A Solid Dispersion of Quercetin Shows Enhanced Nrf2 Activation and Protective Effects against Oxidative Injury in a Mouse Model of Dry Age-Related Macular Degeneration

被引:66
作者
Shao, Yan [1 ]
Yu, Haitao [2 ]
Yang, Yan [3 ]
Li, Min [4 ]
Hang, Li [1 ]
Xu, Xinrong [1 ]
机构
[1] Nanjing Univ Chinese Med, Affiliated Hosp, Dept Ophthalmol, Nanjing 210029, Jiangsu, Peoples R China
[2] Nanjing Univ Chinese Med, Sch Pharm, Nanjing 210023, Jiangsu, Peoples R China
[3] Nanjing Univ Chinese Med, Affiliated Hosp 2, Dept Ophthalmol, Nanjing 210017, Jiangsu, Peoples R China
[4] Nanjing Univ Chinese Med, Affiliated Hosp, Liyang Branch, Dept Ophthalmol, Liyang 213300, Peoples R China
关键词
PHOSPHOLIPID COMPLEX; STRESS; BIOAVAILABILITY; DISSOLUTION; NARINGENIN;
D O I
10.1155/2019/1479571
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Age-related macular degeneration (AMD) represents a major reason for blindness in the elderly population. Oxidative stress is a predominant factor in the pathology of AMD. We previously evaluated the effects of phospholipid complex of quercetin (Q-PC) on oxidative injury in ARPE-19 cells, but the underlying mechanisms are not fully understood. Herein, the solid dispersion of quercetin-PC (Q-SD) was prepared with solubility being 235.54 mu g/mL in water and 2.3x10(4) mu g/mL in chloroform, which were significantly higher than that of quercetin (QT) and Q-PC. Q-SD also exhibited a considerably higher dissolution rate than QT and Q-PC. Additionally, Q-SD had Cmax of 4.143 mu g/mL and AUC of 12.015 mu g center dot h/mL in rats, suggesting better bioavailability than QT and Q-PC. Then, a mouse model of dry AMD (Nrf2 wild-type (WT) and Nrf2 knockout (KO)) was established for evaluating the effects of Q-SD in vivo. Q-SD more potently reduced retinal pigment epithelium sediments and Bruch's membrane thickness than QT and Q-PC at 200 mg/kg in Nrf2 WT mice and did not work in Nrf2 KO mice at the same dosage. Additionally, Q-SD significantly decreased ROS and MDA contents and restored SOD, GSH-PX, and CAT activities of serum and retinal tissues in Nrf2 WT mice, but not in Nrf2 KO mice. Furthermore, Q-SD more potently increased Nrf2 mRNA expression and stimulated its nuclear translocation in retinal tissues of Nrf2 WT mice. Q-SD significantly increased the expression of Nrf2 target genes HO-1, HQO-1, and GCL of retinal tissues in Nrf2 WT mice, not in Nrf2 KO mice. Altogether, Q-SD had improved physicochemical and pharmacokinetic properties compared to QT and Q-PC and exhibited more potent protective effects on retina oxidative injury in vivo. These effects were associated with activation of Nrf2 signaling and upregulation of antioxidant enzymes.
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页数:12
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