Nobiletin improves brain ischemia-induced learning and memory deficits through stimulation of CaMKII and CREB phosphorylation

Yamamoto, Yoshiyuki; Shioda, Norifumi; Han, Feng; Moriguchi, Shigeki; Nakajima, Akira; Yokosuka, Akihito; Mimaki, Yoshihiro; Sashida, Yutaka; Yamakuni, Tohru; Ohizumi, Yasushi; Fukunaga, Kohji

doi:10.1016/j.brainres.2009.07.081

Cited by 117 publications

(70 citation statements)

References 42 publications

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“…14) We have previously demonstrated that nobiletin-impaired hippocampal LTP is restored by nobiletin in ischemia-induced learning and memory deficient mice in an electrophysiological study. 25) Our present results show that c-Fos mRNA expression increases markedly by nobiletin. These results suggest that nobiletin contributes to recovery of reduced LTP by upregulating c-Fos expression in a CREB-dependent gene expression system, resulting in amelioration of learning and memory.…”

Section: Discussionsupporting

confidence: 58%

Upregulation of N-Methyl-D-aspartate Receptor Subunits and c-Fos Expressing Genes in PC12D Cells by Nobiletin

Kimura

Nemoto

Degawa

et al. 2014

Biological & Pharmaceutical Bulletin

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The N-methyl-D-aspartate (NMDA) receptor plays a key role in learning and memory. Our recent studies have shown that nobiletin from citrus peels activates the cAMP response element-binding protein (CREB) signaling pathway and ameliorates NMDA receptor antagonist-induced learning impairment by activating extracellular signal-regulated kinase. For the first time, we have shown that nobiletin significantly upregulated mRNA expression of the NMDA receptor subunits NR1, NR2A, and NR2B in PC12D cells. Furthermore, c-Fos mRNA expression also increased due to the action of nobiletin. Our results indicate that nobiletin modulates the expression of essential genes for learning and memory by activating the CREB signaling pathway, and suggest that this action mechanism of nobiletin plays a crucial role in improving NMDA receptor antagonist-induced learning impairment in model animals with dementia.Key words nobiletin; N-methyl-D-aspartate receptor; c-Fos; gene expression; memory impairment; dementia Alzheimer's disease (AD) is an age-related neurodegenerative disorder with progressive learning and memory impairment. The rise in the number of patients with AD is a severe social problem worldwide. It is now widely recognized that the synaptic dysfunction and neurodegeneration in AD is caused by amyloid β (Aβ). 1,2)It is well-known that the N-methyl-D-aspartate (NMDA) receptor, a glutamate receptor, plays a very important role in learning and memory functions and is widely distributed in the brain, notably in the CA1 region of the hippocampus. 3)This receptor is constructed from NR1 and distinct NR2 (A, B, C, or D) subunits. In particular, binding of glutamate requires both NR1 and NR2 subunits; functional NR1/NR2A and NR1/NR2B receptors have a particularly close relationship with long-term potentiation (LTP) that is a form of synaptic plasticity. 4) Cognitive impairment is caused by hypofunction of the NMDA receptor.5) The NR1 subunit is prerequisite for acquisition of spatial memory, object recognition, olfactory discrimination, and contextual fear memory in the hippocampal CA1, 6,7) whereas the NR2A subunit is required for LTP at the hippocampal CA1 synapses, 8) and NR2B contributes to the maintenance of spatial performance. 9) Furthermore, NR1 and NR2B subunit mRNA and protein levels decrease significantly in patients with AD, and the degree of decrease is associated with progression of the neuropathology. 10)Recent studies have demonstrated that learning and memory requires expression of large number of genes that are associated with the cAMP response element (CRE)-binding protein (CREB).11-13) Elevated Ca 2+ level then triggers multiple protein kinase signal pathways that activate LTP by activating protein kinase A (PKA)/mitogen-activated protein kinase (MAPK) kinase (MEK)/MAPK/CREB. As a consequence of CREB activation, transcriptional regulators such as c-Fos, c-jun, and fra1 are activated that cause secondary expression of numerous molecules related to learning and memory.11) In particular, c-Fos constructs activator p...

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Section: Discussionsupporting

confidence: 58%

Upregulation of N-Methyl-D-aspartate Receptor Subunits and c-Fos Expressing Genes in PC12D Cells by Nobiletin

Kimura

Nemoto

Degawa

et al. 2014

Biological & Pharmaceutical Bulletin

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“…Nobiletin stimulates the cAMP-dependent protein kinase and extracellular signal-regulated kinase signaling pathways in PC12 cells and cultured hippocampus neurons (7,8). In in vivo experiments, nobiletin has been shown to improve memory deficits in an animal model of Alzheimer's disease (12) as well as ischemia-induced memory deficits (18), and to improve motor and cognitive deficits in an animal model of MPTP-induced Parkinson disease (17). 3,5,6,7,8,3',4'-Heptamethoxyflavone (HMF) is a PMF structurally related to nobiletin (4,9).…”

Section: Introductionmentioning

confidence: 99%

3,5,6,7,8,3’,4’-Heptamethoxyflavone reduces interleukin-4 production in the spleen cells of mice

et al. 2016

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In our previous studies, we reported anti-inflammatory functions of 3,5,6,7,8,3',4'-heptamethoxyflavone (HMF), which is a polymethoxyflavone rich in various citrus fruits. Here, we investigated the immunomodulatory function of HMF in mice. HMF administration (50 mg/kg, i.p., 2 times/ week) tended to reduce the production of antigen-specific IgE induced by ovalbumin in combination with aluminum hydroxide gel. Fluorescence-activated cell sorting analysis revealed the reduction of interleukin-4 +

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“…Previous studies of ours indicated that nobiletin (l " Fig. 1), a polymethoxylated flavone isolated from Citrus depressa Hayata (Rutaceae) peels, has the ability to improve learning and memory impairment in dementia model animals such as olfactory-bulbectomized (OBX) mice [1][2][3][4][5][6]. Furthermore, nobiletin also markedly stimulates CRE-dependent transcription by activating the PKA/ERK/CREB signaling pathway in PC12D cells (a subclone of the rat pheochromocytoma cell line PC12) [2,7].…”

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confidence: 95%

Upregulatory Effects of Nobiletin, a Citrus Flavonoid with Anti-dementia Activity, on the Gene Expression of mAChR, ChAT, and CBP

et al. 2015

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!We previously showed that nobiletin, a polymethoxylated flavone from the peels of Citrus depressa Hayata, improves impaired memory in dementia model animals. It was also reported that nobiletin stimulates cAMP response element-dependent transcription through activation of the cAMP response element-binding protein signaling pathway. To determine whether nobiletin alters the expression of genes involved in learning and memory, we performed real-time polymerase chain reaction after treating PC12 cells with nobiletin. Nobiletin upregulated the expression of muscarinic acetylcholine receptor subtype M1, choline acetyltransferase, and cAMP response element-binding protein genes in the cells. The muscarinic acetylcholine receptor M1 and choline acetyltransferase mRNA levels reached maximum values at 6 h after nobiletin treatment, whereas the cAMP response element-binding protein mRNA levels peaked at 12 h. These results suggest that nobiletin enhanced the expression of genes involved in learning and memory by stimulating the cAMP response element-dependent transcription.

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Nobiletin improves brain ischemia-induced learning and memory deficits through stimulation of CaMKII and CREB phosphorylation

Cited by 117 publications

References 42 publications

Upregulation of <i>N</i>-Methyl-D-aspartate Receptor Subunits and c-Fos Expressing Genes in PC12D Cells by Nobiletin

Upregulation of <i>N</i>-Methyl-D-aspartate Receptor Subunits and c-Fos Expressing Genes in PC12D Cells by Nobiletin

<b>3,5,6,7,8,3’,4’-Heptamethoxyflavone reduces interleukin-4 production in the spleen cells of </b><b>mice </b>

Upregulatory Effects of Nobiletin, a Citrus Flavonoid with Anti-dementia Activity, on the Gene Expression of mAChR, ChAT, and CBP

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