Citrus Flavonoid, Reverses Learning Impairment Associated with N-Methyl-D-aspartate Receptor Antagonism by Activation of Extracellular Signal-Regulated Kinase Signaling

Laboratory of Plant Science, Tokyo University of Pharmacy and Life Science, Edo, Tōkyō, Japan
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.97). 06/2007; 321(2):784-90. DOI: 10.1124/jpet.106.117010
Source: PubMed


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.

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    • "Accordingly, to clarify the effects of nobiletin on cognitive impairment associated with NMDA receptor hypofunction, Nakajima et al.34) examined the effects of nobiletin on learning and memory impairment induced by treatment with MK-801, a noncompetitive NMDA receptor antagonist in mice. In that study, nobiletin (10-50 mg/kg i.p.) was injected once daily for seven consecutive days before training for the contextual fear conditioning or passive avoidance test. "
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