Anti-dementia Activity of Nobiletin, a Citrus Flavonoid: A Review of Animal Studies

Nakajima, Akira; Ohizumi, Yasushi; Yamada, Kiyofumi

doi:10.9758/cpn.2014.12.2.75

Cited by 58 publications

(44 citation statements)

References 76 publications

(95 reference statements)

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“…Nobiletin is an O-methylated flavonoid present in citrus peels, with an empirical formula of C 21 H 22 O 8 and a molecular weight of 402.39, which has been reported to possess anti-inflammatory and antioxidant properties (8)(9)(10). Previous studies have reported that nobiletin may protect against cisplatin-induced acute kidney injury by preserving renal function and restoring antioxidant status (11).…”

Section: Introductionmentioning

confidence: 99%

Nobiletin attenuates lipopolysaccharide/D-galactosamine-induced liver injury in mice by activating the Nrf2 antioxidant pathway and subsequently inhibiting NF-κB-mediated cytokine production

Chen

et al. 2016

Molecular Medicine Reports

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Inflammation and oxidative stress serve an important role in the development of lipopolysaccharide/D-galactosamine (LPS/GalN)‑induced acute liver injury. Nobiletin, which is found in high quantities in the peel of citrus fruits, is able to modulate immune responses, including inflammatory response and oxidative stress. The present study aimed to evaluate the protective effects of nobiletin on LPS/GalN‑induced acute liver injury. Male C57BL/6 mice were intraperitoneally treated with nobiletin (50, 100 and 200 mg/kg) 2 h prior to LPS/GalN injection. Liver injury was observed in the LPS/GalN group, as demonstrated by increased levels of serum hepatic enzymes and hepatic inflammatory mediators, as well as by histopathological alterations. Treatment with nobiletin reduced serum alanine aminotransferase and aspartate aminotransferase levels, improved hepatic structure, and suppressed hepatic interleukin (IL)‑1β, IL‑6 and tumor necrosis factor‑α production 24 h after LPS/GalN exposure. Western blot analysis revealed that nobiletin treatment inhibited inducible nitric oxide synthase and cyclooxygenase‑2 liver expression. In addition, nobiletin suppressed LPS/GalN‑induced phosphorylation and degradation of inhibitor of nuclear factor (NF)‑κB (IκB)α, as well as NF‑κB p65 translocation into the nucleus. Nobiletin also upregulated the expression of nuclear NF‑E2‑related factor 2 (Nrf2) and cytoplasmic heme oxygenase‑1. In conclusion, these results indicate that nobiletin serves a protective role in LPS/GalN‑induced acute liver injury via activation of the Nrf2 antioxidant pathway and subsequent inhibition of NF‑κB‑mediated cytokine production. These findings support the potential for nobiletin as a therapeutic agent for the treatment of acute liver injury.

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Section: Introductionmentioning

confidence: 99%

Nobiletin attenuates lipopolysaccharide/D-galactosamine-induced liver injury in mice by activating the Nrf2 antioxidant pathway and subsequently inhibiting NF-κB-mediated cytokine production

Chen

et al. 2016

Molecular Medicine Reports

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“…Nobiletin (Fig. 1) is a type of polymethoxyflavonoid, which is predominantly found in Pericarpium Citri Reticulatae, a traditional Chinese medicine (9). Nobiletin exists in the pericarp of citrus fruits, and exerts extensive physiological effects that are beneficial to health.…”

Section: Introductionmentioning

confidence: 99%

Nobiletin ameliorates isoflurane-induced cognitive impairment via antioxidant, anti-inflammatory and anti-apoptotic effects in aging rats

Zhang

Lü

et al. 2016

Molecular Medicine Reports

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A recent study reported that nobiletin is an active ingredient in Fructus Aurantii immaturus and Pericarpium Citri Reticulatae, which may be capable of preventing ischemic stroke. Therefore, the present study aimed to determine the neuroprotective effects of nobiletin, and to evaluate whether it could ameliorate isoflurane‑induced cognitive impairment via antioxidant, anti‑inflammatory and anti‑apoptotic effects in aging rats. Male Sprague‑Dawley rats (age, 18 months) were used to analyze the neuroprotective effects of nobiletin. Morris water maze test was used to determine cognitive competence. Enzyme‑linked immunosorbent assay and western blot analysis were also used to quantify nuclear factor‑κB, tumor necrosis factor (TNF)‑α, IL‑1β, IL‑6, glutathione, (GSH), GSH‑peroxidase, superoxide dismutase and malondialdehyde concentration and relevant protein expression levels Cognitive competence was increased in isoflurane-treated rats following treatment with nobiletin. In addition, as expected, nobiletin exerted antioxidant, anti-inflammatory and anti‑apoptotic effects on isoflurane‑induced cognitive impairment in aging rats. Treatment with nobiletin induced the activation of phosphorylated (p)‑Akt, p‑cAMP response element binding protein (CREB) and brain‑derived neurotrophic factor (BDNF) protein expression and reduced the levels of B‑cell lymphoma 2‑associated X protein (Bax) in isoflurane‑induced rats. In conclusion, the present study demonstrated that nobiletin may ameliorate isoflurane-induced cognitive impairment through antioxidant, anti‑inflammatory and anti‑apoptotic effects via modulation of Akt, Bax, p‑CREB and BDNF in aging rats. These findings provide support for the molecular mechanisms underlying the effects of nobiletin treatment on isoflurane-induced damage.

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“…On the other hand, the effect of nobiletin on the uncoupling proteins may be mediated by mitochondrial protein kinase A (PKA). It has been found that nobiletin via cytoplasmic PKA-dependent phosphorylation of synaptic proteins exhibited memory-improving effects in various animal models of dementia [37]. PKA, as well as adenylate cyclase, were found in mitochondria.…”

Section: Mitochondrial Target Of Nobiletin's Actionmentioning

confidence: 99%

Mitochondrial Target of Nobiletin's Action

Sharikadze

Jojua

Sepashvili

et al. 2016

Natural Product Communications

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Nobiletin is an O-methylated flavonoid found in citrus peels that have anticancer, antiviral, neuroprotective, anti-inflammatory activities and depending on the cell types exhibits both pro-or anti-apoptotic properties. We have found that nobiletin decreases oxygen consumption by bovine brain isolated mitochondria in the presence of glutamate and malate and increases in the presence of succinate. In parallel, nobiletin increases NADH oxidation, a-ketoglutarate dehydrogenase activities and through matrix substrate-level phosphorylation elevates the a-ketoglutarate-dependent production of ATP. In addition, nobiletin reduces the production of peroxides in the presence of complex I substrates and slightly enhances succinate-driven H 2 O 2 formation. Besides, nobiletin induces transient elevation of membrane potential followed by mild depolarization. Affinity purified nobiletin binding proteins revealed one major anti-NDUFV1 positive protein with 52kD and NADH: ubiquinone oxidoreductase activity. This fraction can produce peroxide that is inhibited by nobiletin. We propose that nobiletin may act as a mild "uncoupler", which through activation of a-ketoglutarate dehydrogenase (a-KGDH)-complex and acceleration of matrix substratelevel phosphorylation maintains membrane potential at an abnormal level. This switch in mitochondrial metabolism could elevate succinate-driven oxygen consumption that may underlay in both pro-and anti-apoptotic effects of nobiletin.

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Anti-dementia Activity of Nobiletin, a Citrus Flavonoid: A Review of Animal Studies

Cited by 58 publications

References 76 publications

Nobiletin attenuates lipopolysaccharide/D-galactosamine-induced liver injury in mice by activating the Nrf2 antioxidant pathway and subsequently inhibiting NF-κB-mediated cytokine production

Nobiletin attenuates lipopolysaccharide/D-galactosamine-induced liver injury in mice by activating the Nrf2 antioxidant pathway and subsequently inhibiting NF-κB-mediated cytokine production

Nobiletin ameliorates isoflurane-induced cognitive impairment via antioxidant, anti-inflammatory and anti-apoptotic effects in aging rats

Mitochondrial Target of Nobiletin's Action

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