Apigenin Protects Mouse Retina against Oxidative Damage by Regulating the Nrf2 Pathway and Autophagy

Abstract

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 in vitro. 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 in vivo. 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.

A Re-Appraisal of Pathogenic Mechanisms Bridging Wet and Dry Age-Related Macular Degeneration Leads to Reconsider a Role for Phytochemicals

“…While maintaining energy homeostasis during the early stages of RPE injury, this is likely to elicit a dysfunction of RPE cells, which cannot cope with high levels of energy production from glycolysis during terminal stages [ 28 ]. Thus, in oxidative-challenged RPE, dysfunctional autophagy, being bound to a loss of Nrf2 and PCG1α, fails to orchestrate mitophagy and mitochondriogenesis, further promoting mitochondrial disintegration and a vicious cycle of oxidative-stress-related events up to caspase-mediated apoptosis [ 30 , 106 , 107 ]. In fact, mitochondrial alterations promote a highly oxidant intracellular milieu, which in turn affects lipid and glucose metabolism leading to the accumulation of oxidized lipids, proteins, and glycogen.…”

Merging the Multi-Target Effects of Phytochemicals in Neurodegeneration: From Oxidative Stress to Protein Aggregation and Inflammation

“…In turn, flavonoids can be sub-classified into flavonols, flavones, flavanols, flavanones, anthocyanidins, and isoflavonoids, according to the structure of the heterocycle C ring. Examples of compounds which are mostly investigated for their potential neuroprotective effects include quercetin, kaempferol and myricetin (flavonols) [ 50 , 51 , 52 , 53 , 54 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 ], scutellarin, baicalein, and apigenin (flavones) [ 50 , 55 , 56 , 61 , 87 , 88 , 89 , 90 ], catechins, epicatechin, and epigallocatechin gallate (EGCG, flavanols), as well as genistein (isoflavonoid), and silymarin (flavonolignan) [ 63 , 91 , 92 , 93 , 94 , 95 , 96 ]. The stilbene group is best exemplified by resveratrol, a well-known phenolic compound found in red wine, grape, and virgin olive oil, which has shown remarkable neuroprotective and anti-aging properties in a plethora of experimental models [ 50 , 58 , 59 , 65 , 69 , 97 , 98 , 99 , 100 , 101 , 102 ].…”

“…In the last decades, the search for an effective and potentially safe strategy to combat oxidative stress-mediated neuronal damage has increasingly prompted the investigation of naturally occurring compounds as antioxidant agents. The attenuation of oxidative stress by bioactive compounds belonging to different classes of phytochemicals including (i) flavonoids (quercetin, kaempferol and myricetin, scutellarin, baicalin, apigenin, catechins, epigallocatechin, and genistein) [ 52 , 61 , 81 , 82 , 83 , 88 , 94 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 ]; (ii) phenolic acids (syringic, gallic, caffeic, chlorogenic and salvianolic acids, and curcumin) [ 70 , 103 , 104 , 105 , 138 , 139 , 140 , 141 , 142 , 143 ]; (iii) flavonolignans (silymarin) [ 96 ]; (iv) stilbenes (resveratrol) [ 59 , 65 , 97 , 98 , 144 ]; (v) terpenes (bacosides/bacopasides, withanolides, and the carotenoids lutein and zeaxanthin) [ 7 , 110 , 113 , 115 , 145 , 146 , 147 ]; (vi) alkaloids (berberine and caffeine) [ 148 , 149 ]; (vii) glucosinolates (sulforaphane) and polyamines (spermine/spermidine) [ 123 , 124 ,…”

“…As shown in various experimental models of neurodegeneration, a failure in the autophagy machinery may predispose to neuronal injury due to extreme oxidative damage intermingling with protein overload and neuroinflammation, while rescuing autophagy may confer protection to grant cell survival [ 7 , 10 , 21 , 24 , 28 , 29 ]. It is remarkable that a wide variety of phytochemicals, including phenolic compounds such as anthocyanins, stilbenes (resveratrol), monophenols (caffeic acid, gallic acid), glucosides and flavonoids (catechin, epicatechin, quercetin, myricetin), and also nitrogen-containing compounds (berberine and spermine), are capable of stimulating autophagy to confer neuroprotection through either Akt/mTOR inhibition or AMPK/SIRT1 or TFEB activation [ 3 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 ]. Thus, in the next section, we discuss evidence bridging the antioxidant effects of these compounds with autophagy-related neuroprotection.…”

“…In this frame, it is remarkable that the common neuroprotective, antioxidant, and anti-inflammatory effects produced by several phytochemicals are associated with rescuing autophagy, meanwhile counteracting behavioral alterations, mitochondrial damage as well as intracellular accumulation and release of potentially detrimental substrates [ 3 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 ]. As recently reviewed, the neuroprotective effects of phytochemicals involve also a double-faceted, yet controversial modulation of the proteasome pathway, which will not be discussed in detail herewith [ 9 ].…”