Department of Ophthalmology, Jiangsu Province Hospital of Chinese Medicine (Affiliated Hospital of Nanjing University of Chinese Medicine), Nanjing 210029, China.
Department of Ophthalmology, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210017, China.
Oxid Med Cell Longev. 2020 May 13;2020:9420704. doi: 10.1155/2020/9420704. eCollection 2020.
Oxidative stress is a critical factor in the pathology of age-related macular degeneration (AMD). Apigenin (AP) is a flavonoid with an outstanding antioxidant activity. We had previously observed that AP protected APRE-19 cells against oxidative injury . However, AP has poor water and fat solubility, which determines its low oral bioavailability. In this study, we prepared the solid dispersion of apigenin (AP-SD). The solubility and dissolution of AP-SD was significantly better than that of the original drug, so the oral bioavailability in rats was better than that of the original drug. Then, the effects of AP-SD on the retina of a model mouse with dry AMD were assessed by fundus autofluorescence (FAF), optical coherence tomography (OCT), and electron microscopy; the results revealed that AP-SD alleviated retinopathy. Further research found that AP-SD promoted the nuclear translocation of Nrf2 and increased expression levels of the Nrf2 and target genes HO-1 and NQO-1. AP-SD enhanced the activities of SOD and GSH-Px and decreased the levels of ROS and MDA. Furthermore, AP-SD upregulated the expressions of p62 and LC3II in an Nrf2-dependent manner. However, these effects of AP-SD were observed only in the retina of Nrf2 WT mice, not in Nrf2 KO mice. In addition, the therapeutic effect of AP-SD was dose dependent, and AP did not work. In conclusion, AP-SD significantly enhanced the bioavailability of the original drug and reduced retinal oxidative injury in the model mouse of dry AMD . The results of the underlying mechanism showed that AP-SD upregulated the expression of antioxidant enzymes through the Nrf2 pathway and upregulated autophagy, thus inhibiting retinal oxidative damage. AP-SD may be a potential compound for the treatment of dry AMD.
氧化应激是与年龄相关的黄斑变性（AMD）病理学的关键因素。芹菜素（AP）是一种具有出色抗氧化活性的类黄酮。我们之前观察到 AP 可保护 APRE-19 细胞免受氧化损伤。然而，AP 的水和脂溶性差，这决定了其口服生物利用度低。在这项研究中，我们制备了 AP 的固体分散体（AP-SD）。AP-SD 的溶解度和溶解性能明显优于原药，因此大鼠的口服生物利用度优于原药。然后，通过眼底自发荧光（FAF）、光学相干断层扫描（OCT）和电子显微镜评估 AP-SD 对干性 AMD 模型小鼠视网膜的影响；结果表明 AP-SD 缓解了视网膜病变。进一步的研究发现，AP-SD 促进了 Nrf2 的核转位，并增加了 Nrf2 及其靶基因 HO-1 和 NQO-1 的表达水平。AP-SD 增强了 SOD 和 GSH-Px 的活性，降低了 ROS 和 MDA 的水平。此外，AP-SD 以 Nrf2 依赖的方式上调了 p62 和 LC3II 的表达。然而，AP-SD 的这些作用仅在 Nrf2 WT 小鼠的视网膜中观察到，而在 Nrf2 KO 小鼠中则没有观察到。此外，AP-SD 的治疗效果呈剂量依赖性，而 AP 则无效。总之，AP-SD 可显著提高原药的生物利用度，并减轻干性 AMD 模型小鼠的视网膜氧化损伤。潜在机制的研究结果表明，AP-SD 通过 Nrf2 通路上调抗氧化酶的表达，并上调自噬，从而抑制视网膜氧化损伤。AP-SD 可能是治疗干性 AMD 的一种潜在化合物。
