Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Xuzhou Normal University, Xuzhou 221116, Jiangsu Province, P R China.
J Pathol. 2010 Oct;222(2):199-212. doi: 10.1002/path.2754.
It is known that a high-cholesterol diet induces oxidative stress, inflammatory response, and beta-amyloid (Abeta) accumulation in mouse brain, resulting in neurodegenerative changes. Quercetin, a naturally occurring flavonoid, has been reported to possess numerous biological activities beneficial to health. Our previous studies have demonstrated that quercetin protects mouse brain against D-galactose-induced oxidative damage. Against this background, we evaluated the effect of quercetin on high-cholesterol-induced neurotoxicity in old mice and explored its potential mechanism. Our results showed that oral administration of quercetin significantly improved the behavioural performance of high-cholesterol-fed old mice in both a step-through test and the Morris water maze task. This is at least in part caused by decreasing ROS and protein carbonyl levels and restoring Cu--Zn superoxide dismutase (Cu, Zn-SOD) activity. Furthermore, quercetin also significantly activated the AMP-activated protein kinase (AMPK) via down-regulation of protein phosphatase 2C (PP2C), which reduced the integral optical density (IOD) of activated microglia cells and CD11b expression, down-regulated iNOS and cyclooxygenase-2 (COX-2) expression, and decreased IL-1beta, IL-6, and TNF-alpha expression in the brains of high-cholesterol-fed old mice through the suppression of NF-kappaB p65 nuclear translocation. Moreover, AMPK activation significantly increased 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and acetyl-CoA carboxylase (ACC) phosphorylation and reduced fatty acid synthase (FAS) expression in the brains of high-cholesterol-fed old mice, which reduced cholesterol levels, down-regulated cholesterol 24-hydroxylase (CYP46A1) and beta-amyloid converting enzyme 1 (BACE1) expression, decreased eukaryotic translation initiation factor 2alpha (eIF2alpha) phosphorylation, and lowered Abeta deposits. However, the neuroprotective effect of quercetin was weakened by intraperitoneal injection of compound C, an AMPK inhibitor. These results suggest that AMPK activated by quercetin may be a potential target to enhance the resistance of neurons to age-related diseases.
已知高胆固醇饮食可导致小鼠大脑氧化应激、炎症反应和β-淀粉样蛋白（Abeta）堆积，从而导致神经退行性变化。槲皮素是一种天然存在的类黄酮，具有许多有益于健康的生物学活性。我们之前的研究表明，槲皮素可保护小鼠大脑免受 D-半乳糖诱导的氧化损伤。在此背景下，我们评估了槲皮素对老年小鼠高胆固醇诱导的神经毒性的影响，并探讨了其潜在机制。我们的结果表明，口服给予槲皮素可显著改善高胆固醇喂养的老年小鼠在穿梭试验和 Morris 水迷宫任务中的行为表现。这至少部分是由于降低 ROS 和蛋白质羰基水平以及恢复 Cu-Zn 超氧化物歧化酶（Cu，Zn-SOD）活性所致。此外，槲皮素还通过下调蛋白磷酸酶 2C（PP2C）显著激活 AMP 激活的蛋白激酶（AMPK），从而减少活化的小胶质细胞和 CD11b 表达的积分光密度（IOD），下调 iNOS 和环氧化酶-2（COX-2）表达，并通过抑制 NF-kappaB p65 核易位降低高胆固醇喂养的老年小鼠脑中的 IL-1beta、IL-6 和 TNF-alpha 表达。此外，AMPK 激活可显著增加 3-羟基-3-甲基戊二酰辅酶 A（HMG-CoA）还原酶和乙酰辅酶 A 羧化酶（ACC）磷酸化，并降低高胆固醇喂养的老年小鼠脑中脂肪酸合酶（FAS）的表达，从而降低胆固醇水平，下调胆固醇 24-羟化酶（CYP46A1）和β-淀粉样蛋白转化酶 1（BACE1）的表达，降低真核翻译起始因子 2alpha（eIF2alpha）磷酸化，并降低 Abeta 沉积。然而，AMPK 抑制剂复合 C 的腹腔注射削弱了槲皮素的神经保护作用。这些结果表明，槲皮素激活的 AMPK 可能是增强神经元对与年龄相关疾病的抵抗力的潜在靶点。
