Nobiletin and its related flavonoids with CRE-dependent transcription-stimulating and neuritegenic activities

Nagase, Hiroyuki; Omae, Naoki; Omori, Akiko; Nakagawasai, Osamu; Tadano, Takeshi; Yokosuka, Akihito; Sashida, Yutaka; Mimaki, Yoshihiro; Yamakuni, Tohru; Ohizumi, Yasushi

doi:10.1016/j.bbrc.2005.10.001

Cited by 146 publications

(124 citation statements)

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“…However, there are few reports on its inhibitory effect on tyrosinase. Citrus polymethoxylated flavones, another group like nobiletin and tangeretin, have attracted recent interest for their potent activities against tumors and other targets [19][20][21][22][23][24][25][26][27] due to their unique polymethoxyl radicals ( Figure 1). Though one report has previously demonstrated the inhibitory potency of nobiletin towards mushroom tyrosinase [28], further work needs to be carried out on their type of inhibition mechanism and intracellular performance in cell models due to the wide availability and commercial advantage of these citrus flavonoids.…”

Section: Introductionmentioning

confidence: 99%

Tyrosinase inhibitory effects and inhibition mechanisms of nobiletin and hesperidin from citrus peel crude extracts

Zhang

Lü

Lin

et al. 2007

Journal of Enzyme Inhibition and Medicinal Chemistry

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The inhibitory effects of nobiletin and hesperidin from citrus peel crude extracts on tyrosinase diphenolase activity are evaluated. IC 50 of nobiletin and hesperidin is 1.49 mM and 16.08 mM, respectively and their inhibition mechanism is competitive type with K i ¼ 2.82 mM and noncompetitive with K i ¼ 9.16 mM, respectively. Crude extracts from citrus peel (C. unshiu Marc.) were extracted with 95% ethanol and fractionated by petroleum ether (PCPE). The ethanol phase (ECPE) was further desorbed from macroporous adsorption resin (FGRE). Their IC 50 values were 8.09 mg/mL, 7.53 mg/mL and 4.80 mg/mL, respectively. Their inhibition on melanogenesis in B16 mouse melanoma cells was also evaluated. FGRE showed a significant inhibition (42.5% at 31.25 mg/mL, p , 0.01) while hesperidin showed almost no inhibition. Nobiletin and PCPE give efficacious antiproliferation effects on B16 mouse melanoma cell with IC 50 values 88.6 mM and 62.96 mg/mL, respectively, by the MTT test. Hesperidin and other crude extracts showed very low cytotoxity to the B16 cell.

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Section: Introductionmentioning

confidence: 99%

Tyrosinase inhibitory effects and inhibition mechanisms of nobiletin and hesperidin from citrus peel crude extracts

Zhang

Lü

Lin

et al. 2007

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…10) We reported previously that CRE-dependent transcription was enhanced by nobiletin by activation of the PKA/MEK/ERK/ CREB signal pathway in PC12D cells. 15,20) Moreover, our previous report showed that nobiletin ameliorates the NMDA receptor antagonist-induced learning impairment in association with ERK activation in mice. 18) This is the first report demonstrating that nobiletin significantly upregulated NR1, NR2A, and NR2B mRNA levels in PC12D cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Nobiletin prominently stimulates CRE-dependent transcription in PC12D cells 20) by activating the PKA/MEK/extracellular signal-regulated kinase (ERK)/CREB signaling pathway.…”

Section: )mentioning

confidence: 99%

“…Nobiletin improves learning and memory impairment in amyloid precursor protein transgenic mice, 16) chronically Aβ-infused AD model rats, 17) olfactory-bulbectomized mice, 18) and NMDA receptor antagonist MK-801-induced learning impaired mice. 19) Nobiletin prominently stimulates CRE-dependent transcription in PC12D cells 20) by activating the PKA/MEK/extracellular signal-regulated kinase (ERK)/CREB signaling pathway. 15) We further revealed that nobiletin restores the CREB phosphorylation suppressed by Aβ peptides in hippocampal neurons.…”

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confidence: 99%

“…1) was isolated from the peels of Citrus depressa HAYATA, as described previously. 20) The compound was dissolved in dimethyl sulfoxide (DMSO; Sigma-Aldrich Co. LLC, St. Louis, MO, U.S.A.) and stored at −20°C.…”

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Upregulation of <i>N</i>-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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Effects of Nobiletin in Animal Models of Cognitive Impairment

Nakajima

Ohizumi

Yamada

2017

Neuroprotective Effects of Phytochemicals in Neurological Disorders

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Nobiletin and its related flavonoids with CRE-dependent transcription-stimulating and neuritegenic activities

Cited by 146 publications

References 29 publications

Tyrosinase inhibitory effects and inhibition mechanisms of nobiletin and hesperidin from citrus peel crude extracts

Tyrosinase inhibitory effects and inhibition mechanisms of nobiletin and hesperidin from citrus peel crude extracts

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

Effects of Nobiletin in Animal Models of Cognitive Impairment

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