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Review

The Age-Related Macular Degeneration (AMD)-Preventing Mechanism of Natural Products

by
Yeon-Kyoung Cho
1,†,
Seung-Min Lee
2,†,
Yeong-Ji Kang
1,
Yeong-Mo Kang
1,
In-Chul Jeon
1,* and
Dae-Hun Park
3,*
1
College of Health and Welfare, Dongshin University, Naju 58245, Korea
2
School of Veterinary Medicine, Kangwon National University, Chuncheon 24341, Korea
3
Oriental Medicine, Dongshin University, Naju 58245, Korea
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Processes 2022, 10(4), 678; https://doi.org/10.3390/pr10040678
Submission received: 2 March 2022 / Revised: 16 March 2022 / Accepted: 29 March 2022 / Published: 30 March 2022
(This article belongs to the Section Pharmaceutical Processes)
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Abstract

:
Age-related macular degeneration (AMD) is related to central visual loss in elderly people and, based on the increment in the percentage of the aging population, the number of people suffering from AMD could increase. AMD is initiated by retinal pigment epithelium (RPE) cell death, finally leading to neovascularization in the macula lutea. AMD is an uncurable disease, but the symptom can be suppressed. The current therapy of AMD can be classified into four types: device-based treatment, anti-inflammatory drug treatment, anti-vascular endothelial growth factor treatment, and natural product treatment. All these therapies have adverse effects, however early AMD therapy used with products has several advantages, as it can prevent RPE cell apoptosis in safe doses. Cell death (apoptosis) is caused by various factors, such as oxidative stress, inflammation, carbonyl stress, and a deficiency in essential components for cells, and RPE cell death is related to oxidative stress, inflammation, and carbonyl stress. Some natural products have anti-oxidative effects, anti-inflammation effects, and/or anti-carbonylation effects. The AMD preventive mechanism of natural products varies, with some natural products activating one or more anti-apoptotic pathways, such as the Nrf2/HO-1 anti-oxidative pathway, the anti-inflammasome pathway, and the anti-carbonyl pathway. As AMD drug candidates from natural products effectively inhibit RPE cell death, they have the potential to be developed as drugs for preventing early (dry) AMD.

1. Introduction

1.1. Definition and Classification of Age-Related Macular Degeneration (AMD)

There are several blindness causes/diseases, such as uncorrected refractive errors, cataracts, age-related macular degeneration, glaucoma, diabetic retinopathy, corneal opacity, and trachoma, and many cases of vision loss is strongly related to aging [1]. At least 2.2 billion people suffer from visual impairment, and half of them, 1 billion people, have vision problems at a moderate level or worse [2]. Age-related macular degeneration (AMD) is one of the causes of blindness that are related to aging; its representative symptom is the loss of central vision [3], and it is caused by retinal pigment epithelial cell death (apoptosis) [4]. AMD can be classified into three categories: normal, geographic atrophy (dry) and exudative (wet) [4]; the dry AMD is divided into early and intermediate, and the exudate AMD can be called advanced [5]. The classification of AMD is based on atrophy occurrence, angiogenesis, and the size/location of drusens [6]. In this review, we discuss the advantages of natural products as treatment methods for geographic atrophy (early/dry) AMD and their therapeutic mechanisms, which are related to anti-oxidative, anti-inflammatory, and anti-carbonyl effects.

1.2. Statistics of AMD

AMD is the fourth most common cause of vision loss worldwide [7]. Worldwide, in 2019, the population aged 65 years was 703 million (9 percent), a number that is expected to double to 1.5 billion in 2050 (16 percent) [8]. In 2020, there were 196 million AMD patients, but in 2040, this population is forecast to grow to 288 million [9], as the prevalence of AMD in the population aged 80 years or over is 66% and the severity of AMD occurrence should increase [10]. Furthermore, as the percentage of elderly people rapidly increases, the risk of AMD occurrence might be thought of as more severe.

1.3. Problems of Current Treatments

The current treatment for AMD can be classified into four categories, device-based treatment, anti-inflammatory drug treatment, anti-vascular endothelial growth factor (anti-VEGF) treatment, and nutritional treatment [11], and there are several adverse effects in device-based treatment, anti-inflammatory drug treatment, and anti-VEGF treatment (Table 1).

2. Pathogenesis of Age-Related Macular Degeneration (AMD)

2.1. The Basic Structure of the Eye

In order to keep clear, visible sight, the macula has four component parts, including a photoreceptor, retinal pigment epithelium (RPE), Bruch’s membrane, and choriocapillaris; the photoreceptor converts light into a signal, it can firmly fix on the RPE, and the Bruch’s membrane supplies blood and exchanges gases (O2 and CO2) between the choriocapillaris and the RPE to support the photoreceptor’s maintenance [4]. RPE death (apoptosis) increases AMD severity, as it makes it difficult to supply nutrition and to exchange gases.

2.2. The Pathogenic Factors of AMD

The important pathogenic factors of AMD are bis-retinoid N-retinyl-N-retinylidene ethanolamine (A2E), especially A2E-epoxides [16] and blue light (in the wavelength range of 480 ± 20 nm) [17]. A2E is a hydrophobic quaternary amine form of lipofuscin [18], which consists of aging pigments and lipofuscins that are distributed in many regions of bio-organisms, such as neurons, the heart, and the retinal pigment epithelium (RPE) [19]. A2E is a very unstable pigment, which easily changes to its oxidized form (A2E-epoxide) and, during A2E oxidization, many reactive oxygen species (ROSs) are produced [20]. Blue light can induce rapid A2E oxidization and then cause irreversible injury to the vision system [21]. A2E is easily cleaved by light, and then photocleaved A2E accumulates to make drusen [22].

2.3. The Relation of Age-Related Macular Degeneration (AMD) and Retinal Pigment Epithelial Cell Death (Apoptosis)

RPE is one of the very useful structures for the visible system, as it not only maintains the photoreceptor’s normal status through supplying blood and exchanging gases (O2 and CO2) from the choriocapillaris [4], but also preserves the immune function via defending against various harmful stimulators, such as reactive oxygen species (ROS), carbonylated metabolites, and inflammatory factors [23]. It has high levels of superoxide dismutase (SOD) [24,25,26] and catalase [27] for chelating ROS. As polyunsaturated fatty acids (PUFAs) are plentiful in the RPE membrane, it is very vulnerable to reactive oxygen species [28] and, due to aging, the balance between the level of the ROS and that of anti-oxidants can easily be disrupted [29]. Many ROS, such as hydrogen peroxide (H2O2), superoxide anion radical (O2−), hydroxyl radical (OH⋅), and nitric oxide (NO), are toxic to the cytoplasmic membrane, as they can initiate oxidization, which destroys the membrane structure [20,29]; however, in the case of NO, which is one of the most harmful ROS, the relation between AMD occurrence and NO’s function is unclear, as some groups reported that the level of serum NO was higher in AMD patients than in normal people [30], but other groups presented the opposite results [31]. When the ROS destroy the RPE layer, many ophthalmological problems, such as AMD and blindness, can occur. A2E can be changed to A2E-epoxide by blue light, and, at the same time, many ROS, such as H2O2, O2−, and OH⋅, can be synthesized and start the oxidization of RPEs, thus destroying them [16,20,32,33]. Although drusen is one of the hallmarks for discriminating AMD [34], there are many debates regarding drusen formation. However, it is related to both RPE cell death and ROS synthesis via A2E oxidization [35].
Accumulated drusen not only induces central region blindness, but also stimulates inflammation in RPE [36], and the exacerbation of an inflammatory response is a trigger of AMD occurrence [35]. Although inflammation is one of the homeostasis responses of bio-organisms and is an important immune defense mechanism against foreign bodies [37], and inflammation is necessary to effectively control abnormal situations, when an exacerbated inflammatory situation occurs, the inflammatory cells can stimulate ROS synthesis and can cause excessive oxidative stress on the inflammatory regions [38]. In order to maintain the immune balance, there is a network among immune cells that can modulate cytokines, including pro-inflammatory ones (interleukin (IL)-1β, IL-6, IL-13, and tumor necrosis factor (TNF)-α) [39] and anti-inflammatory ones (IL-10 and tumor growth factor (TGF)-1) [40]. The oxidative stress is closely connected with inflammation, and, in particular, A2E stimulates RPE cell inflammation by increasing the level of IL-1β via the NLRP3 inflammasome [34].
Carbonyl stress means that, without the oxidative stress during the Maillard reaction, carbonylated products, such as malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), and 4-hydroxyhexanal (4-HHE), are synthesized from some compounds, such as lipids, protein, and DNA, via carbonylation [41]. PUFAs in the membrane layer in RPE cells consist of 50% docosahexaenoic acid (DHA), 10% oleic acid (OA), and 8% arachidonic acid (AA) [42], carbonylated products are derived from PUFAs in RPE cells [43], and many diseases are related to their functions [42]. The chemical structures of 4-HNE and 4-HHE are similar, and both of them have cytotoxicity based on similar pathogenic pathways, such as blocking some enzymes’ functions and stimulating cell cycle arrest and cell death, and, as they can be derived from PUFAs in RPE cell membranes, they are important biomarkers for evaluating AMD [43,44]. For example, the level of serum MDA in patients who suffer from wet-type AMD is higher [45], and the levels of MDA and 4-HNE in the retina are higher in normal mice than in intravitreal paraquat-injected mice used as AMD models [44].
From the toxicological point of view, although each type of stress can induce RPE cells to be damaged by itself, all of them participate via their toxicological network in AMD occurrence via RPE cell apoptosis (Figure 1).

3. Three Stresses and the Mechanism of Natural Products to Prevent Retinal Pigment Epithelial Cell Death (Apoptosis)

3.1. Anti-Oxidative Stress and Natural Products

3.1.1. Nuclear Factor Erythroid-Derived-2-like (Nrf2)/Heme Oxygenase-1 (HO-1)-Antioxidant Responsive Element (ARE) System

The nuclear factor erythroid-derived-2-like (Nrf2)/heme oxygenase-1 (HO-1)-antioxidant responsive element (ARE) system is one of the representative antioxidant systems, and it is an effective defensive pathway in RPE against oxidative stress [46]. Nrf2 binds to the Kelch domain of Keap1 [47], but when oxidative stress occurs, this combination can be dissociated, inducing the transcription of several genes protecting against hazards, producing anti-cancer, anti-oxidative, anti-inflammatory, and detoxifying effects. [48,49,50,51]. HO-1, which is transcribed by Nrf2, has several biological effects, such as oxidative stress prevention, apoptosis regulation, and inflammation modulation [52]. Within natural products, there are many Nrf2/HO-2 modulators that can regulate various diseases, such as Alzheimer’s disease [53], cerebral ischemia [54,55], chronic obstructive pulmonary disease [56], diabetes [57,58], Parkinson’s disease [59,60], and stroke [61]. Recently, there has been an increasing study of natural product-derived controllers on the Nrf2/HO-1-ARE system for preventing AMD occurrence/severity (Figure 2). The chemical formula of canolol is 4-vinyl-2,6-dimethoxyphenol, which is isolated from canola oil and has Nrf2/HO-1-related anti-oxidative effects in RPE cell apoptosis via the ERK pathway [62]; genipin is a glycosidic ligand that is included in Mast and Eucommia ulmoides, regulates Nrf2/HO-1 signaling for suppressing oxidative stress, and finally inhibits RPE cell death through the regulation of B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (BAX), and capsase-3 [63]; hesperetin, which can be isolated from Citrus aurantium L’s peel, increases Nrf2/HO-1-ARE’s activation and upregulates levels of both SOD and glutathione [64]; narigenin, 4′,5,7-trihydroxyflavanone is a component that is plentiful in grapefruit and increases the activations of Nrf2 and HO-1, which can decrease intracellular ROS [65]; and salvianolic acid A is the water extract of Saliva miltiorrhiza, which stimulates Nrf2/HO-2 activation and has protective effects against RPE cell death through phosphoinositide 3-kinase (PI3K)/AMP-activated protein kinase (AKT)/mammalian target of rapamycin complex 1 (mTORC1) signaling [66].

3.1.2. Other Anti-Oxidative Stress Pathways

There are many natural anti-oxidants that can alleviate AMD occurrence or decrease AMD severity, and there are many natural products related to controlling AMD, such as carotenoids, including β-carotene; vitamin E, including tocopherols and tocotrienols; vitamin C, which is known as ascorbic acid and ascorbate; and selenium [67,68]. An ethanol extract of Arctium lappa L. leaves contains large amounts of polyphenols and flavonoids and prevents RPE cell death via down-regulating intracellular ROS levels [69]. Delpinidin is one of the anthocyanidins, which are a class of polyphenols in fruits and vegetables and consist of six components, including cyanidin, delphinidin, malvidin, pleargonidin, peonidin, and petunidin [70], with anti-apoptotic effects on H2O2-damaged RPE cells via the modulation of the Bcl family [71]. Glabridin is one of the isoflavonoids, which originates from Glycyrrhiza glabra L. root and prevents NaIO3-induced RPE cell death via the extracellular signal-regulated kinase (ERK) 1/2 and p38 mitogen-activated protein kinase (MAPK) pathway [72].

3.2. Anti-Inflammatory Effects of Natural Products

3.2.1. Inflammasome and Inflammation

Inflammasomes are multiprotein oligomers in the cytoplasm and are produced during inflammatory responses [73]. They are usually observed in the epithelial barrier tissues, which act as the first line of bio-organisms’ defense; when foreign bodies enter the host, pattern recognition receptors (PRRs) in the host’s epithelial tissues respond to microbe-derived pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs), which are generated by the host cells. Recently, the study of inflammasome and natural products has increased (Figure 3) [74]. The recognition of the entrance of PAMPs or DAPs is initiated by PRRs’ binding, including Toll-like receptors (TLRs), retinoic acid-inducible gene (RIG)-I-like receptors (RLRs), NOD-like receptors (NLRs), and C-type lectin receptors (CLRs) [75]. As a result of inflammasomes’ activation, monocytes are recruited around the foreigners’ entrance site, changed to macrophages or dendritic cells, and secrete cytokines and chemokines, such as IL-1β, TNF-α, IL-6, and IL-12 (secreted by M1 macrophages) or IL-4 and IL-13 (secreted by M2 macrophages) [76,77,78,79]. Baicalin is an isolated flavonoid from Scutellaria baicalensis Georgi that suppresses the NLR3 inflammasome-induced pyroptosis of RPE cells [80]; Lycium barbarum polysaccharides inhibits pyroptosis, which is induced by an NLRP3/caspase-1/membrane N-terminal cleavage product of GSDMD (GSDMD-N) [81]; puerarin is an isolated constituent from the Pueraria montana root that suppresses NLRP3 inflammasome activation [82]; grape seed proanthocyanidin extract was found to alleviate RPE cell senescence, which was caused through the nicotinamide phosphoribosyltransferase (NAMP)/SIRTI/NLRP3 pathway [83]; and cyanidin-3-glucoside (C3G), which is plentiful in purple-colored fruits/vegetables, down-regulates NLRP3 inflammasome activation [84].

3.2.2. Other Anti-Inflammatory Pathways

Curcumin [1,7-bis-(4-hydroxy-3-methoxyphenyl)-hepta-1,6-diene-3,5-dione], which is one of the major constituents in Curcuma longa, has several biological effects, including anti-allergy, anti-oxidative, and anti-inflammatory effects; in particular, it suppresses bcl-2 family-related RPE cell death through the extracellular signal-regulated kinase (ERK)/NF-κB-COX-2 signaled anti-inflammation pathway [85]. Nepetin, which is called eupafolin or 6-methoxyluteolin, a flavonoid isolated from several herbs, such as Eupatorium ballotaefolium, Rosmarinus officinalis, and Clerodendrum petasites [86,87,88], decreases inflammation-related cytokines, such as IL-6 and IL-8, via the NF-κB/MAPK (ERK1/2, JNK and p38MAPK) pathway [89]. Resveratrol [3,4′,5 trihydroxy-stilbene], which is one of the components in grapes, can suppress the levels of inflammatory cytokines, such as IL-1β, IL-6, TNF-α, and TGF-β, via the NF-κB pathway in RPE cells [90]. Saffron is one of the components of Crocus sativus L.’s stigma and has anti-inflammatory effects [91] through modulating both inflammation-related cytokines such as proinflammatory cytokines (IL-1β, IL-17, IFN-γ, and TNF-α) and anti-inflammatory cytokines (IL-4 and IL-10) [92]. Wogonin [5,7-dihydroxy-8-methoxyflavone], which is isolated from Scutellaria baicalensis Georgi root, down-regulates LPS-induced inflammatory cytokines, such as IL-1β, IL-6, IL-8, and TNF-α, through the TLR4-NF-κB/COX-2 signal [93].

3.3. Anti-Carbonyl Stress Effects and Natural Products

Allicin is an organosulfur compound isolated from Allium sativum L. It has several biological effects, such as antimicrobial effects, immune-regulation, and anti-cancer effects [94]; in an H2O2-induced AMD in vitro model, it decreased the level of MDA [95]. Flavonoid-rich fractions from blueberries suppressed active carbonyl compounds, such as MDA and 4-HHE, and the lipid oxidative compound lipid hydroperoxide (LOOH) [42]. Freeze-dried grapes, which contain resveratrol, flavans, flavonols, anthocyanins, and simple phenolics, effectively prevented 4-HNE in RPE cells and then blocked blindness caused by RPE actin’s damage [96]. Quercetin and C3G, which are plentiful in various fruits and vegetables, prevented RPE cell damage through lipid oxidation and carbonyl stress via 4-HNE [97]. Tomatoes have many constituents, including carotenoids, such as lycopene, phytoene, phytofluene, β-carotene, γ-carotene, δ-carotene, and lutein, and polyphenols, such as naringenin chalcone, rutin, quercetin, and chlorogenic acid [98]; tomato extract contains high levels of β-carotene, lycopene, and traces of lutein, which decreased protein carbonyls in H2O2-treated RPE cells by 30% [99]. Based on a human study, a nutritional supplement containing 408 mg of vitamin C, 241 mg of vitamin E, 30 mg of zinc, and 9 mg of lutein once a day for 3 months effectively reduced serum MDA levels [100].

4. Discussion

AMD is related to aging and the percentage of AMD patients is higher in older people. In 2020, the United Nations reported that, in 2019, the number of people aged 65 years or more was 703 million worldwide, and in 2050, this number could almost double to reach 1.5 million [8]. In 2020, 196 million people suffered from AMD, and in 2040, this number is expected to rise to 288 million [9]. Depending on aging, the severity and the occurrence of AMD might increase, and although there are several treatment methods, such as device-based therapy, anti-inflammatory drug therapy, and anti-VEGF treatment, because AMD is an incurable disease, the best treatment is to prevent its occurrence. The current incidence rate of AMD in young and juvenile people has been rapidly increasing as the usage time of smart devices increases [101]; in order to reduce morbidity, smart devices’ usage time should be reduced [102].
AMD is initiated by RPE cell death and, as it is difficult to supply blood to photoreceptors, angiogenesis finally occurs from the choroid vessel to photoreceptors [103]. RPE cell death is related to oxidative stress, inflammatory stress, and carbonyl stress [23], and although each type of stress is harmful to cells, all three stresses influence RPE cell death as all occur simultaneously. It is difficult to completely cure AMD, and thus its prevention is the best therapeutic strategy. In this study, the relation between AMD and the suppression of the three types of stress by natural products was reviewed. These natural products include anti-oxidants, including Nrf2/HO-1 stimulators, namely, canolol, genipin, hesperetin, narigenin, salvianolic acid, carotenoids, Arctium lappa L. leaves, delpinidin, polyphenols, and glabridin [62,63,64,65,66,67,68,69,70,71,72]; anti-inflammatory agents, such as baicalin, Lycium barbarum polysaccharides, puerarin, grape seed proanthocyanidin, C3G, curcumin, nepetin, resveratrol, saffron, and wogonin [80,81,82,83,84,85,86,87,90,91,93]; and anti-carbonyl stress suppressors, such as allicin, blueberries, grapes, quercetin, tomatoes, and nutritional supplements containing vitamin C, vitamin E, zinc, and lutein [42,82,94,96,98,99,100]. However, there are several AMD-prevented mechanisms of natural products excluding anti-oxidation, anti-inflammation, and anti-carbonylation. Docosa-hexaenoic acid, which is a major compound in omega-3 fatty acid, inhibited RPE cell death through the down-regulation of pro-apoptotic factors, such as Bax and Bad, and the up-regulation of anti-apoptotic factors, such as Bcl-2 and Bcl-xL [33]. Dietary lutein, which originates from fruits and vegetables, such as kiwi fruit, grapes, orange juice, maize, spinach, and zucchini [104], significantly decreased AMD incidence in humans [105,106], and the anti-AMD mechanism can be supposed to inhibit ROS-induced RPE cell damage via the 25C cycle and cyclin B1-related G2/M phase arrest [107]. Taurocholic acid, which is a yellowish crystalline bile acid and is called cholaic acid, cholytaurine, or acidum cholatauricum [108], inhibited both VEGF-induced tube formation and the migration of choroidal endothelial cells (RF/6A cells) in a study of anti-angiogenesis effects [109]. Vaccinium uliginosum L. fractions, which contain a large amount of polyphenol, prevented blue-light-induced ARPE 19 cell damage [110]. In 2022, de Guimaraes et al. [111] reported that drug candidates for early (dry) AMD treatment were undergoing a clinical study (Table 2). Based on the therapeutic target, they can be classified as antioxidants, reducers of toxic byproducts, visual cycle modulators, anti-inflammatory and complement inhibition drugs, neuroprotection, gene therapy, cell-based therapies, mitochondrial enhancers, and nanosecond laser therapy.
Recently, trials to develop stem cell therapy for AMD have increased [112]; stem cell therapy for AMD uses the microsurgical method to replace damaged RPE cells using several cell types, such as embryonic stem cells (ESCs) [113], pluripotent stem cells (PSCs) [114], and mesenchymal stem cells (MSCs) [115]. An RPE monolayer patch using human ESCs has been evaluated in a clinical phase I trial in order to use microsurgical tools in subretinal space, and the study was deemed successful [116]. Human PSCs have the ability to differentiate most cell types, and many studies have been conducted to find therapeutic conditions for AMD [117]. Intravitreal MSCs injection increased the survival of both RPE cells and photoreceptors in a retinitis pigmentosa model [118]. Although there have been many trials of stem cell usage on AMD patients, there are still several obstacles to their use as AMD therapeutics. One is that stem cells have a pluripotency to differentiate between many types of cell, which means that it is difficult to control the making of a proper cell type, namely RPE [119]. Other problems are that the safety of the stem cell method is not completely confirmed, and that, in order to successfully settle cells down on the subretinal space after the operation, the immunosuppressor should be treated, but the systemic immunosuppression could inhibit the stem cells’ effective settling down [120]. Another study found that, in order to clinically apply stem cell therapy to AMD patients, there are many obstacles still to be solved, including safety, the differentiation of the proper cell type, and the effective usage of immunosuppressors [121].
Especially in the early and intermediated stages of AMD (dry AMD), natural product supplements, such as nutritional materials (antioxidants, anti-inflammatory materials, and anti-carbonyl ones), are effective for decreasing AMD occurrence.

Author Contributions

Conceptualization, I.-C.J. and D.-H.P.; writing—original draft preparation; Y.-K.C. and S.-M.L.; writing—review and editing, I.-C.J. and D.-H.P.; visualization, Y.-J.K. and Y.-M.K.; supervision, D.-H.P. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

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Figure 1. Age-related macular degeneration (AMD) occurrence caused by oxidative stress, carbonyl stress, and inflammation. A2E-epoxide and reactive oxygen species (ROS) are synthesized by A2E and the blue light reaction. The synthesized ROS attack the cell membrane of the retinal pigment epithelium (RPE) and destroy it via oxidative stress. The gathered ROS recruit the immune cells and secrete immune mediators, such as IL-1β, IL-6, IL-13, TNF-α, and IFN-γ (inflammation). The attack of ROS on the cell membrane in RPE initiates the carbonylation of (1) the cell membrane’s lipid layer and (2) DNA, and carbonylated products, such as malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), and 4-hydroxyhexanal (4-HHE), disrupting the cell membrane and DNA (carbonyl stress). The correlation of these stresses induces RPE cell death (apoptosis). Processes 10 00678 i001: carbohydrate.
Figure 1. Age-related macular degeneration (AMD) occurrence caused by oxidative stress, carbonyl stress, and inflammation. A2E-epoxide and reactive oxygen species (ROS) are synthesized by A2E and the blue light reaction. The synthesized ROS attack the cell membrane of the retinal pigment epithelium (RPE) and destroy it via oxidative stress. The gathered ROS recruit the immune cells and secrete immune mediators, such as IL-1β, IL-6, IL-13, TNF-α, and IFN-γ (inflammation). The attack of ROS on the cell membrane in RPE initiates the carbonylation of (1) the cell membrane’s lipid layer and (2) DNA, and carbonylated products, such as malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), and 4-hydroxyhexanal (4-HHE), disrupting the cell membrane and DNA (carbonyl stress). The correlation of these stresses induces RPE cell death (apoptosis). Processes 10 00678 i001: carbohydrate.
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Figure 2. The anti-oxidative mechanism of natural products through the Nrf2/HO-1-ARE system. Nrf2 and the Keap 1 complex are dissociated by ERK/JNK/p38MAPK signals, and Nrf2 enters the nucleus in order to function as an HO-1 transcription factor. This ARE system is initiated by several natural products, such as canolol, genipin, Eucommia ulmoides, hesperetin, narigenin, and Saliva miltiorrhiza. Nrf2, nuclear factor erythroid 2-related factor 2; HO-1, heme oxygenase-1; ARE, antioxidant response element; Keap 1, Kelch-like ECH-associated protein 1; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; and p38MAPK, p38 mitogen-activated protein kinase.
Figure 2. The anti-oxidative mechanism of natural products through the Nrf2/HO-1-ARE system. Nrf2 and the Keap 1 complex are dissociated by ERK/JNK/p38MAPK signals, and Nrf2 enters the nucleus in order to function as an HO-1 transcription factor. This ARE system is initiated by several natural products, such as canolol, genipin, Eucommia ulmoides, hesperetin, narigenin, and Saliva miltiorrhiza. Nrf2, nuclear factor erythroid 2-related factor 2; HO-1, heme oxygenase-1; ARE, antioxidant response element; Keap 1, Kelch-like ECH-associated protein 1; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; and p38MAPK, p38 mitogen-activated protein kinase.
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Figure 3. The inflammasome synthesis/activation and the anti-inflammasome effect of natural products. (1) PRRs in the cell membrane bind to PAMPs or DAMPs. (2) After the recognition of PRRs, NF-κB p65/p55 and IκB can be separated from each other and NF-κB p65 enters the nucleus in order to function as a transcription factor for both NLRP3 and pro-IL-1β (3). (4) A2E produces phagosomes and they release cathepsin B. (5) ROS are generated and stimulate the complex formation of NLRP3, active IL-1β, and cathepsin B to activate caspase-1. (6) Active caspase-1 binds to IL-18 to produce the inflammasome. Natural products, such as baicalin, Lycium barbarum, puerarin, grape seed, and cyanidin-3-glucoside, can block inflammasome formation to ameliorate inflammation in PRE cells. PRRs, pattern recognition receptors; PAMPs, microbe-derived pathogen-associated molecular patterns; DAMPs, danger-associated molecular patterns; NLRP3, NLR family pyrin domain containing 3; and A2E, N-retinylidene-N-retinyl-ethanolamine.
Figure 3. The inflammasome synthesis/activation and the anti-inflammasome effect of natural products. (1) PRRs in the cell membrane bind to PAMPs or DAMPs. (2) After the recognition of PRRs, NF-κB p65/p55 and IκB can be separated from each other and NF-κB p65 enters the nucleus in order to function as a transcription factor for both NLRP3 and pro-IL-1β (3). (4) A2E produces phagosomes and they release cathepsin B. (5) ROS are generated and stimulate the complex formation of NLRP3, active IL-1β, and cathepsin B to activate caspase-1. (6) Active caspase-1 binds to IL-18 to produce the inflammasome. Natural products, such as baicalin, Lycium barbarum, puerarin, grape seed, and cyanidin-3-glucoside, can block inflammasome formation to ameliorate inflammation in PRE cells. PRRs, pattern recognition receptors; PAMPs, microbe-derived pathogen-associated molecular patterns; DAMPs, danger-associated molecular patterns; NLRP3, NLR family pyrin domain containing 3; and A2E, N-retinylidene-N-retinyl-ethanolamine.
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Table
Table 1. Current treatments for age-related macular degeneration and the adverse effects of each treatment.
Table 1. Current treatments for age-related macular degeneration and the adverse effects of each treatment.
TreatmentPrinciples of TreatmentAdverse EffectsReferences
Device-based treatment(1) To eliminate the drusen
(2) To inhibit the choroidal vascularization		Macular edema, retinovascular disease[12]
[13]
Anti-inflammatory drug treatment(1) To block the inflammatory pathway
(2) To inactivate cyclo-oxygenase or/and lipoxygenase		Hypertension, insulin resistance, insomnia, skin thinning, gastric ulceration[14]
Anti-vascular endothelial growth factor (anti-VEGF) treatment(1) To prohibit VEGF activation
(2) To bind to the VEGF receptor
(3) To block the tyrosine kinase pathway		Bleeding and infection risk by intravitreal injection[15]
Table
Table 2. Ongoing clinical trials for early (dry) AMD drugs.
Table 2. Ongoing clinical trials for early (dry) AMD drugs.
Category/NameClinical Trial ID (NCT #)Study PhaseRoute of DeliveryStatusSponsor
Antioxidative
Age-related eye disease study (AREDS)00000145IIIOralCompletedNational Eye Institute
AREDS200345176IIIOralCompletedNational Eye Institute
OT-55100306488IITopicalCompletedNational Institutes of Health Clinical Center
Reduction in toxic byproducts
GSK93377601342926IIIVCompletedGlaxoSmithKline
RN6G01577381IIIVTerminatedPfizer
Visual cycle modulators
ACU-442901802866IIb/IIIOralCompletedKutoba Vision, Inc.
Fenretinide00429936IIOralCompletedSirion Therapeutics, Inc.
C20-D3-vitamin A (ALK-001)03845582IIIOralOngoing/recruitingAleus Pharmaceuticals, Inc.
Anti-inflammatory and complement inhibition
Eculizumab00935883IIIVCompletedPhilip J. Rosenfeld, MD
Lampalizumab02247531IIIIntravitrealTerminatedHoffman-La Roche
Sirolimus (rapamycin)00766649I/IISubconjunctivalCompletedNational Eye Institute
Avacincaptad pegol (Zimura)02686658II/IIIIntravitrealCompletedIVERIC bio, Inc.
Pegcetacoplan (APL-2)03525613IIIIntravitrealCompleted/not recruitingApellis Pharmaceuticals, Inc.
Tedisolumab (LFG316)01527500IIIntravitrealCompletedNovartis Pharmaceuticals, Inc.
Risuteganib03626636IIntravitrealCompletedAllegro Ophthalmics
Neuroprotection
Ciliary nerve trophic factor00447954IIIntravitrealCompletedNational Eye Institute
Brimonidine tartrate02087085IIBIntravitrealTerminatedAllergan
Gene therapy
AAVCAGsCD5903144999IIntravitrealCompletedHemera Biosciences
GT00503846193I/IISubretinalOngoing/recruitingGyroscope Therapeutics
Cell-based therapies
Palucorcel (CNTO-2476)01226628I/IISubretinalCompletedJanssen Research & Development, LLC
MA09-hRPE01344993I/IISubretinalCompletedAstelas Institute for Regenerative Medicine
CPCB-RPE102590692I/IIaSubretinalOngoing/not recruitingRegenerative Patch Technologies
Mitochondrial enhancers
Elamipretide03891875IISubcutaneousOngoing/recruitingStealth Biotechnologies, Inc.
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Cho, Y.-K.; Lee, S.-M.; Kang, Y.-J.; Kang, Y.-M.; Jeon, I.-C.; Park, D.-H. The Age-Related Macular Degeneration (AMD)-Preventing Mechanism of Natural Products. Processes 2022, 10, 678. https://doi.org/10.3390/pr10040678

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Cho Y-K, Lee S-M, Kang Y-J, Kang Y-M, Jeon I-C, Park D-H. The Age-Related Macular Degeneration (AMD)-Preventing Mechanism of Natural Products. Processes. 2022; 10(4):678. https://doi.org/10.3390/pr10040678

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Cho, Yeon-Kyoung, Seung-Min Lee, Yeong-Ji Kang, Yeong-Mo Kang, In-Chul Jeon, and Dae-Hun Park. 2022. "The Age-Related Macular Degeneration (AMD)-Preventing Mechanism of Natural Products" Processes 10, no. 4: 678. https://doi.org/10.3390/pr10040678

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