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Russo, C.; Rusciano, D.; Santangelo, R.; Malaguarnera, L.; Russo, C. Oxidative Stress Implications for Retinal Diseases. Encyclopedia. Available online: https://encyclopedia.pub/entry/55639 (accessed on 23 April 2024).
Russo C, Rusciano D, Santangelo R, Malaguarnera L, Russo C. Oxidative Stress Implications for Retinal Diseases. Encyclopedia. Available at: https://encyclopedia.pub/entry/55639. Accessed April 23, 2024.
Russo, Cristina, Dario Rusciano, Rosa Santangelo, Lucia Malaguarnera, Cristina Russo. "Oxidative Stress Implications for Retinal Diseases" Encyclopedia, https://encyclopedia.pub/entry/55639 (accessed April 23, 2024).
Russo, C., Rusciano, D., Santangelo, R., Malaguarnera, L., & Russo, C. (2024, February 28). Oxidative Stress Implications for Retinal Diseases. In Encyclopedia. https://encyclopedia.pub/entry/55639
Russo, Cristina, et al. "Oxidative Stress Implications for Retinal Diseases." Encyclopedia. Web. 28 February, 2024.
Oxidative Stress Implications for Retinal Diseases
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Oxidative stress plays a significant role in the pathogenesis of various retinal diseases, including diabetic retinopathy (DR), age-related macular degeneration (AMD), glaucoma, and retinopathy of prematurity (ROP).

retinopathies oxidative stress eye drops lipid nanoparticles alkylation

1. Introduction

The eye’s structure interfaces with the external milieu, rendering it susceptible to environmental and metabolic oxidative stress due to the continuous generation of free radicals. This exposure may lead to structural and functional alterations, giving rise to conditions such as glaucoma, macular degeneration, diabetic retinopathy, dry eye disease, and retinal dystrophies [1][2]. Mitochondria serve as the primary generators of intracellular oxidants, alongside other sources such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidases. However, the capability for intracellular reactive oxygen species (ROS) production extends beyond mitochondria; other cellular organelles, including peroxisomes and the endoplasmic reticulum, also contribute to this process. Additionally, enzymes such as xanthine oxidase, nitric oxide synthase (NOX), cyclooxygenases, and lipoxygenases play a role in intracellular ROS production. ROS and reactive nitrogen species (RNS) primarily affect cellular structures such as proteins, lipids, and deoxyribonucleic acid (DNA), resulting in damage at various cellular levels. Despite this potentially harmful activity, basal levels of ROS are crucial for certain cellular functions, including signal transduction pathways, gene expression, defense against bacterial invasion, and cellular growth or death. Endogen protective agents against ROS are released in the body, such as glutathione peroxidase, superoxide dismutase, or non-enzymatic compounds such as vitamin D, vitamin E, glutathione (GSH), and nicotinamide.
Dysregulation of antioxidant protection is associated with aging and may contribute to the development of most pathological conditions. Within the field of ophthalmology, various studies have reported that, under specific conditions, free radicals may induce chronic inflammatory reactions, altering the physiology of the eye and the visual system [3]. Specifically, ROS can regulate the activity of the transcription factor NF-kB, leading to the upregulation of pro-inflammatory cytokines such as IL-1, IL-6, and TNF-α. Furthermore, the formation of ROS resulting from impaired mitochondria can activate the NOD-like receptor protein 3 (NLRP3) inflammasome, subsequently triggering the release of inflammatory cytokines such as IL-1β and IL-18 [4].
Certain phytochemical compounds, known for their anti-inflammatory and antioxidant properties, such as resveratrol, curcumin, and vitamin D, can be utilized in the prevention or treatment of diseases associated with oxidative stress [5][6][7].
Numerous clinical studies have explored the potential of oral treatment with food supplements to alleviate oxidative eye diseases, indicating the role of specific nutrients in preventing or slowing their progression. The Age-Related Eye Disease Study (AREDS) and AREDS-2 investigated the effects of nutritional supplements on age-related macular degeneration (AMD), a major cause of vision loss in older adults. AREDS demonstrated that a combination of antioxidant vitamins (C and E) and zinc reduced AMD progression and vision loss by about 25% [8]. AREDS-2 found that lutein and zeaxanthin were beneficial, especially for individuals in advanced stages and/or with low dietary intake [9]. Separate studies emphasized the protective roles of lutein, zeaxanthin, and omega-3 fatty acids in retinal health. In aging retinal tissue, a decline in natural antioxidant capacity, specifically a reduction in macular xanthophylls like lutein, zeaxanthin, and mesozeaxanthin, plays a significant role in AMD progression. Considering this, incorporating carotenoid phytochemicals as supplementary therapy in AMD treatment seems reasonable, offering neuroprotection and positive impacts at various AMD stages, including advanced AMD [10]. Omega-3 fatty acids, primarily found in fatty fish, may also protect retinal cells from damage. Associations of xanthophylls and omega-3 have shown benefits in preventing AMD progression and visual function deterioration [11]. Most recently, a newly discovered class of naturally occurring lipid mediators derived from omega-3 very-long-chain polyunsaturated fatty acids (VLC-PUFAs) has been described. Elovanoids (ELVs) play a crucial role in maintaining cellular homeostasis and protecting cells from oxidative stress and damage. More specifically, the mechanism by which ELV-N34 protects neuronal cells from oxidative damage has been found to occur through the inhibition of the thioredoxin enzyme TXNRD1 [12].
Vitamins C and E, with strong antioxidant potential, play a crucial role in protecting cells from oxidative damage. Although individual studies on vitamin C and E supplementation for AMD have yielded mixed results, other studies suggest that a combination of these antioxidants may be beneficial [13]. Several other studies have investigated antioxidant food supplements’ potential to improve vision and slow the progression of diabetic retinopathy in people with diabetes or in patients with glaucoma [14]. The finding that oxidative stress biomarkers may improve after treatment with antioxidants has furthered interest in the clinical application of such treatments.
More recently, attention has shifted toward the specific mechanisms exerted by some specific anti-inflammatory and antioxidant compounds such as melatonin, N-acetyl-cysteine (NAC), edaravone, idebenone, and epigallocatechin-3-gallate (EGCG) (see Graphical abstract).

2. Oxidative Stress Implications for Retinal Diseases

Oxidative stress plays a significant role in the pathogenesis of various retinal diseases, including diabetic retinopathy (DR), age-related macular degeneration (AMD), glaucoma, and retinopathy of prematurity (ROP). Disruption of mitochondria in photoreceptors and nerves may contribute to the development of such retinal diseases and optic neuropathies. The retina, a crucial structure that generates the optic nerve, receives focused light from the lens, converts it into neural signals, and, finally, reaches the brain occipital cortex for visual recognition. The retina contains two main structures: the neuroretina and the retinal pigmented epithelium. At the center of the retina lies the macula, which is responsible for central vision [15]. The high metabolic activity in the macula exposes it to elevated levels of ROS, generated by the process of vision [16]. The constant exposure of the retina to environmental light, which also contains high-energy UV rays, further contributes to ROS formation [17]. Cumulative and permanent damage caused by electromagnetic radiation impinging on the eye can affect not only the retina but also other ocular tissues such as the cornea, lens, and iris. Such chronic oxidative damage may contribute to the development of various eye pathologies. Vingolo et al. underscored the role of oxidative stress in the progression of ROP due to photoreceptor cell degeneration and dysfunction of the retinal pigmented epithelium [18]. Oxidative stress also induces inflammation of retinal pigmented epithelial (RPE) cells, autophagic cell death, and apoptosis, which are associated with AMD and DR [19][20]. In AMD, oxidative damage to the retinal pigment epithelium (RPE) and photoreceptor cells is a key factor in disease progression. Several studies have underscored the impact of oxidative stress on AMD development and the intricate interplay between genetic susceptibility and environmental factors. Oxidative stress has been shown to be a major contributor to photochemical retinal injury, with antioxidant vitamins A, C, and E showing protective effects against such injury. The formation of lipofuscin, thought to arise from oxidatively damaged photoreceptor outer segments, is associated with retinal damage. While the relationship between dietary and serum levels of antioxidant vitamins and age-related macular disease remains somewhat unclear, the protective role of high plasma concentrations of alpha-tocopherol has been convincingly demonstrated. Macular pigment, which absorbs blue light and may quench reactive oxygen intermediates, is also believed to mitigate retinal oxidative damage [21]. Similarly, in DR, chronic hyperglycemia induces oxidative stress, leading to inflammation, vascular dysfunction, and neuronal damage in the retina. Brownlee’s work has extensively explored the molecular mechanisms linking hyperglycemia, oxidative stress, and diabetic complications, emphasizing the role of advanced glycation end-products (AGEs) and the polyol pathway [22]. Understanding these molecular pathways is essential for the development of targeted therapies aimed at mitigating oxidative stress and preventing the progression of AMD and DR. Of course, oxidative stress is not the sole culprit in eye pathologies. Therefore, antioxidants are, at best, expected to attenuate or delay the progression of such pathologies but do not constitute a cure.
However, the death of photoreceptor cells leads to a progressive decrease in their number, thus resulting in a reduced oxygen demand in the inner retina (since the retinal circulation is not regulated) and toxic hyperoxia in the external retina [23]. In primary open-angle glaucoma (the prevalent form of adulthood glaucoma), the increased intraocular pressure (IOP) and/or microvascular dysfunctions increase oxidative stress and activate inflammatory pathways, finally triggering retinal ganglion cell (RGC) apoptosis through the Bax/caspase-9 pathway [24]. Elevated IOP can activate microglia to release inflammatory cytokines, including interleukins IL1β, IL-6, and TNF-α, leading to nitric oxide (NO) and ROS production [25]. In the central nervous system, activated microglia can damage RGCs [26]. Moreover, ROS may modulate the immune response [27] and alter RGC pathways, adversely affecting their health and promoting neuroinflammation.
Oxidative stress also plays a significant role in the main hereditary retinal dystrophies, such as retinitis pigmentosa (RP), Leber hereditary optic neuropathy (LHON), and Stargardt disease (SD).
Retinitis pigmentosa encompasses a cluster of related retinal disorders characterized by a gradual and progressive loss of vision [28]. In individuals with RP, vision loss unfolds as the light-sensing cells within the retina undergo a gradual deterioration. The symptoms of RP primarily revolve around vision loss. Initially, there is a diminished ability to see in low-light conditions, primarily observed during childhood. Challenges with night vision can impede navigation in low-light settings. As the condition advances, blind spots emerge in the peripheral vision, eventually converging to create tunnel vision. Over the course of years or decades, central vision, crucial for tasks such as reading, driving, and recognizing faces, also succumbs to the disease. In adulthood, many individuals with RP ultimately reach a state of legal blindness. Oxidative stress is considered a significant contributor to the pathogenesis and progression of RP [18][29]. Several mechanisms link oxidative stress to the degeneration of photoreceptor cells in RP. Photoreceptor cells have high metabolic activity, and this leads to an increased production of ROS as byproducts. The excessive generation of ROS can overwhelm the cellular antioxidant defense mechanisms, leading to oxidative stress. Mutations in genes associated with RP can disrupt the balance between oxidants and antioxidants in the retina. For example, mutations affecting the function of antioxidant enzymes or proteins involved in the cellular defense against oxidative stress can compromise the retina’s ability to neutralize ROS. Some forms of RP are associated with mitochondrial dysfunction, leading to an increased production of ROS within mitochondria. Mitochondrial dysfunction and the resulting oxidative stress contribute to the degeneration of photoreceptor cells. Oxidative stress can trigger inflammatory responses and apoptotic cell death in the retina [30]. In RP, the death of photoreceptor cells is often mediated by apoptosis, and oxidative stress is implicated in initiating and amplifying these apoptotic pathways [31]. Oxidative stress can lead to the peroxidation of lipids in cell membranes. In RP, this can affect the integrity of photoreceptor cell membranes, leading to structural damage and cell death. Understanding the interplay between genetic factors and oxidative stress in RP is crucial for developing therapeutic strategies. Some research efforts focus on antioxidants and neuroprotective agents to mitigate oxidative damage and slow down the progression of RP [32]. Additionally, gene therapies aimed at correcting specific genetic mutations associated with RP are being explored as potential treatments [33]. Overall, addressing oxidative stress is a promising avenue for developing interventions to preserve vision in individuals with RP [34].
Leber hereditary optic neuropathy (LHON) is an inherited vision loss disorder with a typical onset during the teenage years or early twenties, with occasional cases emerging in childhood or later adulthood. Notably, males are more frequently affected than females, and the reasons for this gender discrepancy are unknown [35]. LHON initially presents with blurred and cloudy vision, affecting one or both eyes. If one eye is affected initially, the other typically succumbs within weeks or months. Over time, there is a progressive decline in visual acuity and color perception in both eyes, predominantly impacting central vision, which is crucial for tasks such as reading and driving. Vision loss results from the death of optic nerve cells responsible for transmitting visual information to the brain. While central vision may gradually improve in a small percentage of cases, for most, the vision loss is severe and irreversible. LHON is triggered by mutations in the MT-ND1, MT-ND4, MT-ND4L, or MT-ND6 genes within mitochondrial DNA (mtDNA), which is distinct from nuclear DNA. These genes guide the production of proteins essential for mitochondrial function that are involved in converting oxygen, fats, and sugars into energy. Mutations disrupt this process, causing optic nerve cell death and LHON features [36]. The exact mechanisms behind how these genetic changes induce LHON symptoms remain unclear. Interestingly, a significant percentage of individuals with LHON-associated mutations may remain asymptomatic. More than 50 percent of males and over 85 percent of females with a mutation may not experience vision loss or related health issues. Environmental factors such as smoking and alcohol use are under investigation, with conflicting study results. Researchers are also exploring the role of additional gene changes in LHON symptom development.
Since oxidative stress is among the main culprits of LHON, antioxidant treatments have been used to fight disease progression [37]. Clinically, oral treatment with the antioxidant idebenone is the main approach to delaying disease progression [38]. Indeed, Raxone® was approved by the FDA as an oral treatment for LHON [39].
Stargardt macular dystrophy (STGD) is an inherited eye disorder characterized by a gradual loss of vision [40]. This prevalent form of juvenile macular degeneration typically manifests its signs and symptoms from late childhood to early adulthood, progressing over time. The prevalence of STGD is estimated to be around 1 in 9,000 individuals. The condition specifically impacts the macula, where the fatty yellow pigment called lipofuscin accumulates in the retinal pigment epithelium (RPE) cells. Due to impaired recycling and disposal mechanisms, lipofuscin accumulates with toxic effects, damaging rod and cone photoreceptors in an area crucial for clear vision. Over time, this abnormal buildup results in issues such as impaired night vision, making it challenging to navigate in low light. Some individuals also experience difficulties with color vision. The primary cause of Stargardt macular degeneration is often attributed to variants or mutations in the ABCA4 gene, which is responsible for producing a protein involved in transporting potentially harmful substances out of light-sensing cells (photoreceptors) in the retina. Variants in the ABCA4 gene hinder the protein’s ability to remove toxic byproducts, resulting in the accumulation of lipofuscin and subsequent cell death in the retina, leading to progressive vision loss [41]. Photo-oxidative damage to RPE and photoreceptors may derive from the buildup of a substance known as A2E within RPE cells, formed through the condensation of phosphatidylethanolamine (PE) and the all-trans-retinal released from photoactivated rhodopsin [42]. A2E, acting as a photosensitizer, generates reactive singlet oxygen and undergoes photo-oxidation, leading to retinal damage and apoptosis in photoreceptor and RPE cells. The resulting photo-oxidation products of A2E activate the complement system, causing inflammation and DNA damage in RPE cells. A2E, along with its photo-oxidized products, including methylglyoxal, disrupts mitochondrial dynamics and function, ultimately inducing apoptosis in RPE cells. Photosensitization of A2E expedites the production of inflammatory cytokines, contributing to DNA damage, telomere deletion, and triggering RPE senescence. Furthermore, the photo-oxidation of bisretinoids such as A2E enhances lipid peroxidation and upregulates the expression of oxidative stress and complement activation genes, concurrently downregulating protective complement regulatory proteins [43]. Therefore, antioxidant treatment with xanthophylls such as lutein and zeaxanthin, which are naturally present in the macula, and with other exogenous antioxidants might also play a role in STGD, attenuating the symptoms and the progression of the pathology. In fact, a clinical study in which patients were orally treated with the antioxidant saffron showed a stabilization of the disease over the 6 months of treatment, while placebo-controlled patients showed further progression [44]. Moreover, the presence of melanin, also endowed with antioxidant potential, in RPE cells may contribute to the endogenous free radical scavenging activity of this tissue, contrasting the insurgence and progression of STGD [45].
To date, there are two possible ways to fight these hereditary retinal dystrophies. The first, more challenging but with great expectations, is gene therapy, aiming at the correction of the genetic mutations that cause the pathology [46]. The second, easier in its application, already practiced and under continuous evaluation, is based on the treatment with antioxidants [47].
Antioxidant treatments are usually given by the oral systemic route. For instance, the only approved antioxidant treatment for LHON (Raxone®) is taken by the oral route. Similarly, nutraceutical treatment of RP (NUTRARET: see above) occurs through the oral route. Given the fact that the eye remains peripheral to the systemic circulation and represents only a small part of the body, high doses are necessary in order to reach an effective concentration within the eye and at the retinal level. Moreover, the blood–retinal barrier may limit the types of molecules that can reach the retina. Topical treatment would be much better, bringing the treatment in close proximity to the retina. However, eye injections can be used for treatments given at an interval of months; otherwise, they become too risky for the health of the eye. The other option is topical treatment with eye drops. In this case, the major obstacle is the epithelial barrier of the cornea and conjunctiva, which limits the number of molecules able to cross it and progress all the way to the retina. Appropriate formulations are required in order to enhance delivery through the epithelial barriers [48][49].

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