Nobiletin, a Citrus Flavonoid, Reverses Learning Impairment Associated withN-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 Nmethyl-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.

Hepatoprotective Effects of Flavonoids from Shekwasha (Citrus depressa) against D-Galactosamine-Induced Liver Injury in Rats

“…On the other hand, there are a number of reports concerning a variety of biological effects of tangeretin and nobiletin, especially nobiletin, in addition to the concentrations of polymethoxy flavones in various species of citrus (10,11). For instances, direct and indirect evidences have been provided for anti-cancer effects (12)(13)(14)(15)(16)(17)(18)(19)(20), anti-inflammatory effects (21)(22)(23)(24), inhibition of NO production (25,26), enhancement of differentiation and lipolysis of adipocytes (27), prevention of cartilage destruction (28), improvement of memory impairment (29) and neurodegradation (30). However, no liver injury-suppressive effect of tangeretin and nobiletin has been reported yet.…”

Anti-neuroinflammatory Activity of Nobiletin on Suppression of Microglial Activation

“…43) Nobiletin rescued impaired memory in olfactory-bulbectomized mice accompanied by cholinergic neurodegeneration and reversed olfactory bulbectomy-induced reduction of acetylcholinesterase and choline acetyltransferase. 22) Nobiletin improved learning and memory impairment in several brain disease models, such as a N-ethyl-D-aspartate receptor antagonism model, 44) an ischemia animal model with bilateral common carotid artery occlusion (BCCAO), 24) and an amyloid precursor protein (APP) transgenic mouse model which over expresses human APP 695 harboring the double Swedish and London mutation.…”

Nobiletin, a Citrus Flavonoid That Improves Memory Impairment, Rescues Bulbectomy-Induced Cholinergic Neurodegeneration in Mice

“…We have recently reported that nobiletin activates an extracellular signal-regulated kinase (ERK) / mitogen-activated protein kinase (MAPK)-dependent signaling pathway to trigger CREB phosphorylation and CRE-dependent transcription in cultured hippocampal neurons and PC12D cells (6,7). In addition, nobiletin reverses learning impairment associated with N-methyl-D-aspartate (NMDA)-receptor antagonism by activation of ERK signaling in the hippocampus of mice (14). A number of studies have shown that the CREB / CREdependent transcription pathway regulates the expression of genes involved in synapse formation, neuronal survival (BDNF, BCl-2), and long-term memory formation (C / EBP) (10).…”