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

Nakajima, Akira; Yamakuni, Tohru; Haraguchi, Mitsuya; Omae, Naoki; Song, Si Young; Kato, Chieko; Nakagawasai, Osamu; Tadano, Takeshi; Yokosuka, Akihito; Mimaki, Yoshihiro; Sashida, Yutaka; Ohizumi, Yasushi

doi:10.1254/jphs.sc0070155

Cited by 132 publications

(91 citation statements)

References 14 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Akachi

Shiina

Ohishi

et al. 2010

J Nutr Sci Vitaminol

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SummaryWe attempted to isolate the constituent(s) responsible for the suppressive effect of the juice of shekwasha, a citrus produced in Okinawa Prefecture, on D -galactosamine (GalN)-induced liver injury in rats. Liver injury-suppressive activity, as assessed by plasma alanine aminotransferase and aspartate aminotransferase activities, was found only in the fraction that was extracted with n -hexane when three fractions were added to the diet and fed to rats. Of five compounds isolated from the n -hexane-soluble fraction by silica gel column chromatography, three compounds had liver injury-suppressive effects when five compounds were singly force-fed to rats at a level of 300 mg/kg body wt 4 h before the injection with GalN. The structures of the three active compounds were determined as 3 ′ ,4 ′ ,5,6,7,8-hexamethoxyflavanone (citromitin), 4 ′ ,5,6,7,8-pentamethoxyflavone (tangeretin) and 3 ′ ,4 ′ ,5,6,7,8-hexamethoxyflavone (nobiletin), which are known flavonoids mainly existing in citrus. Nobiletin, the most important compound in the n -hexane-soluble fraction, also had suppressive effects on liver injuries induced by carbon tetrachloride, acetaminophen and GalN/lipopolysaccharide (LPS) in addition to liver injury induced GalN. Nobiletin suppressed GalN/LPS-induced increases in plasma tumor necrosis factor (TNF)-␣ and nitric oxide (NO) concentrations and hepatic mRNA levels for inducible NO synthase and DNA fragmentation. These results suggest that nobiletin suppressed GalN/LPS-induced liver injury at least by suppressing the production of both TNF-␣ and NO. The results obtained here indicate that the hepatoprotective effect of shekwasha juice is mainly ascribed to several polymethoxy flavonoids included in the juice. Key Words D -galactosamine, liver injury, shekwasha, Citrus depressa , flavonoids Fruits and vegetables are important as sources of several nutrients such as vitamins, minerals and dietary fibers. Fruits and vegetables also contain a variety of constituents, which are characteristic of the species of plant. It is widely recognized that relatively high intakes of fruits and vegetables are desirable for prevention of diseases and maintenance of healthy conditions ( 1 ). Previously we reported that several kinds of fruit had suppressive effects on D -galactosamine (GalN)-induced liver injury in rats when various kinds of lyophilized fruit were added to the diet ( 2 ). Furthermore, recently we found that some fruit juices, e.g., camu-camu and shekwasha, also had suppressive effects on GalNinduced liver injury in rats, and we identified the active compound (unpublished data). These findings indicate that certain fruits (and possibly vegetables) have a hepatoprotective effect in addition to nutritional effects.Since the liver is the central organ of many types of metabolism, the hepatoprotective effect of foods is worthwhile to investigate in detail, not only from the viewpoint of food science but also from the viewpoint of nutrition.In the present study, we attempted to isolate the constituent(s) res...

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Section: Discussionmentioning

confidence: 99%

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

Akachi

Shiina

Ohishi

et al. 2010

J Nutr Sci Vitaminol

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“…Galantamine exerts dual effects on the cholinergic system: inhibition of AChE and stimulation of postsynaptic nicotinic receptors [8]. Based on the efficacy of galantamine, screening studies have led to the identification and isolation of natural AChE inhibitors from herbs [9], plants [10], seeds and fruits [11]. In addition, recent studies have indicated that dietary polyunsaturated fatty acids (PUFAs) may be able to modulate cholinergic activity, either through enhancement of ACh release or inhibition of ACh hydrolysis (Table 1).…”

Section: Introductionmentioning

confidence: 99%

Dietary polyunsaturated fatty acids improve cholinergic transmission in the aged brain

2009

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The cholinergic theory of aging states that dysfunction of cholinergic neurons arising from the basal forebrain and terminating in the cortex and hippocampus may be involved in the cognitive decline that occurs during aging and Alzheimer's disease. Despite years of research, pharmacological interventions to treat or forestall the development of Alzheimer's disease have primarily focused on enhancing cholinergic transmission, either through increasing acetylcholine (ACh) synthesis or inhibition of the acetylcholinesterase enzyme responsible for ACh hydrolysis. However, recent studies have indicated that dietary supplementation can impact the cholinergic system, particularly during aging. The purpose of the present review is to examine the relevant research suggesting that cholinergic functioning may be maintained during aging via consuming a diet containing polyunsaturated fatty acids (PUFAs). The data reviewed herein indicate that, at least in animal studies, inclusion of PUFAs in the diet can improve cholinergic transmission in the brain, possibly leading to improvements in cognitive functioning.

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“…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. 2).…”

Section: Discussionmentioning

confidence: 51%

“…14) We previously identified nobiletin, a polymethoxylated flavone from Citrus depressa peels, as a natural compound with neurotrophic effects such as neurite outgrowth on PC12D cells, 15) which is a subclone of PC12 cells that is known as a model of neuronal differentiation cell system. 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.…”

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confidence: 99%

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

Cited by 132 publications

References 14 publications

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

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

Dietary polyunsaturated fatty acids improve cholinergic transmission in the aged brain

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

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