Nobiletin, a Citrus Flavonoid, Improves Memory Impairment and Aβ Pathology in a Transgenic Mouse Model of Alzheimer's Disease

Abstract

Increasing evidence suggests that the elevation of ␤-amyloid (A␤) peptides in the brain is central to the pathogenesis of Alzheimer's disease (AD). Our recent studies have demonstrated that nobiletin, a polymethoxylated flavone from citrus peels, enhances cAMP/protein kinase A/extracellular signalregulated kinase/cAMP response element-binding protein signaling in cultured hippocampal neurons and ameliorates A␤-induced memory impairment in AD model rats. For the first time, we report that this natural compound improves memory deficits in amyloid precursor protein (APP) transgenic mice that overexpress human APP695 harboring the double Swedish and London mutations [APP-SL 7-5 transgenic (Tg) mice]. Our enzyme-linked immunosorbent assay (ELISA) also showed that administration of nobiletin to the transgenic mice for 4 months markedly reduced quantity of guanidine-soluble A␤ 1-40 and A␤ 1-42 in the brain. Furthermore, consistent with the results of ELISA, by immunohistochemistry with anti-A␤ antibody, it was evidently shown that the administration of nobiletin decreased the A␤ burden and plaques in the hippocampus of APP-SL 7-5 Tg mice. These findings suggest that this natural compound has potential to become a novel drug for fundamental treatment of AD.

Long-term inhibition of dipeptidyl peptidase-4 in Alzheimer’s prone mice

“…This test was applied as previously described (Onozuka et al, 2008). Briefly, mice were placed into the corner of a wooden box 50 X 50 X 40 cm and allowed to freely explore for 10 min.…”

Determination of Nobiletin in Rat Plasma after Ingestion of <i>Citrus depressa</i> Juice by Capillary Liquid Chromatography with Electrochemical Detection Using Boron-doped Diamond Electrode

“…4 In addition, nobiletin has been found to exert antitumor activities, 5,6 to inhibit fulminant hepatitis, 7 and to improve memory impairment. 8 Although pharmacokinetic studies of nobiletin have been performed to examine the further characterizations of the metabolism and the biological effects of nobiletin, it have been carried out at relatively high dosage of nobiletin [9][10][11] since a sensitive analytical method has not been available. In order to discuss the realistic effects of nobiletin which, for example, are observed after daily beverage ingestion, an analytical method with high sensitivity is necessary for determining nobiletin in plasma.…”

Antimetastatic effect of nobiletin through the down-regulation of CXC chemokine receptor type 4 and matrix metallopeptidase-9

“…Numerous in vivo and in vitro studies have demonstrated the anti-inflammatory activities of nobiletin and its metabolites (Chen et al, 2007;Choi et al, 2007;Li et al, 2007;Murakami et al, 2000). Nobiletin helps to lower cholesterol levels (Whitman et al, 2005) and some studies indicate that it may improve impaired memory loss (Onozuka et al, 2008) and treat acne (Sato et al, 2007). Nobiletin has been shown to exhibit antitumor activities as indicated by the attenuation of pro-MMP-7 protein and its mRNA expression in HT-29 cells (Kawabata et al, 2005), down-regulation of leptin levels in mice with azoxymethane-and dextran sulfate sodium-induced colon carcinogenesis (Miyamoto et al, 2008), and the suppression of invasion and migration in human gastric adenocarcinoma AGS cells (Lee et al, 2011).…”