• Yuechen Guan, Junming Wang, Xiaohui Wu, Lingling Song, Yanmei Wang, Mingzhu Gong, and Bingyin Li.
• College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China.
• Brain Res. 2021 Dec 1; 1772: 147661.

AbstractQuercetin is a flavonoid compound rich in many natural plants with a wide range of pharmacological effects and nutritional value. Although previous studies have initially shown the antidepressant effect of quercetin in some models. However, the exact mechanism of the antidepressant effect of quercetin on the depression model induced by chronic unpredictable mild stress (CUMS) is still unclear or has not been clearly elucidated. The present study aimed to investigate the antidepressant effect of quercetin in vivo on a CUMS-induced depression model that is closest to human depression, and to explore its mechanism of action around nuclear factor-E2-related factor 2 (Nrf2) related signaling pathways, for the first time. Our results demonstrated that CUMS for 21 consecutive days caused significant decreases in the sucrose preference, and the horizontal score and vertical score in the open field test of mice respectively by 22.6%, 34.4%, and 66.6% (all P < 0.01), and a significant increase in the immobility time during the forced swimming test by 110.5% (P < 0.01), but fortunately, after chronic oral administration of high dose quercetin at 40 mg/kg, the abnormalities of the above indicators were significantly reversed by 26.2%, 40.1%, 152.7%, 43.5% (all P < 0.01). Further western blot analysis showed that CUMS caused the phosphorylation or expression levels of phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), Nrf2 and heme oxygenase-1 (HO-1) proteins in the hippocampus of mice to significantly down-regulate by 60.0%, 72.1%, 90.0% and 50.1% (all P < 0.01), while after chronic oral administration of high dose quercetin at 40 mg/kg, the abnormalities of these proteins were significantly up-regulated by 85.8%, 182.0%, 325.1% and 60.3% (all P < 0.01). In addition, CUMS also caused significant reduction in the levels of antioxidants including superoxide dismutase (SOD) and glutathione-s transferase (GST) in the mice hippocampus by 51.3%, 40.3% (both P < 0.01), while after chronic oral administration of high dose quercetin at 40 mg/kg, the abnormalities of the above indicators were significantly reversed by 69.2% and 49.5% (both P < 0.01), as well as significant elevation in the levels of lipid peroxide malondialdehyde (MDA), inflammation medium nitric oxide (NO) and inducible nitric oxide synthase (iNOS) by 156.4%, 255.4% and 72.7% (all P < 0.01), while after chronic oral administration of high dose quercetin at 40 mg/kg, the abnormalities of the above indicators were significantly reversed by 45.9%, 26.8% and 55.2% (all P < 0.01). The medium dose of quercetin (20 mg/kg) only reversed some of the above indicators, while the low dose of quercetin (10 mg/kg) had no reversal effect on the above indicators. Collectively, the present study confirmed for the first time that quercetin weakened CUMS-induced depression in vivo, and its mechanism was at least partially attributable to the upregulation of hippocampal Nrf2 and the inhibition of iNOS, thereby correcting the central inflammatory response, and the imbalance between oxidation and antioxidant.Copyright © 2021 Elsevier B.V. All rights reserved.

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