Neuroprotection provided by polyphenols and flavonoids in photoreceptor degenerative diseases

Abstract

The intricate landscape of neurodegenerative diseases complicates the search for effective therapeutic approaches. Photoreceptor degeneration, the common endpoint in various retinal diseases, including retinitis pigmentosa and age-related macular degeneration, leads to vision loss or blindness. While primary cell death is driven by genetic mutations, oxidative stress, and neuroinflammation, additional mechanisms contribute to disease progression. In retinitis pigmentosa, a multitude of genetic alterations can trigger the degeneration of photoreceptors, while other retinopathies, such as age-related macular degeneration, are initiated by combinations of environmental factors, such as diet, smoking, and hypertension, with genetic predispositions. Nutraceutical therapies, which blend the principles of nutrition and pharmaceuticals, aim to harness the health benefits of bioactive compounds for therapeutic applications. These compounds generally possess multi-target effects. Polyphenols and flavonoids, secondary plant metabolites abundant in plant-based foods, are known for their antioxidant, neuroprotective, and anti-inflammatory properties. This review focuses on the potential of polyphenols and flavonoids as nutraceuticals to treat neurodegenerative diseases such as retinitis pigmentosa. Furthermore, the importance of developing reliable delivery methods to enhance the bioavailability and therapeutic efficacy of these compounds will be discussed. By combining nutraceuticals with other emerging therapies, such as genetic and cell-based treatments, it is possible to offer a more comprehensive approach to treating retinal degenerative diseases. These advancements could lead to a viable and accessible option, improving the quality of life for patients with retinal diseases.

Introduction

Nutraceutical therapies (NUT) represent a field at the intersection of nutrition and pharmaceuticals, aiming to harness the health-promoting properties of bioactive compounds for therapeutic purposes, emphasizing the dual role of these substances in promoting health and preventing or treating diseases. NUT incorporates diverse compounds, including bioactive compounds such as vitamins, minerals, amino acids, antioxidants, free fatty acids, and phytochemicals in general, which exhibit bioactive properties beyond their nutritional value. The recent literature points out polyphenols as a prominent bioactive group of molecules (Kaleem and Ahmad, 2018; Piccolella et al., 2019).

These compounds, which are abundant micronutrients in our diet, play a crucial role in preventing diseases, with health-promoting effects to combat chronic and degenerative processes. The health effects of polyphenols (flavonoids, phenolic acids, lignins, and stilbenes), especially flavonoids, are contingent upon both the quantity consumed and their bioavailability (Piccolella et al., 2019). Flavonoids stand out as the most prevalent polyphenols within the human diet, being known to date approximately 10,000 variants. This extensive diversity arises from three types of substituents positioned differently within their molecular structures (Naróg and Sobkowiak, 2023). These compounds exhibit a C6–C3–C6 backbone structure and are categorized into several major classes: flavones, flavonols, flavanones, flavanonols, isoflavones, flavan-3-ols, anthocyanins, and chalcones. Widely distributed across nearly all plant-based foods, flavonoids are particularly abundant in vegetables, fruits, teas, flowers, and seeds (Shen et al., 2022).

These molecules are associated with numerous bioactive properties, such as anticancer, anti-diabetic, antibacterial, antiparasitic, antiviral, anti-aging, immunomodulatory, anti-inflammatory, immunobalance, neuroprotective, and antioxidant properties. Notably, the primary activity of flavonoids is their antioxidant capability, which helps prevent damage caused by free radicals by scavenging free reactive oxygen species (ROS). This property stands out as one of most extensively studied aspects of flavonoid activity (Dias et al., 2021; Naróg and Sobkowiak, 2023; Ferreira et al., 2024). The primary challenge in exploring the therapeutic potential of flavonoids lies in their poor solubility in water and low bioavailability, often hindered by a slow absorption rate and rapid metabolism – as addressed later in this review. This limitation is attributed to the structural characteristics of flavonoids, which can be countered by chemical modifications, nanoparticles, and other mechanisms discussed in this review (Koirala et al., 2016; Carullo et al., 2020).

Based on meta-analysis tracking trends from 2003 to 2023, we investigated several terms (Figure 1A–D). The correlation between health-related terms shows an increasing number of links and higher weighting, indicating a growing number of articles emphasizing two terms (Figure 1C). This is evidenced by the increase in the number of triangles in the graphs over time, which means a greater interaction between the terms, as well as the density of the graph (the ratio between the edges and the maximum number of edges that the graph can contain), which jumped from 0.68 in 2003 to 0.97 in 2023 (Figure 1B). Still, it is possible to note a gradual decrease in the average path length over the years, indicating that the terms are increasingly closer to each other, reflecting their more significant mutual influence on each other (Figure 1C).

Figure 1.

Trend over time and meta-analysis combining several terms.

(A) Graphs representing the correlation between terms by their weighted degree, showing a higher correlation as time goes by. (B) Regression line of the total number of triangles and the density per year (2003–2023). (C) Regression line of the average path length and the weighted average grade per year (2003–2023). (D) Line graphs show the timeline of publications (number per year), from PubMed.com, using the keyword “flavonoids” (updated to 2023) - with coefficient R² indicated in the graphs. Created with BioRender.com. AD: Alzheimer’s disease; ALS: amyotrophic lateral sclerosis; AMD: age-related macular degeneration; HD: Huntington’s disease; NUT: nutraceutical therapy; PD: Parkinson’s disease; ROS: reactive species of oxygen; RP: retinitis pigmentosa.

Notably, there has been growing interest in flavonoids, NUTs, and polyphenols from 2003 to 2023, evidenced by the increased connections with terms such as neuroprotective, diseases, and anti-inflammatory (Figure 1A). These terms increase their weighted degree in the 10 years studied, indicating their growing influence in disease treatment. Over the past two decades, there has been an increased interest in flavonoids, supported by a rising number of published papers (Figure 1D). Economically, NUTs have also expanded significantly, with a projected increase in market size (Ashfaq et al., 2023).

Polyphenols and flavonoids have recently demonstrated remarkable outcomes in the treatment of developmental and age-related diseases, including chronic diseases, Alzheimer’s disease (AD), Parkinson’s disease (Abdul-Latif et al., 2021; Prajapati et al., 2021; Calderaro et al., 2022; Minocha et al., 2022; Bovi Dos Santos et al., 2024; Ferreira et al., 2024; Wu et al., 2024), and enhancing cognition (Gómez-Pinilla, 2008; Brickman et al., 2014). Surprisingly, studies in humans demonstrated that the dietary intake of flavonoids contributes to a delay in the biological aging process, particularly in organs such as the heart and liver (Xing et al., 2023). Also, dietary intake of flavonoids was positively associated with lower mortality risk, AD, and age-related macular degeneration (AMD) development (Kim et al., 2017; Gopinath et al., 2018; Zong et al., 2024). In mouse models, the increased lifespan was demonstrated to be associated with the mechanism of ameliorating cellular senescence (Xu et al., 2021; Wang et al., 2022c). Besides these important effects, polyphenols also regulate epigenetic factors, like histone modifications such as methylation (Wu et al., 2022).

Connected to these findings, the modern human diet has shifted towards increased consumption of ultra-processed foods and additives, potentially resulting in a diminished supply of nutrients and micronutrients. This, coupled with a reduced intake of fruits and vegetables, may contribute to a higher susceptibility to diseases and neurodegeneration, once a healthy diet is crucial for the prevention of several diseases (Aidoo et al., 2023; Nagata et al., 2024; Zhang et al., 2023c; Dong et al., 2024; Whelan et al., 2024). Additionally, a cross-sectional study indicates that the elderly tend to have lower food intake, resulting in a reduced consumption of flavonoids (Zujko et al., 2015). This could be associated with the increasing prevalence of neurodegenerative diseases, considering both improved diagnosis and lifespan due to advancements in science (Hepsomali and Groeger, 2021). These collective findings underscore the practical significance for public health, as flavonoids can be supplemented through simple daily dietary modifications and improvements in eating habits. These substances may be employed as therapeutic agents or used as prophylactic strategies for neurodegenerative diseases.

Nevertheless, the potential applications of flavonoids in addressing retinal degeneration, particularly concerning photoreceptor cells (PR), are still undervalued. The demise of PR in blinding diseases is a complex and multifaceted process, varying significantly across different conditions. While the underlying causes differ, common mechanisms contribute to PR loss in many retinopathies and blinding diseases, including retinitis pigmentosa (RP), AMD, and certain forms of inherited retinal dystrophies (committing 1 to 3000 worldwide) (Wright et al., 2010; Broadgate et al., 2017). Genetic mutations, inflammatory responses, vascular dysfunctions, oxidative stress, and several other pathophysiological processes contribute to the intricate landscape of retinal degeneration (Olivares-González et al., 2021b; Ortega et al., 2021).

Retinal dystrophies present a progressive and severe loss of vision that can be widespread to the whole visual field or concentrated in its center (Provis et al., 2005; Wright et al., 2010), leading to legal blindness. The blinding diseases are considered a significant public health problem (Broadgate et al., 2017; DeAngelis et al., 2017; Retina International, 2025), and the lack of efficient treatments, especially for RP, leads to a sense of hopelessness in those patients. Therefore, treatments that focus on these processes or aim at stabilizing PR during disease progression hold promise for positively impacting the visual lifespan of patients. Fortunately, polyphenols emerge as potential strategies for therapies aiming at PR degeneration, especially cursing with the oxidative stress present in retinal dystrophies (Tao et al., 2016a; Jing et al., 2023; Yan et al., 2023), in which the use of vitamins and oxidants has been proposed as treatments (DeAngelis et al., 2017).

RP is the most prevalent subtype of retinal dystrophy (Chiang and Trzupek, 2015; Bravo-Gil et al., 2017; Costa et al., 2017). It is characterized by a diverse range of mutations exhibiting significant heterogeneity, stemming from a variety of genetic alterations linked to both syndromic and non-syndromic (autosomal recessive, dominant, and X-linked) forms of the condition. In this disease, the patient initially loses peripheral vision due to rod cell loss and gradually affects the central vision by secondary cone cell death. The clinical symptoms are related to photoreceptor and/or retinal pigment epithelium (RPE) misfunction (Daiger et al., 2013; Xu et al., 2014; Costa et al., 2017).

With estimated incidence in 1 to 3500–5000 individuals (Xu et al., 2014; Bravo-Gil et al., 2017; Costa et al., 2017) varying according to the racial group (Okonkwo et al., 2023), RP progression varies depending on the associated mutation. Although the prevalence of the disease may differ depending on the study, it is estimated that non-syndromic RP cases are linked to autosomal dominant (30%–40%), followed by X-linked (5%–15%) and autosomal recessive (50%–60%) mutation. Syndromic RP represents 20%–30% of the cases (Verbakel et al., 2018; Cortinhal et al., 2024). More rarely, RP can be exhibited as spontaneous/simplex RP cases (Bravo-Gil et al., 2017). Approximately 60 genes are involved in the RP (Broadgate et al., 2017), and the majority are associated with phototransduction, visual processes, or related pathways (Xu et al., 2014).

The RP progression is directly influenced by the type of gene and mutation involved in the clinical presentation. Among the mutations associated with RP, some result in loss-of-function (e.g., RHO, PDE6A, PDE6B, among others), leading to impaired protein activity and progressive degeneration, while others create a toxic cellular environment (e.g., RHO [autosomal dominant mutation], PRPF31, RP1, among others), accelerating photoreceptor death. Furthermore, most cases of autosomal dominant RP tend to progress more slowly, as cone photoreceptors may remain functional for a longer period. In contrast, autosomal recessive forms are typically more aggressive, often leading to earlier and more severe retinal degeneration (Jauregui et al., 2019; O’Neal et al., 2024). Regardless of the type of mutation, the first insult of cell death due to the rods creates an imbalance in retinal homeostasis, which could lead to the death of the secondary photoreceptor. Although the secondary deaths are mainly related to cones, some rods die due to the secondary death.

However, cone cell death may occur via distinct mechanisms from those affecting rods, due in part to differences in genetic factors and the unique functions of phototransduction (Campochiaro and Mir, 2018). In a very characteristic way, cone cells usually die after most rods have already degenerated. This may occur once the rod death leads to an increase of toxic substances and activates microglia and Müller cells, which in turn increases the phagocytosis of other photoreceptor cells. On the other hand, the relationship between oxidative stress and cone cell death is robust, with several reports linking the decrease in oxidant species with cone survival (Campochiaro and Mir, 2018; Brunet et al., 2022; Cantó et al., 2022; Vingolo et al., 2022; Kanan et al., 2023).

In contrast, AMD also leads to photoreceptor loss but differs significantly in its etiology and clinical presentation. Unlike RP, whose onset is predominantly driven by inherited genetic mutations affecting phototransduction, AMD is largely influenced by environmental factors, such as body fat, smoking, sedentary lifestyle, diet, and hypertension (Lambert et al., 2016; Pennington and DeAngelis, 2016a). Moreover, CFH and CETP mutations were related to AMD risk (Buschini et al., 2015; DeAngelis et al., 2017). AMD is a known cause of the major age-blinding disease, affecting approximately 1 in 30 individuals as they age (Pennington and DeAngelis, 2016a; Hanna et al., 2022). For example, it is estimated that AMD affects 6.5% of people older than 45 years (Klein et al., 2011), and 1 in 3 people over 85 years old, as cited in (Broadgate et al., 2017). As age is the major risk factor, and considering that life expectancy has been increasing and is projected to rise even further, the 170 million people diagnosed nowadays with IRDs tend to increase to nearly 300 million by 2040 (Wong et al., 2014; Pennington and DeAngelis, 2016a).

AMD typically presents with central vision loss due to drusen formation in the macula, reduced visual acuity, and abnormal color vision (Buschini et al., 2015; Broadgate et al., 2017). Although AMD affects the RPE and often follows a different pathological cascade compared to RP, oxidative stress remains a critical component in both diseases. In AMD, oxidative damage to the RPE and photoreceptors is a key driver of pathology, and therapeutic strategies have focused on antioxidants, anti-vascular endothelial growth factor (VEGF) treatments (for wet AMD), and lifestyle modifications to mitigate these effects (Buschini et al., 2015; Pennington and DeAngelis, 2016b). Besides these environmental and genetic factors, Buschini et al. (2015) extensively reviewed the strategies for AMD management, focusing on reducing inflammation, drusen formation, oxidative stress, and other pathological processes.

Focusing on RP, it is clear that while both RP and AMD share aspects of oxidative stress and inflammation, the primary pathology in RP is rooted in inherited mutations that disrupt photoreceptor function and survival. This leads to a characteristic pattern where rod loss precedes and likely precipitates cone degeneration through toxic byproduct accumulation and glial activation. In contrast, the progression of AMD, driven largely by environmental and metabolic factors, culminates in the loss of central vision through distinct mechanisms involving RPE dysfunction. By emphasizing the unique genetic underpinnings and sequential photoreceptor loss in RP, our work aims to deepen the understanding of the mechanisms underlying PR cell loss. At the same time, insights from AMD research, particularly regarding oxidative stress and inflammation, offer valuable comparative perspectives that could help refine intervention strategies for both conditions.

In contrast to AMD, RP still does not have a consistent therapy for all the patients, only for a small group of people, being Luxturna® the sole FDA-approved treatment, employing genetic therapy focused on the RPE65 mutation. This reinforces the need for treatments that are economically accessible and capable of benefiting a broader group of patients, thereby enhancing life quality and extending vision lifespan across mutations. One such therapy that might be able to accomplish this goal could be NUT based on polyphenols. Several clinical trials have been engaged in NUT, but primarily used for retinopathies like glaucoma, diabetic retinopathy, and AMD (Additional Tables 1–4). Still, there are few NUT clinical trials in progress or evaluating the efficacy of this therapy for RP, none of these employ polyphenols as NUT strategy.

Additional Table 1.

Clinical trials based on dietary supplements or nutraceutical therapy for AMD

Clinical data ID	Compounds	Methods	Results	Years
NCT00060749	DHA	Daily oral supplementation for three months (2000 mg/day). Group 1: 20 mg lutein, 2 mg zeaxanthin, 510 mg omega-3-FA;	No perceived effect of DHA supplementation on macular function.	2003
NCT00763659	Combination of lutein/zeaxanthin and omega-3- fatty acids	Group 2: 10 mg lutein, 1mg zeaxanthin, 255 mg Omega-3-FA; both daily oral supplementation about one year.	Increase in of the macular pigment optical density, improvement and stabilization of best-corrected visual acuity test.	2008
NCT00951288	Saffron (Crocus Sativus extract)	Daily oral supplementation for three months 20 mg/day.	Improved focal electroretinograms amplitude and threshold, improving retinal flicker sensitivity in early AMD.	2009
NCT01042860	Lutein	Daily oral supplementation for twelve months 10 mg/day.	Increase of macular pigment optical density levels in early-stage AMD patients.	2010
NCT01258335	Omega-3-fatty acids	Omega-3 fatty acids 4 g orally daily.	No measurable changes in visual acuity or retinal function by multifocal electroretinographic testing.	2010
NCT01404845	Lutein and zeaxanthin	2 capsules per day, for 8 months (5 mg lutein + 1 mg zeaxanthin / capsule).	Finished, no results published.	2011
NCT01316198	Lutein and zeaxanthin	4 weeks of supplementation with a beverage containing 10 mg lutein and 3 mg zeaxanthin per day.	The concentrations of the xanthophylls in plasma and the MPOD increased significantly in the kale group after 4 weeks of intervention. Nevertheless, the improvements did not persist over 4 weeks of washout.	2011
NCT04756310	Retilut and theavit	Two capsules/day before breakfast each day for 2 years.	Reduction of inflammatory cytokines and improved the fatty acid profile and serum lutein concentration.	2014
NCT02264938	Lutein (12 mg), zeaxanthin (2 mg), astaxanthin (8 mg), omega-3 fatty acids (DHA 540 mg + EPA 360mg), vitamin C (40 mg), vitamin E (20 mg), zinc (16 mg), copper (2 mg)	Daily oral supplementation with antioxidants for 1 year.	Antioxidant vitamin and mineral supplementation (AREDS: vitamin C, E, beta-carotene, and zinc) probably slows down progression to late AMD	2014
NCT02625376	Trans-resveratrol	Group 1: Dietary supplementation with resveratrol 250 mg BD 2 capsules daily. Group 2 (active comparator): Dietary supplementation with Resvega BD, two capsules daily: one in the morning and evening for 24 months.	Results not published.	2015
NCT03919019	Macuprev (Ganoderma lucidum (Reishi), calendula officinalis, lutepure-marigold (5% lutein and 1% zeaxanthin), blueberry, rutin, alpha-lipoic acid, bromelain, NAC, vitamin C, B9, B12, D3, selenium, zinc and copper)	Oral supplementation (Macuprev) 2 capsules per day for 6 months.	Intermediate AMD, Macuprev® supplementation increases the function of the macular pre-ganglionic elements.	2018
NCT03946085	Lumega-Z carotenoid liquid-supplement and AREDS2	Experimental group (LM): carotenoid supplementation Lumega-Z for 6 months Active Comparator (PV): AREDS2 for 6 months	Benefits in visual performance in the LM group.	2019
NCT05062486	Resveratrol, quercetin, curcumin	Daily oral intake of 100 mg resveratrol, 120 mg quercetin, 1000 mg curcumin, for 24 months.	Unknown status, no results published.	2021
NCT05005884	Oral phenolics	Oral phenolics 250 mg two times daily for 1 month.	Unknown status, no results published.	2021
NCT06391411	Mix containing lutein (10 mg), zeaxanthin (2 mg), saffron (20 mg), vitamin C (80 mg), vitamin E (12 mg) and zinc (10 mg).	Intravitreal injections of anti-VEGF (aflibercept 2 mg, 0.05 mL) at a fixed regimen and daily supplementation with a micronutrient mix containing lutein (10 mg), zeaxanthin (2 mg), saffron (20 mg), vitamin C (80 mg), vitamin E (12 mg) and zinc (10 mg) for 6 months.	In progress, no results.	2024

Additional Table 4.

Clinical trials based on dietary supplements or nutraceutical therapy for RP

Clinical data ID	Compounds	Methods	Results	Years
NCT00000116	Docosahexaenoic acid + vitamin A.	Daily oral administration of 1200 mg/d docosahexaenoic acid and 15000 IU/d vitamin A as retinyl palmitate, for 5 years.	No effect in the course of disease in patients with retinitis pigmentosa.	1999
NCT00346333	Lutein	Daily oral administration of 12 mg of Lutein plus 15,000 IU/d of Vitamin A palmitate, over a 4-year interval.	Slower loss of midperipheral visual field on average among nonsmoking adults with retinitis pigmentosa taking vitamin A.	2006
NCT01256697	9-cis rich powder of the alga dunaliella bardawil.	Daily oral administration of capsules containing 300 mg of 9-cis β-carotene-ich alga dunaliella bardawil or placebo (starch) for 90 days - 90 day washout period - Other capsule administration for more 90 days.	Increased retinal function in patients with RP.	2010
NCT01680510	Alga dunaliella bardawil	Daily oral administration of capsules containing alga dunaliella bardawil 9-cis beta-carotene rich powder for 24 weeks followed by a washout period with placebo capsules.	Active, not recruiting	2012
NCT02018692	9-cis-beta caroten rich D. Brdawiil extract (food supplement made from alga dunaliella bardawil).	Daily oral supplementation for 24 weeks (5 mg/kg).	Not yet recruiting, last updated post in 2024.	2013
NCT02244996	Lycium barbarum (also known as "Goji berry").	Daily oral supplementation for twelve months (10 g of granules).	Reduced thinning of the macular layer, no significant differences in the sensitivity of the visual field or amplitude of the full- field electroretinogram.	2014

This review aims to comprehensively explore the potential therapeutic benefits of nutraceutical interventions, specifically focusing on polyphenols and flavonoids in the management of PR deterioration, focusing on RP and AMD intricate pathophysiology.

Search Strategy

A comprehensive literature search was conducted using PubMed and Google Scholar to identify relevant studies on nutraceutical approaches in retinal diseases. The keywords included: “retina,” “polyphenols,” “retinitis pigmentosa,” “nutraceutical,” “dietary compounds,” “retinal degeneration,” “flavonoids,” “neuroprotection,” and “natural compounds.” Additionally, the reference lists of selected studies were screened for relevant literature on research investigating the effects of flavonoids and other nutraceutical compounds on health and diseases of the central nervous system. The cited articles were all in English, with a preference for the most recent publications. However, key older references were included when necessary to trace the discovery and development of nutraceutical compounds. For the meta-analysis, the search covered publications ranging from 2003 to 2023, using PubMed exclusively for studies where the keywords appeared in the title/abstract. All terms used in the graphs were searched in combination to ensure a comprehensive analysis of the available data. Data on clinical trials were collected from ClinicalTrials.gov, using keyword combinations such as “dietary compounds,” “nutraceutical,” “supplementation,” “flavonoids,” and “polyphenols” and several retinopathies as seem in Additional Tables 1–4.

Pathophysiology of Photoreceptor Degeneration

Understanding the intricate pathophysiological mechanisms underlying PR death is crucial for identifying targeted therapeutic approaches. This holds particularly true for conditions such as RP and AMD, complex retinal disorders that majorly impact photoreceptors. Although each condition may have distinct causes, they exhibit common issues such as cellular stress, metabolic stress, oxidative stress, and extensive neuroinflammatory response. Regardless of the specific biological dysfunction associated with the mutated gene, the most common outcome is PR death by apoptosis – and triggering oxidative stress and proinflammatory responses. As discussed ahead, NUT based on polyphenols and flavonoids might be a valuable therapy for RP.

Pathways of photoreceptor cell death in retinitis pigmentosa

Focusing on the RP group of mutations and considering its multigenic factor, the pathogenesis may vary between patients; however, certain aspects of the pathophysiology remain consistent (Martin-Merida et al., 2019; Gallenga et al., 2021; Zhao et al., 2022). In RP with rod mutations in the PDE6B (Koyanagi et al., 2019; Kuehlewein et al., 2021) or rhodopsin genes (Ploier et al., 2016), the mechanisms involve dysregulated visual cycles, like phototransduction, and the altered catalytic function of the mutated PDE6B protein results in the accumulation of cyclic GMP. Consequently, the cyclic nucleotide-gated (CNG) channels are overactivated, causing a significant increase in intracellular calcium ions (Ca²⁺). Elevated calcium levels lead to two notable consequences: the initiation of apoptosis and the disruption of chromatin. These effects ultimately culminate in the loss of rod cells (see more in Gao et al., 2020; Li et al., 2023). Increased levels of cellular cGMP and the consequent upregulation of protein kinase G (PKG) signaling disrupt various cellular functions, affecting endoplasmic reticulum (ER) stress (Paquet-Durand et al., 2009; Xu et al., 2013), and ER Ca²⁺ homeostasis (Butler et al., 2017; Yang et al., 2021). This dysregulation also activates histone deacetylase (HDAC)/poly-ADP-ribose polymerase (PARP) signaling pathways, leading to DNA condensation/damage and eventual cell death (Sancho-Pelluz et al., 2010). Furthermore, heightened cGMP signaling and subsequent cellular Ca²⁺ overload initiate the calpain-associated cell death pathway. Additionally, ER stress, PARP signaling activation, and calpain signaling induce mitochondrial damage, triggering the release of the apoptosis-inducing factor and exacerbating the cell death process (Paquet-Durand et al., 2007; Comitato et al., 2020).

The ER is a crucial organelle responsible for protein biosynthesis, folding, and secreted proteins, as well as serving as a reservoir for free calcium ions. Maintaining ER homeostasis is vital for proper cellular function, and disruptions can trigger unfolded protein response and ER stress, leading to impaired protein processing, trafficking, and degradation (Chen et al., 2023). ER plays a pivotal role in cellular and ER Ca²⁺ homeostasis, regulated by IP3Rs, RyRs, and SERCA (Butler et al., 2017; Zhang et al., 2023a). In CNG channel-deficient mice, IP3Rs can change cGMP-dependent PKG activation, and disrupt ER Ca²⁺ homeostasis, resulting in increased expression/activity of IP3R1 and RyR2, exacerbating ER stress and photoreceptor death (Ma et al., 2015; Butler et al., 2017). Inhibition of PKG or depletion of cGMP restores ER Ca²⁺ balance and ameliorates ER stress-associated photoreceptor degeneration. Elevated PKG signaling, as observed in conditions like CNG channel deficiency in a model of ACHM (Cnga3^−/−), exacerbates ER stress and opsin mistrafficking (Sundaram et al., 2014; Ma et al., 2015; Butler et al., 2017).

Additionally, ER stress contributes to aberrant protein trafficking and activation of calpain-associated cell death pathways leading to cell death (Nakagawa et al., 2000; Haidara et al., 2008). Chemical or genetic inhibition of ER marks or ER Ca²⁺ efflux mitigates ER stress and improves protein trafficking (Hu et al., 2012; Butler et al., 2017; Chen et al., 2022c). High intracellular calcium levels prompt the activation of calpains, enzymes that cleave proenzymes into their active forms, targeting various cytoplasmic and nuclear substrates, such as caspase-3 and PARP. This activation initiates a cascade of events, including the release of apoptosis-inducing factor from mitochondria, and promoting apoptosis (Sanges et al., 2006; Vosler et al., 2009; Vu et al., 2022; Yan et al., 2022). Several polyphenols have been reported to impact ER/mitochondrial stress and cell death pathways (Ha et al., 2014; Bardak et al., 2017; Liu et al., 2018; Pawlowska et al., 2019). For instance, morin has been shown to ameliorate neuron cell loss and improve function in a Huntington’s disease rat model by affecting these pathways, also modulating IP3R (El-Emam et al., 2024). Additionally, the flavonoids baicalin and baicalein have been identified as inhibitors of guanylate cyclase, thereby reducing cGMP levels in rat aortic rings (Huang et al., 2004).

ER stress is highly observed in RHO mutations, the first mutated gene identified in RP (Dryja et al., 1990), and mutations in this gene are also related to congenital stationary night blindness (Zhou et al., 2012). Rhodopsin is a light-sensitive protein present in rod photoreceptors that plays a crucial role in phototransduction (Zhou et al., 2012). Under normal physiology, rhodopsin is synthesized in the photoreceptor’s ER and translocated to the outer segments of the photoreceptor to participate in the phototransduction process (Athanasiou et al., 2018). Seven distinct classes of RHO mutations have been observed, and the related cell death subtype might vary according to the mutation (Azam and Jastrzebska, 2025), which impacts both clinical presentation and rhodopsin cellular distribution (Lewin et al., 2014). The alterations observed in RHO lead to cellular defects related to incorrect protein folding, changes in posttranslational modifications, and mutations that prevent RHO dimerization – these alterations might affect RHO’s intracellular traffic, stability, and function (Zhou et al., 2012; Athanasiou et al., 2018; Azam and Jastrzebska, 2025). RHO alterations may lead to either autosomal dominant or autosomal recessive RP, associated with Rho gain-of-function and Rho loss-of-function mutations, respectively (Athanasiou et al., 2018). One of the most common RHO mutations is P23H, a prevalent form of adRP that results in a non-functional Rho monomer. The P23H mutation is characterized by a misfolded Rho protein that affects its function in phototransduction, contributing to rod photoreceptor dysfunction. P23H mutation leads to RHO retention in the ER, unfolded protein response activation, and subsequent rhodopsin degradation, activating several intracellular pathways such as oxidative stress, release of intracellular calcium and neuroinflammation (Athanasiou et al., 2018; Zhen et al., 2023).

In addition to gene alteration present in rod photoreceptors, RP can also be caused by alterations in genes within RPE cells, such as the RPE65, a retinoid isomerase. This is due to the RPE’s role in the visual cycle, as it is in these cells that retinal regeneration occurs after photoisomerization, which is crucial for photon capture and the regeneration of rhodopsin after phototransduction (Cai et al., 2009). RPE65 is essential in this process, and mutations in this protein can lead to both RP and Leber congenital amaurosis (Jauregui et al., 2018). Due to RPE65 function in retinal regeneration, any kinds of dysfunction interferes with retinal regeneration, affecting photoreceptor function, particularly rods (Pierrache et al., 2020). Interestingly, some studies suggest that the type of RPE65 mutation might affect the age of disease onset, with truncating mutations leading to earlier onset, while missense mutations are associated with later onset (Lopez-Rodriguez et al., 2021). However, others reported no relation between RPE65 genotype and phenotype (Chung et al., 2019; Aoun et al., 2021).

Pathways of photoreceptor cell death in age-related macular degeneration

AMD, encompassing early and intermediate stages, is characterized by the presence of medium or large drusen (protein, lipid, and minerals aggregates), respectively, and/or RPE anomalies (Belmouhand et al., 2022; Oncel et al., 2023). Patients in early or intermediate stages may develop either of the two late-stage forms of the disease: dry AMD or wet AMD, both resulting in photoreceptor death and vision loss (Davis et al., 2005; Ferris et al., 2013; Ruan, Jiang and Gericke, 2021).

The dry AMD is characterized by sharply demarcated atrophic lesions of photoreceptors and RPE cells (Sadda et al., 2016; Holz et al., 2017), and abnormal choriocapillaris perfusion contributes to disease progression (Shi et al., 2021). These lesions result in a region of RPE hypopigmentation and/or hyperpigmentation, typically originating around the fovea perimeter (see more in Fleckenstein et al., 2021). This condition leads to disorganization and eventual loss of photoreceptor inner and outer segments, culminating in photoreceptor death. Additionally, age-related toxic accumulation of autofluorescent lipofuscin within the RPE is evident (Ibbett et al., 2019; Zhang et al., 2019; Edwards et al., 2023), and RPE mitochondrial dysfunction may be involved in disease progression (Senabouth et al., 2022). Recently, the first therapy for dry AMD was approved by the FDA with pegcetacoplan (Heier et al., 2023).

In wet AMD, leaking choroidal neovascular vessels lead to RPE or photoreceptor detachment, hemorrhage, and subsequent fibrovascular scarring, which is responsible for most cases of blindness (Gass et al., 2003; Brandli et al., 2022; Liu et al., 2023). This AMD form is characterized by the pathological proliferation of new blood vessels into the macula, leading to macular edema, subretinal hemorrhage, and fibrous scarring. These abnormal vessels can be leaky, causing fluid and blood accumulation in the subretinal space and neural retina, resulting in fibrotic scar, rapid and severe vision impairment (Bakri et al., 2019; Liu et al., 2023; Pawloff et al., 2023). Fibrotic changes in the late stages of neovascular AMD can further contribute to photoreceptor dysfunction and degeneration (Bloch et al., 2013; Bakri et al., 2019; Fan et al., 2023). While anti-VEGF therapies targeting VEGF have shown visual improvement in many patients by reducing abnormal blood vessel growth and leakage, a portion of patients does not experience visual improvement (Finger et al., 2020). Interestingly, polyphenols such as curcumin and resveratrol demonstrated anti-angiogenic effects on retinal and choroidal neovascular on administration (Nagai et al., 2014; Sulaiman et al., 2014; Ivanescu et al., 2015). In the AMD animal model, a prodrug of the flavonoid epigallocatechin-3-gallate shows interesting results in alleviating the choroidal neovascular and neuroinflammation via downregulation of the hypoxia-inducible factor-1α/VEGF/VEGF receptor 2 pathways (Xu et al., 2020). The RPE plays a critical role in supporting the function of PR, such as glycolysis (Sinha et al., 2020) and lipid metabolism (Farnoodian et al., 2023), phagocytosis of PR outer segments (Reyes-Reveles et al., 2017; Iker Etchegaray et al., 2023), secretion of neurotrophic factors to stabilize the neural retina (Ahluwalia et al., 2023), and cleaning for damaged ROS (Atienzar-Aroca et al., 2016; Sinha, Naash and Al-Ubaidi, 2020; Chen et al., 2022a). Furthermore, the RPE actively participates in the visual cycle by recycling all-trans retinal back to 11-cis retinal, a process vital for phototransduction (Jin et al., 2005). Because each RPE cell interacts with multiple PRs, it becomes a highly metabolically active tissue, ensuring the continuous regeneration and recycling of lipid-rich photoreceptor outer segments to maintain optimal visual function (Bazan et al., 1992; Storti et al., 2017; Kocherlakota et al., 2023).

However, in AMD, dysfunction of the RPE has a significant impact on photoreceptor function. Impaired phagocytosis by RPE cells leads to the accumulation of undigested waste within the RPE, contributing to oxidative stress and, ultimately, photoreceptor damage (Inana et al., 2018; Scrivo et al., 2018). Dysregulated autophagy further exacerbates intracellular waste accumulation and inflammation, while disturbances in lipid metabolism disrupt energy metabolism and nutrient supply to the retina, impairing photoreceptor function and survival (Mitter et al., 2014; Somasundaran et al., 2020). Extracellular deposits such as drusen and reticular pseudodrusen create a hostile microenvironment, obstructing nutrient diffusion and promoting local inflammation, further compromising PR health by structural disruption of the segment’s junction (Doyle et al., 2012; Hartmann et al., 2012; Sadigh et al., 2015; Marsh-Armstrong et al., 2022). In summary, AMD-induced changes in RPE function can contribute to photoreceptor degeneration. Understanding the mechanisms of photoreceptor cell death is crucial for developing new treatment strategies and identifying biomarkers for these complex retinal diseases.

Polyphenols such as curcumin and quercetin have been described as having several regulatory mechanisms in RPE cells. They promote pro-survival responses to injurious stimuli and also downregulate VEGF (Bardak et al., 2017; Parmar et al., 2020). In vitro observations of Sheu et al. (2010) have demonstrated that natural products like polyphenols and carotenoids, such as resveratrol and lutein, exert a protective effect on RPE cells when exposed to acrolein and H₂O₂. Importantly, these compounds also alleviate the inhibition of phagocytosis by acrolein. Additionally, quercetin exhibits a property to enhance RPE phagocytosis of degraded photoreceptors’ outer segments by inhibiting mTOR pathways (Huang et al., 2018). It is noteworthy that a clinical trial examined patients with AMD following anti-VEGF therapy and their dietary intake of polyphenols. Higher intakes of polyphenols were found to potentially correlate with improved long-term treatment outcomes in AMD (Detaram et al., 2021).

Oxidative stress & vascular dysfunction

Oxidative stress arises from an excessive production of ROS and/or a decrease in antioxidant levels. ROS, primarily comprising superoxide anions, hydrogen peroxide, and hydroxyl radicals, are generated during cellular energy production, where molecular oxygen is reduced to water. The maintenance between ROS generation and antioxidant defense balance is crucial for several disease prevention, including those that curse with photoreceptor degeneration. Elevated ROS levels are recognized for their damaging effects on major cellular macromolecules, such as lipids, proteins, and nucleic acids, ultimately leading to neuronal dysfunction and neurodegeneration (Böhm et al., 2023).

The retinal tissue displays a high metabolic rate, leading to increased oxygen consumption. Additionally, considering its exposure to direct light, the retina becomes susceptible to oxidative stress (Böhm et al., 2023). Studies using animal models of RP, such as rd1 and rd10 mice, have demonstrated elevated ROS production in degenerative retinal loci, indicating oxidative stress as a key pathology in retinal degeneration. RP patients present several clinical alterations associated with oxidative stress: blood samples show higher levels of ROS and H2O2, with an imbalance of the oxidative-antioxidant ratio. The aqueous humor and vitreous presented reduced antioxidant capacity and increased oxidative stress markers, with DNA and protein oxidative damage (Martínez-Fernández de la Cámara et al., 2013; Wang et al., 2022b; Vingolo et al., 2022). Therapeutic interventions targeting oxidative stress in animal models, such as treatment with antioxidants such as vitamin E, superoxide dismutase (SOD) mimetics, vitamin C, and N-acetylcysteine, have shown promising neuroprotective effects in preserving rod and cone PRs. Polyphenols, as previously mentioned, are especially renowned for their role as scavengers of ROS. They not only sequester and neutralize these molecules but also induce the upregulation of important endogenous antioxidants such as glutathione, SODs, and catalase. This dual action helps to maintain a more balanced oxidative-antioxidant ratio (Song et al., 2015; Shen et al., 2022; Naróg and Sobkowiak, 2023).

Similarly to the neuroinflammatory response, the extent of vascular dysfunction is directly correlated with the progression of RP in terms of PR cell loss, manifesting as a secondary event prior to rod PR degeneration. Oxidative stress can be directly correlated to the retinal vascular; this correlation is likely attributed to alterations in the metabolic demand of the retina, particularly in the outer retina (Lang et al., 2019). The oxygen in the outer retina is supplied by retinal blood vessels located at the blood-retinal barrier (BRB) and choroidal vasculature, supported by the RPE (Selvam et al., 2018). The rod PR loss leads to increased oxygen levels in the extracellular matrix of the outer retina, resulting in increased oxygen influx towards the inner retina, leading to a state of hyperoxia. It is noteworthy that individuals with RP exhibit reduced oxygen consumption in the retina and higher oxygen saturation compared to non-RP controls. This phenomenon may be attributed to the absence of regulation of retinal circulation, resulting in a spontaneous increase in oxygen supply (Lang et al., 2019; Wang et al., 2022b). The PR degeneration also impacts reducing blood flow in the choroid by elevated expression of endothelin-1, a vasoconstriction modulator; this might be associated with reactive gliosis and RPE cells in response to oxidative stress. Ultimately, deterioration of the vasculature may lead to vascular remodeling, retinal atrophy, and BRB disruption (McMurtrey and Tso, 2018; Lang et al., 2019; Peddada et al., 2019; Kajtna et al., 2022). The combination of oxidative stress exacerbated inflammation and disruption of the vasculature is also associated with secondary cell loss of PR cone cells (Piano et al., 2019). Studies in retinopathies like diabetic retinopathy and AMD highlights the positive usage of flavonoids and polyphenols, impacting the vasculature and ROS contention, providing a solid base for these compounds as therapeutic potential (Allegrini et al., 2022; Choo et al., 2022; Fanaro et al., 2023; Wang et al., 2024).

Neuroinflammation

The inflammatory response in RP and AMD is associated with several important cells – these being the macro – and microglia cells. Microglia, the resident immune cells of the retina, present a ramified morphology in healthy retinas, carrying out the function of immune surveillance of the microenvironment. However, upon stimulation by changes in the microenvironment, whether they are signs of injury, infection, or cellular stress, they undergo activation, initiating an immune response, and their morphology is altered into an ameboid-like. This alteration enhances their mobility within the tissue and their phagocytic capability, facilitating the engulfing and removal of cellular debris, and pathogens (Murenu et al., 2022; Leinonen et al., 2023).

This activation is a hallmark of neuroinflammation and has been observed in several RP models and human patients (Ma et al., 2012; Roche et al., 2016; Zhou et al., 2017; Yu and Saban, 2023). The degeneration of PR or formation of the druses in early stages triggers microglia activation and migration to the injury site in response to the stress signals (i.e., metabolic and oxidative stress) emitted and the remnants of dying cells. The release of inflammatory mediators further contributes to the neuroinflammatory milieu in the retina. Although this response is intended to clear cellular debris and facilitate tissue repair, excessive or prolonged inflammation may intensify the degenerative process (Peng et al., 2014; Blank et al., 2018; Lew et al., 2020; Murenu et al., 2022; Augustin et al., 2023). Notably, the phagocytosis of viable photoreceptors has been demonstrated to contribute to the progression of the degeneration (Zhao et al., 2015). The activated state can also be classified based on the polarization/phenotype expressed, traditionally categorized as M1 pro-inflammatory and M2 anti-inflammatory (Jurga et al., 2020). During the degeneration, microglial cells express the M1 phenotype releasing cytokines that lead to increased PR cell death, such as tumor necrosis factor-α (Zhou et al., 2017). In this state, several pathways exhibit increased expression and regulation of the response, mainly nuclear factor-κB, Toll-like receptor 4, mitogen-activated protein kinase, and others. Studies focused on AD and retina showed potent regulation of flavonoids in several important aspects of the microglia, such as regulation of these pathways, ultimately leading to phenotype change, generally to an anti-inflammatory state or reduced activation state (Jang and Johnson, 2010; Carullo et al., 2020; Medrano-Jiménez et al., 2022).

The neuroinflammation response in the retina is also mediated by macroglial cells such as Müller cells. Müller cells are the most numerous macroglial types in the retina, characterized by their radial morphology. Functionally, Müller cells perform the maintenance of the BRB, besides being responsible for helping in the cytoarchitecture, retinal homeostasis/functional stability, and playing an active role in the modulation of the phototransduction process and photoreceptor metabolism (de Hoz et al., 2016). Like the microglial response to the PR degeneration, the Müller cells undergo reactive gliosis, mediating the release of cytokines, chemokines, and molecules of a neuroprotective nature. This response may exacerbate the degeneration of neurons and vasculature (de Hoz et al., 2016; Tan et al., 2020; Leinonen et al., 2023). This process is characterized by morphological changes and alterations in gene expression, increased proliferation, and expression of cellular markers characteristic of inflammation (Uren et al., 2014; Fernández-Sánchez et al., 2015; Hippert et al., 2015; Roche et al., 2016; Tomita et al., 2021; Navneet et al., 2024; Xu et al., 2024).

Finally, at the late stage of the retinal degeneration progression, Müller cells are responsible for the retinal remodeling (Jones et al., 2016; Navneet et al., 2024). Conversely, some studies suggest that Müller cells may also play a neuroprotective role by releasing factors that promote cell survival. Some studies focused on other retinopathies such as diabetic retinopathy show increasing evidence of the effects of flavonoids in macroglial cells, reducing the GFAP expression, which contributes to a lower reactive gliosis state (Nones et al., 2010; Matos et al., 2020; Fanaro et al., 2023). Understanding the balance between neurotoxic and neuroprotective functions of the crosstalk of microglial cells and Müller cells is essential for devising targeted therapeutic strategies (Roche et al., 2018; Díaz-Lezama et al., 2023).

In addition to the glial response, the immune system is also affected, with infiltrates of white blood cells observed in RP and AMD retinas due to BRB dysfunction and systemic inflammation (Murakami et al., 2020; Tan et al., 2020; He et al., 2022; Mohan et al., 2022; Ascunce et al., 2023). Furthermore, samples of blood of patients show higher numbers of activated T cells, immune cells fundamental to humoral response, which in this case appears to express the Th1 phenotype response (McMurtrey and Tso, 2018). Related to this systemic inflammation, it is also an aspect that nutraceutical strategies utilizing flavonoids modulate, as seen in rheumatic diseases (Yi, 2021), reducing systemic inflammation in human trials of coronary artery disease patients (Serafini et al., 2010). Ferreira et al. (2024) extensively reviewed polyphenols as immunonutrients, pointing out their effects in chronic diseases and inflammation. Noteworthy, as described above, patients with retinal degeneration showed several systemic alterations, further supporting the NUT with flavonoids as a promising therapeutic strategy (Zhao et al., 2022).

Pre-Clinical Data of Polyphenols & Flavonoids

The pre-clinical data presented here is majorly based on RP animal models (Additional Table 5). As discussed before, several mutations are recognized and classified as RP-link mutations, the same ones found in human RP patients can be studied in murine models. Animal models have been developed to facilitate the study of disease progression, aiming at discoveries to improve the quality of life of patients with RP. One of the most used models for laboratory studies is the mice with alteration in the gene PDE6B (Ali et al., 2017; Xu et al., 2017). This gene, essential for cGMP stability in phototransduction (Ali et al., 2017; Xu et al., 2017), is altered in 50%–60% of patients with non-syndromic RP of the autosomal recessive type (Ali et al., 2017; Xu et al., 2017). With the specific RD1 and RD10 mutation in rods, the Pde6B^rd1 and Pde6B^rd10 mouse, respectively, are the most well-characterized animal models, RD10 being the one that most closely matches disease progression in humans (Punzo et al., 2009; Stasheff et al., 2011; He et al., 2017; Iraha et al., 2018; Trachsel-Moncho et al., 2018). The degeneration timeline of these mice has been widely described over the years by various scholars. In both models, the timeline that determines the onset of rod photoreceptor cell death, its peak, and the onset of secondary cone photoreceptor death is well known (Barhoum et al., 2008; He et al., 2017). One of the main differences besides different time progressions is that RD10 retinas are more mature by the time the degeneration starts (Stasheff et al., 2011; Olivares-González et al., 2021a).

Additional Table 5.

Pre-clinical data utilizing in vivo experimentation with retinal degeneration models and polyphenols as treatment

Years of publication	Compounds	Animal models	Methods	Results	References
2017	Curcumin	RD1 mice	Intravitreal injection, at a dose of 10 μM/L dissolved in DMSO, in mice at P7 (before the start of rod cell death).	Reduced number of TUNEL-positive cells, and visual function improved. Regulation of microglial activation.	Wang et al., 2017
2021	Quercetin and myricetin	P23H rhodopsin knock-in mice	Intraperitoneal injection, at a dose of 20 mg/kg body weight, starting from P14 to P21.	Reduction of pro-inflammatory markers.	Ortega and Jastrzebska, 2021
2021	Quercetin and myricetin	Abca4-/-Rdh8-/ - or BALB/c mice	The Abca4-/-Rdh8-/- or BALB/c mice. The flavonoid compounds at a concentration of 20 mg/kg or DMSO vehicle were delivered to mice through intraperitoneal administration 30 minutes before exposure to bright light.	Preservation of photoreceptor cells and visual function. Reduced number of TUNEL-positive cells, GFAP expression and reactive oxygen species.	Ortega etal., 2021
2022	Quercetin and myricetin		RhoP23H/P23H was used to test the protective effects of flavonoids against retinal degeneration at 14-21 days of age for RhoP23H/P23H and at 21-33 days of age for RhoP23H/+. Flavonoids were dissolved in DMSO/phosphate-buffered saline vehicle and administered to mice by intraperitoneal injection every other day at the same time of the day, three injections total at 20 mg/kg.	Preservation of photoreceptor cells and visual function. Downregulation of the UPR signaling and oxidative stress-related markers.	Ortega etal., 2022
2022	Kaempferol		Control (4% v/v dimethyl sulfoxide in normal saline) or kaempferol 20 mg/kg in vehicle solution was injected intraperitoneally once per day for 5 days after light injury.	Preservation of photoreceptor cells and visual function. Reduced number of TUNEL-positive cells.	Piano et al., 2022
2022	Quercetin and naringenin		Tvrm4 mice is pre-treated with naringenin 100 mg/kg/die, quercetin 100 mg/kg/die, naringenin 50 + quercercetin 100 mg/kg/die or vehicle dimethyl sulfoxide (DMSO 0.025%) in the drinking water for 35 days. On the 30th day, retinal degeneration was induced by exposure for 1 min to the white light of 12,000 lux intensity, and the treatment was repeated for another 5 days.	Preservation of photoreceptor cells and visual function. Upregulation of endogenous antioxidant enzymes, downregulation of apoptosis markers.	Noguchi et al., 2023
2011	Curcumin		P23H line 1 transgenic rat retina, 100 mg/ kg body weight of curcumin dissolved in alimentum was administered every day by oral gavage from P30 until P70 days. For evaluation of gene expression, curcumin was administered from postnatal day 7 (P7) to P30.	Preservation of photoreceptor cells and visual function. Reduced number of TUNEL-positive cells. Downregulation of apoptosis markers.	Vasireddy et al., 2011
2015	Curcumin		A domestic sow was inseminated with semen from a Tg P23H miniswine founder. Her daily diet was supplemented with curcumin (100 mg/Kg body weight) from embryonic (E) day 80 to E112. The same diet without curcumin was fed to a second inseminated control sow.	Preservation of photoreceptor cells and morphology.	Scott et al., 2015
2019	Quercetin and naringenin		rd10 mice were used in a range of ages from P18 (when they are able to drink on their own) to P45 (peak of death of cone photoreceptors). Stock solutions of naringenin and quercetin were prepared in DMSO and added to their drinking water, resulting in a dose of 100 mg/kg/die per animal	Preservation of photoreceptor cells and visual function. Downregulation of SOD1 and SOD2, as well as a reduction in lipid peroxidation.	Piano et al., 2019
2010	Resveratrol		Mice were orally administered with vehicle or resveratrol at a dose of 50 mg/kg body weight (BW) by using a gastric intubation daily for 5 days until light exposure.	Preservation of photoreceptor cells and visual function. Reduction of TUNEL-positive cells. Suppression of SIRT1 and AP-1.	Kubota et al., 2010
2018	Resveratrol		Mice were injected intraperitoneally with RSV at a dose of 22.4 mg/kg body wt per day for 7 consecutive days before the ERG. On the third day of RSV administration, the animals’ pupils were dilated with atropine sulfate solution. Then the mice were separated into individual boxes and exposed to bright continuous light for 12 h to induce retinal degeneration.	Preservation of photoreceptor cells and visual function.	Liu et al., 2018
2019	Resveratrol - Prodrug JC19		Rd10 mice postnatal day 13 (P13) were anesthetized with ketamine/xylazine (80/12 mg/kg BW) and subretinally injected with 1 of 5% DMSO (vehicle), 0.1 mMJC19 or 5.0 mMJC19.	Preservation of photoreceptor cells and visual function.	Valdés- Sanchez et al., 2019
2023	Resveratrol		RSV was dissolved in dimethyl sulfoxide (DMSO) at 65 mg/ mL and then diluted with phosphate buffer saline to get a 6.67% concentration of DMSO. RSV was administered to the rats of the R group by gavage at two modes: (1) a dose of 200 mg/kg at 0 h (h), 2, 10 h after the MNU-administration, and then once a day for the following two days; (2) a daily dose of 50 mg/kg 3 days (d) prior to and 3 d after the MNU-administration	Preservation of photoreceptor cells and visual function. Reduction of TUNEL-positive cells. Suppression of SIRT1.	Yan et al., 2023
2024	Resveratrol - Prodrug Piceid Octanoate		Postnatal day 14 (P14) rd10 mice were anesthetized with ketamine/xylazine (80/12 mg/kg body weight) and intravitreally injected with 1 μL of 10 mM PIC-OCT diluted in 5% DMSO	Preservation of photoreceptor cells and visual function. Reduction of TUNEL-positive cells.	Moshtaghion et al., 2024
2022	Epigallocatechin gallate		EGCG was dissolved in normal saline injection (10 mg/mL). EGCG was freshly prepared, and the rats were given an IP injection at a dose of 25 mg/kg every wk from postnatal day (P) 100 to P160, with a total of 7 doses administered	Preservation of visual function, improved antioxidant enzymes and reduced oxidative damage.	Perdices et al., 2022
2015	Green tea extract - epigallocatechin gallate		Female rats received a single intraperitoneal injection of 40 mg/kg MNU at 7 wk of age. A daily dose of 250 mg/kg GTE was orally administered by gastric intubation starting 3 days before MNU administration, and administration was continued once daily for a maximum 10 days	Preservation of photoreceptor cells. Reduction of TUNEL-positive cells. Downregulation of H0-1.	Emoto et al., 2015
2014	Green tea extract - epigallocatechin gallate		The oral administration of 250 mg/kg/day GTE was initiated 3 days before MNU injection and continued once daily throughout the experiment. Rats were sacrificed at 12, 24, and 72 h and 7 days after MNU injection, and the eyes were examined morphologically and morphometrically.	Preservation of photoreceptor cells and morphology.	Emoto et al., 2014
2023	Epigallocatechin gallate and lutein		RP model mice were administered with an MNU solution after two wk of intragastric administration. The gavage dose of LUT was set at 100 mg per kg (BW per day), 16 the gavage dose of EGCG was set at 500 mg per kg (BWper day), and the ratio between LUT and EGCG was referred from the previous study. 18 LUT was dissolved in soybean oil, and EGCG was dissolved in water to prepare the corresponding concentration solution. The quality of LUT in the LUT-EGCG group is equivalent to that in the LUT and EGCG groups alone. The dose of MNU was set at 50 mg kg.	Preservation of photoreceptor cells and morphology. Upregulation of antiapoptotic genes. Downregulation of IL-6.	Jing et al., 2023
2017	Epigallocatechin gallate		EGCG was dissolved in 0.9% sodium chloride injection (10 mg/mL). EGCG was freshly prepared, and mice were given an IP injection at a dose of 50 mg/kg. An equal volume of 0.9% sodium chloride was used as a control. EGCG was given daily for 7 days to some mice before they were sacrificed. For some mice, daily IP injections of EGCG were given for 7 days before light-induced degeneration and also after until the mice were sacrificed.	Preservation of photoreceptor cells and visual function. Downregulation of SOD1, SOD2 and Gpx4.	Qi et al., 2017
2012	Anthocyanin extracts		Anthocyanin extracts (50 mg/kg) were daily administered orally (p.o.). The effects of anthocyanin treatment were evaluated at 1,2, and 4 wk after administration in MNU-injected rats.	Preservation of photoreceptor cells, morphology and visual function. Downregulation of GFAP.	Paik et al., 2012
2016	Anthocyanin - peonidin		Two hours after MNU administration, the mice of the experimental group received an intravenous injection of peonidin at a dose of 80 mg/kg body weight. Thereafter, they received an intravenous injection of peonidin once a day for four consecutive days. Meanwhile, the mice of the vehicle-treated group received intravenous injections of physiological saline containing 0.05% acetic acid.	Preservation of photoreceptor cells, morphology and visual function.	Tao et al., 2016a
2014	Cyanidin-3-O- glucoside (C3G)		Experimental RD was induced in rats by the intraperitoneal injection of N-methyl-N-nitrosourea (MNU) at 50 mg/kg. C3G extracted from mulberry (Morus alba L.) fruit (50 mg/kg) was orally administered, daily for 1, 2 and 4 weeks after MNU injection.	Preservation of photoreceptor cells and morphology. Downregulation of GFAP.	Lee et al., 2014
2016	Cyanidin-3-O- glucoside (C3G)		After a week-long adaptation period, the rabbits were randomly divided into five groups (n = 8 per group), as follows: normal group (no light exposure and vehicle administration; NG), light-induced retinal damage model group (18 000 lx light exposure and vehicle administration; MG), the C3G group (18 000 lx light exposure and administration of C3G, 50.00 mg/kg/day), the PCA group (18 000 lx light exposure and administration of PCA, 17.15 mg/kg/day), and the FA group (18 000 lx light exposure and administration of FA, 21.61 mg/kg/day). C3G, PCA, and FA were administered at the same molar concentration for each group (0.11 mmol/kg body weight).	Preservation of photoreceptor cells and morphology. Reduced TUNEL-positive cells. Downregulation of inflammation. Modulated apoptotic-associated genes.	Wang et al., 2016

C3G: Cyanidin-3-O-glucoside; DMSO: dimethyl sulfoxide; EGCG: epigallocatechin gallate; FA: ferulic acid; GFAP: glial fibrillary acidic protein; IP: intraperitoneal injection; MNU: N-methyl-N-nitrosourea; PCA: protocatechuic acid; RD: retinal degeneration; RD1: retinal degeneration 1; RSV: resveratrol; SOD1-2: superoxide dismutase 1 and 2; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling; UPR: unfolded protein response.

In addition to the animal models mentioned above, which only cover autosomal recessive mutations, there are also important models for studying autosomal dominant mutations, such as the RPE65 mice models, known as RPE65^rd12 and RPE65^R91W knock-in. Both present a mutation in gene Rpe65, an important gene to RPE function and photoreceptor maintenance, being RD12 crucial in the development of Luxturna® (Liu et al., 2024). Still, there are also mutant-rhodopsin carrying models, like Rho^P23H and Rho^-/-, a knockout model) (Barwick and Smith, 2023; Vasudevan et al., 2024). Finally, and less utilized, the NR2E3-associated models (RD7 mice) (McNamee et al., 2024). This covers only partially the main used animal models, since there are induced models such as the N-methyl-N-nitrosourea-induced (MNU), which consists of systemic injection of MNU, a DNA-alkylating agent that targets rod photoreceptors, leading to apoptosis, very similar to the animal models described above (Tao et al., 2015). Another chemically induced model is the sodium iodate (NaIO₃)-induced retinal degeneration, an intravenous or intraperitoneal injection of sodium iodate that causes oxidative stress and direct toxicity to RPE, leading to secondary photoreceptor death (Kannan and Hinton, 2014). Still, there is non-chemically induced degeneration, such as light-induced retinal degeneration, that consists of prolonged exposure to intense light (Kubota et al., 2010; Grimm and Remé, 2013). Lastly, in vitro models are becoming more relevant and reliable, particularly with the advent of retinal organoids that allow a controlled and reproducible environment for studying retinal development and disease, offering a cleaner translation to humans, since the organoids are originated from induced pluripotent human cells (Schnichels et al., 2021; Móvio et al., 2023; Bovi Dos Santos et al., 2024).

In summary, whether using genetic, induced, or in vitro models, each approach provides unique insights into the complex mechanisms of retinal degeneration, offering precise temporal control over treatment protocols. These models enable a broad spectrum of studies, from preventive strategies to therapeutic interventions, spanning genetic, pharmacological, and nutraceutical therapies.

Quercetin, naringenin & myricetin

Quercetin is one of the most extensively studied flavonoids for the treatment of retinopathies, especially in RP (Ortega and Jastrzebska, 2021). Primarily present in food sources such as onions, buckwheat, citrus fruits, grapes, cherries, and others (Wang et al., 2022a), this compound has been associated with a range of biological activities, including anti-aging, anti-inflammatory, antioxidant, and several others (Alizadeh and Ebrahimzadeh, 2022).

In 2017, Herrera-Hernández et al. showed several in silico analyses that treatment of mutated Rho opsin associated with RP with quercetin shows an allosteric modulation of the opsin, having a positive effect on the stability and conformational properties, indicating a good target for a therapeutic approach. Later in 2019, Ortega et al. described the same effects for quercetin, myricetin, and their mono-glycosylated forms known as quercetin-3-rhamnoside and myricetrin (Figure 2A, B, F, and G). The same group also examined the relationship between these compounds and inflammatory response in P23H knock-in mice, administering 20 mg/kg every other day for 7 days resulted in a significant reduction in pro-inflammatory markers (Ortega and Jastrzebska, 2021).

Figure 2.

Chemical structure of the polyphenols cited in pre-clinical data.

Dietary flavonoids are predominantly present in their glycoside forms. However, in the plasma, glycosides are rarely found. Deglycosylation of flavonoids occurs in both the small and large intestines, depending on the type of sugar moiety attached. Interestingly, some flavonoid metabolites exhibit stronger or weaker physiological activities than their precursor compounds (Murota et al., 2018; Muñoz-Reyes et al., 2021).

The flavonoids further enhanced structural rigidity and promoted receptor self-association to biological membranes, making them even more intriguing by treating cells expressing the P23H opsin mutation — showing partial restoration to normal cellular trafficking, a feature observed in RP-linked rho mutations. In another report, authors also investigated these flavonoids in a P23H mice model with chronic treatment (20 mg/kg every other day for 7 and 14 days), showing improvement of this receptor stability and function, leading to improved retinal morphology and function electroretinography (ERG) by increased rod and cone opsins. This was achieved by reducing oxidative stress markers by the free radical scavenger property of these flavonoids and downregulation of the unfolded protein response signaling (Ortega et al., 2022).

Considering the potential therapy focused on quercetin potentials, in 2019 Piano et al. evaluated the nutraceutical therapy by treating Rd10 animal model with quercetin and naringenin, another flavonoid (Figure 2A and C). The chronic treatment with quercetin or naringenin (100 mg/kg/day) showed preserved retinal morphology and improved functionality via ERG, evidenced by a reduction in cone PR loss and ROS levels in the retina, as assessed through oxidative stress markers such as SOD1, SOD2, and acrolein. Subsequently, the authors investigated both flavonoids in another animal model, Tvrm4 mice, which are heterozygous for an I307N dominant mutation of Rho. In this study, they assessed the effects of each flavonoid individually and in combination, evaluating functional, morphological, and molecular biological parameters. When administered separately, the flavonoids reduced oxidative stress and apoptosis markers. However, co-treatment resulted in a state described as “anti-oxidative stress,” well-known as anti-oxidative imbalance (50 + 100 mg/kg/day of naringenin and quercetin, respectively) (Piano et al., 2022). In acute models of light-induced retinal degeneration, intraperitoneally administration of quercetin and myricetin at a dose of 20 mg/kg 30 minutes before light exposure showed incredible results in the rescue of photoreceptors, preserving ERG responses, and reducing cell death pathways via apoptosis and inflammatory response (Ortega et al., 2021). In a model of all-trans-retinal induced photoreceptor atrophy and degeneration, quercetin was able to alleviate cell death by reducing ROS generation (Yang et al., 2024). Another flavonoid, kaempferol, when administered at 20 mg/kg for 5 days after light exposure, resulted in a reduction of PR cell death and significant ERG improvements (Noguchi et al., 2023). Those results summarize the potential of flavonoids in treating PR degenerating diseases.

Curcumin

Curcumin is considered a bioflavonoid, abundant in plant-derived curry spice, the turmeric. This compound has been extensively studied due to its multi-targeted applicability, known as anti-inflammatory, antioxidant, anti-diabetic, anti-cancer, and anti-aging (Kotha and Luthria, 2019; Figure 2D). Based on this description, curcumin was utilized as a treatment for AD (Allegrini et al., 2022), Parkinson’s disease, and multiple sclerosis (Bássoli et al., 2023).

For RP, curcumin presented exciting results in animal models: when administered orally to P23H rats, curcumin was able to cross the BRB being found in the retina, RPE, sclera and vitreous. Curcumin induced a dissociation of mutated protein aggregation, ultimately diminishing endoplasmic reticulum stress. Further improved retinal structure and function, as well as the gene expression and localization of rhodopsin and other important genes to photoreceptors; this was achieved with a dose of 100 mg/kg orally for 40 days (Vasireddy et al., 2011). The prenatal exposure in embryonic transgenic P23H miniswine the same dose of curcumin was also able to reduce the degeneration, preventing the mutant rhodopsin mistrafficking, reaching similarity to control, with rod preserved morphology (Scott et al., 2015). Further supporting flavonoids in NUT mutation-independent, curcumin was also evaluated in Rd1 mice. A 7-day treatment by intravitreal injection (10 µM/L) leads to potent immunomodulatory effects in microglial cells, including suppression of their activation and amelioration of rod loss, resulting in a better ERG response (Wang et al., 2017).

Resveratrol

Resveratrol is a polyphenol found in various plants, including grapes, blueberries, raspberries, and peanuts (Figure 2E). Similarly to the other compounds described before, it presents a multi-targeted applicability. Unique to this compound is its property to activate Sirt1, a NAD⁺-dependent deacetylase. Sirt1 activity is stimulated by high levels of NAD⁺, which deacetylates lysine residues on histone and cytoplasmic proteins, thereby influencing histone stability, transcriptional activity, and translocation of specific proteins. Sirt1 is reported to be located not only in the nucleus, but also in the mitochondria and plays a role in stress response pathways, such as apoptosis and inflammation, highlighting this polyphenol as a promising therapeutic target (Najafi et al., 2021). In a light-induced retinal degeneration model, pre-treatment with 50 mg/kg for 5 days prior to exposure resulted in reduced cell death and improved ERG responses (Kubota et al., 2010).

Liu et al. (2018) evaluated both in vitro with 661W photoreceptors lineage cells and in vivo light-induced retinal degeneration mice and Sirt1 pathways involved. In vitro analysis demonstrated potential neuroprotective effects, reducing cell death via ROS reduction, improving the ratio of reduced/oxidized glutathione/glutathione disulfide, and mitigating mitochondrial dysfunction. In vivo injections intraperitoneally of resveratrol for seven consecutive days at a dose of 22.4 mg/kg before the light damage inhibited retinal dysfunction and photoreceptor cell loss, reducing the expression of parthanatos-related proteins. In the Rd10 animal model, treatment via subretinal injection at a dose of 5 mM of resveratrol showed positive dose-dependent effects on function and retinal preservation (Valdés-Sánchez et al., 2019).

The positive results mentioned above were not observed in the MNU rat model when resveratrol was administered by gavage at a dose of 50 mg/kg. This discrepancy is discussed as a matter of the model itself, attributed to the MNU-induced depletion of NAD⁺, which prevented the deacetylation of SIRT1 and subsequently hindered the beneficial effects (Yan et al., 2023). More recently, a novel acylated resveratrol prodrug, piceid octanoate, has been utilized in both in vitro studies and in Rd10 mice models, demonstrating several positive outcomes. These include promoting SIRT1 nuclear translocation, preserving the NAD⁺/NADH ratio, and suppressing intracellular ROS formation. These effects are attributed to the upregulation of antioxidant genes and the preservation of mitochondrial function. In rd10 mice, a single intravitreal injection of PIC-OCT at a dose of 10 mM inhibited PARP formation, increased Sirt1 expression, significantly reduced the number of TUNEL-positive cells, preserved ERG responses, and enhanced performance in light chamber tests (Moshtaghion et al., 2024).

These results underscore the potential properties of polyphenols, especially flavonoids, in the treatment of photoreceptor degeneration, independent of the mutation carried, by its multifaceted nature potential, modulating primarily an antioxidant response in the retina, affecting also other important pathways that ultimately lead to retinal degeneration.

Epigallocatechin gallate

Epigallocatechin gallate (EGCG) is the most abundant catechin-based flavonoid in green tea leaves, described as antioxidant, anti-inflammatory, neuroprotective, and others (Figure 2H). The systemic treatment with EGCG in a dose of 25 mg/kg every week in the P23H animal model showed better visual acuity and retinal electrical function when compared to the vehicle group, these results being linked to balancing of antioxidant enzymes and oxidative damage (Perdices et al., 2022). When RP-induced degeneration by MNU model was pre-treated orally with green tea extract, which includes approximately 54% of EGCG, resulted in a decreased number of TUNEL-positive cells and ONL preservation, with the suppression of PR cell death (Emoto et al., 2015). Another study used EGCG in a chronic isolated or a co-treatment with lutein, another natural compound classified as a carotenoid, demonstrated synergic effects, rescuing the ONL by reducing pro-inflammatory cytokines, this was achieved at doses of 500 mg/kg of EGCG (Jing et al., 2023a). In support of these findings, the study demonstrated an increased presence of EGCG in the retina of treated animals, confirming that the green tea extract successfully crossed the blood–retinal barrier. Specifically, animals received a dose of 250 mg/kg/day for 3 days prior to MNU injection, resulting in retinal EGCG levels of 117.7 nM at 1 hour and 0.213 nM at 2 hours post-administration (Emoto et al., 2014). When administered seven days before light-induced damage at 50 mg/kg, EGCG attenuated the PR degeneration (Qi et al., 2017).

Anthocyanins

Anthocyanins, plant pigments abundant in vegetables and fruits such as sweet potato and eggplant, are commonly applied as food colorants. These compounds serve as both exogenous and intrinsic antioxidants, with documented benefits extending to visual acuity (Shen et al., 2022). This class of flavonoids has been described to have several positive impacts on degenerative processes of the retina. These include reducing GFAP expression and inhibiting important apoptosis mediators in photoreceptor cells (Paik et al., 2012; Tao et al., 2016a). Treatment with peonidin at the dose of 80 mg/kg after 4 days of MNU administration showed some interesting results, ameliorating the PR degeneration and preserving the inner visual signal pathways (Figure 2I). Using a multi-electrode array and ERG showed preserved retinal function, later demonstrated by histological analysis, impacting both scotopic and photopic functions (Paik et al., 2012; Tao et al., 2016b). This positive effect of anthocyanins was also described with the anthocyanins of black soybean and kuromanin chloride (Figure 2J; Paik et al., 2012; Lee et al., 2014). Orally administered cyanidin-3-glucoside for 3 weeks before light exposure prevented retinal damage (Wang et al., 2016).

Nanocarriers and Synergies Between Therapies as Innovative Strategies for Delivering Nutraceuticals

The applicability of flavonoids remains a concern, primarily due to their lower bioavailability resulting from poor gastrointestinal absorption, which is attributable to their hydrophobicity, or even first-pass metabolism. In this sense, several strategies have been proposed to overcome this issue, nanocarrier systems have been proposed as a significant one (Koirala et al., 2016; Puri et al., 2022). Among the main nanotechnologies applied to flavonoid delivery, several reports highlight phytosomes (Chen et al., 2022b), nanodiamonds (Gismondi et al., 2015; Chipaux et al., 2018), inorganic nanoparticles (Sysak et al., 2023), and others have shown promising results in enhancing the effectiveness of bioactive compounds, for example enhancing anti-inflammatory and antioxidant effects (Bunkar et al., 2019; Ghezzi et al., 2021; Gorantla et al., 2021; Kaushal et al., 2022; Ashfaq et al., 2023; Rakotondrabe et al., 2023; Sarabia-Vallejo et al., 2023; Yuan et al., 2024; Additional Table 6).

Additional Table 6.

Nanocarriers, compositions, advantages, and limitations

Carries	Compositions	Synthesis methods	Advantages	Limitations	References
Liposomes	Liposomes comprise phospholipid bilayers, which can encapsulate hydrophilic and hydrophobic compounds. Polyphenols and flavonoids are typically encapsulated within the aqueous core or the lipid bilayers.	Typically formed by hydrating a thin film of lipids (e.g., phosphatidylcholine) in an aqueous solution containing polyphenols or flavonoids. This is followed by sonication or extrusion to form small vesicles.	Enhanced bioavailability: protects polyphenols and flavonoids from degradation and enhances absorption. Targeted delivery: can be surface-modified to target specific tissues or cells. Biocompatible: generally well-tolerated by the body. Concentration: higher loads of both hydrophilic and hydrophobic drugs, controlled release.	Limited stability: Liposomes can be susceptible to degradation over time. Production costs: can be expensive to produce on a large scale. Size variability: size distribution can vary, affecting consistency in dosing.	Gorantla et al., 2021; Yuan et al., 2024; Ashfaq et al., 2023; Kaushal et al., 2022
Micelles	Micelles are formed from amphiphilic molecules (surfactants) in aqueous solutions, with a hydrophobic core and hydrophilic shell. They can encapsulate hydrophobic compounds like certain polyphenols and flavonoids.	Micelles self-assemble in aqueous solutions above a critical concentration (critical micelle concentration), forming spherical structures with a core-shell morphology.	Solubilization: improves the solubility of hydrophobic polyphenols and flavonoids. Enhanced bioavailability: facilitates absorption through biological membranes. Ease of formulation: generally simple to prepare and stabilize	Stability concerns: can be sensitive to dilution and environmental factors. Limited loading capacity: may not accommodate high concentrations of polyphenols or flavonoids. Biocompatibility: Surfactants used in micelle formation may have toxicity concerns at higher concentrations.	Bunkar et al., 2019; Gorantla et al., 2021; Kaushal et al., 2022
Phytosomes	Phytosomes are complexes of polyphenols or flavonoids incorporated into the polar heads of phospholipids, typically phosphatidylcholine.	Prepared by combining polyphenols or flavonoids with phospholipids under controlled conditions to form complexes, such as solvent evaporation, freeze-drying, and antisolvent precipitation.	Enhanced bioavailability: protects polyphenols and flavonoids from degradation, enhances permeability, stability, absorption, and solubility. Targeted delivery: can be designed for specific absorption pathways.	Specificity of phospholipids: The choice of phospholipid can affect the characteristics of the phytosome. Production complexity: requires careful formulation and manufacturing processes. Potential variability: composition and performance can vary based on formulation and manufacturing conditions.	Yuan et al., 2024; Chen et al., 2022b; Kaushal et al., 2022
Niosomes	Niosomes are non-ionic surfactant vesicles that encapsulate hydrophilic and hydrophobic compounds like polyphenols and flavonoids.	Formed by hydration of a mixture of non-ionic surfactants and cholesterol, followed by sonication or extrusion to create vesicles.	Biocompatibility: generally well-tolerated and biodegradable. Improved bioavailability and bioaccessibility: enhances absorption in the gastrointestinal tract. Versatility: can encapsulate a wide range of bioactive compounds. Cost- effective: less expensive compared to other vesicular systems like liposomes.	Potential instability: may aggregate or fuse over time, affecting stability. Variable release profiles: requires careful formulation to achieve the desired release. Scalability: Large-scale production can present challenges.	Gorantla et al., 2021;
Nanoemulsions or Microemulsions	Lipid-based colloidal dispersions of oil and water stabilized by a mixture of surfactants or emulsifiers, with droplet sizes in the nanometer range.	Prepared by methods such as high-pressure homogenization or sonication, where polyphenols or flavonoids are dispersed in an oil phase and emulsified in an aqueous phase.	Enhanced stability: long-term stability of encapsulated compounds, protection from adverse storage conditions, degradation, light, pH, and elevated temperature. Improved bioavailability and bioaccessibility: enhances absorption due to small droplet size and increased surface area. Versatility: can encapsulate both hydrophilic and hydrophobic compounds	Production complexity: requires specialized equipment for homogenization or sonication. Surfactant toxicity: potential toxicity concerns with surfactants used to stabilize nanoemulsions. Cost: production costs can be higher compared to conventional formulations.	Ashfaq et al., 2023; Kaushal et al., 2022
Self- nanoemulsifying system	Formulations that spontaneously form nanoemulsions in the gastrointestinal tract under mild agitation or digestion conditions.	Typically contain a mixture of oil, surfactant, co-surfactant, and polyphenols or flavonoids, which form a nanoemulsion upon exposure to aqueous media/biological fluids.	Enhanced absorption: facilitates solubilization and absorption ofpoorly water- soluble polyphenols or flavonoids. Improved stability: protects compounds from degradation in the gastrointestinal environment. Reduced variability: provides consistent dosing due to self-emulsification properties.	Digestive variability: The efficiency of self-emulsification can vary depending on digestive conditions. Bioavailability challenges: ensuring adequate absorption across intestinal membranes can be complex, also low loading capacity and leakage.	Ashfaq et al., 2023; Kaushal et al., 2022
Solid lipid nanoparticles (SLNs)	SLNs are composed of solid lipids (e.g., triglycerides or waxes) with a crystalline nature, that encapsulate polyphenols or flavonoids within a solid lipid matrix.	SLNs are typically prepared by dispersing melted lipids containing polyphenols or flavonoids in an aqueous surfactant solution, followed by homogenization or sonication to form nanoparticles.	High loading: efficient encapsulation of polyphenols and flavonoids due to high lipid content. Improved stability: protects encapsulated compounds from degradation. Sustained release: can provide sustained release profiles.	Potential lipid crystallization: may affect long-term stability. Limited drug loading: Some polyphenols or flavonoids may not efficiently load into SLNs. Size distribution: Control over particle size distribution can be challenging.	Ashfaq et al., 2023; Kaushal et al., 2022; Yuan et al., 2024;
Nanostructured lipid carriers (NLCs)	Nanostructured lipid carriers (NLCs), introduced as the next generation LNPs, are composed ofa core containing a combination of solid and liquid lipids at room temperature.	NLCs are typically produced by high- pressure homogenization or solvent evaporation methods, where lipid mixtures are melted and mixed with the bioactive compounds, followed by solidification. Aim to overcome the shortcomings of SLNs, for instance, increased drug loading capacity and improved stability by preventing drug leakage from the nanoparticles during storage	High drug loading capacity: can incorporate high amounts ofpolyphenols/flavonoids. Enhanced stability & bioavailability: protects encapsulated compounds from degradation. Controlled release: provides sustained and controlled release of the bioactive.	Complex formulation: requires optimization of lipid mixtures and surfactant ratios. Polymorphic transitions: potential changes in lipid crystal forms can affect stability. Scalability issues: Large- scale production can be challenging.	Bunkar et al., 2019; Ashfaq et al., 2023; Yuan et al., 2024;
Exosomes	Exosomes are nanosized extracellular vesicles naturally secreted by cells, composed of lipid bilayers containing proteins, lipids, and nucleic acids.	Exosomes are isolated from cell culture supernatants or bodily fluids. They can potentially encapsulate bioactive molecules like polyphenols and flavonoids through engineering or loading processes.	Biological compatibility: natural carriers for cell-to-cell communication. Targeting capability: can be engineered to target specific cells or tissues. Stability: exhibits stability in circulation, biological fluids, and low immunogenicity.	Complex isolation: isolation and purification methods can be challenging. Loading efficiency: The loading of polyphenols and flavonoids into exosomes can be variable.	Yuan et al., 2024
Polymeric micelle	Polymeric micelles are self- assembled nanoparticles formed from amphiphilic block copolymers (e.g., PEG-PLA, PEG-PCL), which can encapsulate hydrophobic drugs such as polyphenols and flavonoids in their core.	Prepared by dissolving block copolymers in a solvent, followed by evaporation or dialysis to form micelles.	Enhanced solubility: improves the solubility of hydrophobic polyphenols and flavonoids. Targeted delivery: can be surface-modified for targeted delivery to specific tissues. Concentration: high loading capacity. Enhanced stability: protection from adverse conditions, like pH and elevated temperature.	Potential toxicity: Some polymers used may have toxicity concerns. Size distribution: Control over size distribution can be challenging. Biocompatibility: compatibility with biological systems needs careful consideration, due to low stability and poor permeability. High cost.	Yuan et al., 2024; Kaushal et al., 2022; Gorantla et al., 2021.
Polymeric nanoparticle	Polymeric micelles are self- assembled nanoparticles formed from amphiphilic block copolymers (e.g., PEG-PLA, PEG-PCL), which can encapsulate hydrophobic drugs such as polyphenols and flavonoids in their core.	Typically formed by methods such as nanoprecipitation, emulsion/solvent evaporation, or electrospraying, where polymers and polyphenols or flavonoids are mixed under controlled conditions.	Biocompatibility: Biodegradable polymers are generally well-tolerated. Versatility: can encapsulate a wide range ofcompounds, including polyphenols and flavonoids. Controlled release: allows high encapsulation efficiency, controlled and sustained release.	Potential toxicity of polymers: Depending on the polymer used, toxicity concerns may arise. Formulation complexity: requires optimization of formulation parameters. Complex production process.	Gorantla et al., 2021; Ghezzi et al., 2021;
Dendrimers	Dendrimers are branched, tree-like synthetic macromolecules with high surface functionality, suitable for drug delivery applications.	Dendrimers are synthesized through repetitive branching reactions, creating multiple generations with numerous surface functional groups for drug attachment.	High functionalization: multiple sites for drug conjugation enhance loading capacity. Controlled size and structure: well-defined architecture aids in the predictability of behavior. Enhanced solubility: improves the solubility and bioavailability ofpolyphenols and flavonoids	Synthesis complexity: requires precise and multi-step synthetic processes. Potential toxicity: higher generations may exhibit cytotoxicity, and are also non-biodegradable. Purification challenges: extensive purification is needed to remove by-products.	Gorantla et al., 2021; Ghezzi et al., 2021;
Nanocrystals	Nanocrystals are pure solid drug particles of nanometer size, stabilized by surfactants or polymers.	Nanocrystals are produced through top- down methods like high-pressure homogenization and milling, or bottom-up methods like antisolvent precipitation, involving reducing drug particle size to nanometer scale.	Enhanced solubility: greatly improves solubility and dissolution rates of poorly water-soluble polyphenols and flavonoids. High drug loading: consists of nearly 100% drug, leading to high loading capacity. Bioavailability: increases bioavailability due to the large surface area.	Stability issues: potential for aggregation, Ostwald ripening over time, and limited control over release profile. Processing complexity: requires high energy input and specialized equipment. Scalability: Large-scale production can be challenging and expensive. Stability issues like agglomeration.	Yuan et al., 2024
Nanodiamonds	Nanodiamonds are crystalline carbon nanoparticles with sizes typically less than 100 nanometers, suitable for drug delivery and imaging applications.	Produced by detonation synthesis or chemical vapor deposition, and polyphenols or flavonoids can be encapsulated or surface-modified.	Biocompatibility: well-tolerated by biological systems. Surface functionalization: can be functionalized with drugs or targeting moieties. High surface area: enables high drug loading capacity.	Production cost: can be expensive compared to other nanoparticles. Size control: Achieving uniform size distribution can be challenging. Long-term effects: long-term biocompatibility and clearance need thorough investigation.	Chipaux et al., 2018; Gismondi et al., 2015
Co-crystal	Co-crystals are crystalline structures composed of the active pharmaceutical ingredient (e.g., polyphenols or flavonoids) and a co-former molecule, bonded through non-covalent interactions.	Prepared by solvent evaporation, grinding, or slurry methods, where the active compound and co-former are mixed in a suitable solvent and allowed to crystallize.	Improved properties: enhances the solubility and stability of polyphenols and flavonoids. Tailored properties: allows for precise control over physical and chemical properties. Enhanced bioavailability: protects polyphenols and flavonoids from degradation and enhances absorption.	Synthesis complexity: requires optimization of conditions for co-crystal formation.	Yuan et al., 2024
Cyclodextrin complex	Cyclodextrin complexes are inclusion complexes formed by encapsulating polyphenols or flavonoids within cyclodextrins (e.g., P-cyclodextrin).	Complexation occurs through methods such as kneading, co-precipitation, or freeze-drying, where polyphenols or flavonoids are mixed with cyclodextrins.	Enhanced solubility: improves solubility and stability of polyphenols and flavonoids. Protection from degradation: increases stability against light, heat, and oxidation. Improved bioavailability and bioaccessibility: enhances absorption in the gastrointestinal tract.	Speciflcity of cyclodextrins: Selection of the appropriate cyclodextrin and complexation conditions is critical. Complexation efficiency: not all polyphenols or flavonoids may form stable complexes, also has leakage problems. Toxicity: exhibit nephrotoxicity.	Yuan et al., 2024; Sarabia- Vallejo et al., 2023
Metal nanoparticles (silver, gold, metal oxides, and others)	Metal nanoparticles are composed of atoms arranged in nanoscale dimensions, often functionalized with ligands or coatings.	Synthesized by reducing metal salts in the presence of stabilizing agents, allowing for the encapsulation of polyphenols or flavonoids.	Biocompatibility: generally compatible with biological systems. Surface functionalization: This can be functionalized by targeting ligands for specific delivery. Therapeutic potential: used in imaging, diagnostics, and therapy. Synergy: allows multiple combinations of polyphenols. Improve the biological effects of polyphenols.	Biological fate: clearance and biodistribution and long term toxicity, in vivo need thorough study. Environmental impact: potential environmental concerns related to nanoparticle disposal. Cost: production costs can be higher compared to other nanoparticles. Regulatory considerations.	Sysak et al., 2023; Gorantla et al., 2021

NLCs: Nanostructured lipid carriers; PEG-PCL: polyethylene glycol-poly(ε-caprolactone); PEG-PLA: polyethylene glycol-polylactic acid; SLNs: solid lipid nanoparticles.

In general, nanocarriers were developed in an attempt to overcome physic-chemical limitations such as reduced aqueous solubility, protection from environmental degradation, and/or biological metabolism. Furthermore, new perspectives were open in terms of improved therapeutic effects since some of these delivery systems evoked changes in polyphenol biopharmaceutical profiles or even showed therapeutic potential when administered alone. These delivery systems must be designed to ensure easy patient compliance and retain the bioactive properties of the compound. Furthermore, they should target the site of action to maximize benefits and provide controlled release, depending on the treatment requirements (Yang et al., 2017). Yuan et al. (2024) extensively reviewed and summarized the potential of these delivery systems in general. Overall, these delivery systems are beneficial in protecting highly sensitive polyphenols, thereby ensuring enhanced bioavailability, sustainable release, and storage stability. Figure 3 displays the most used nanocarriers (with different compositions) and therapy associations.

Figure 3.

Potential delivery systems for polyphenols and conjugated therapies with nutraceuticals.

The top section illustrates various nanotechnology-based systems that enhance the efficacy, bioavailability, and safety of polyphenols and flavonoids as nutraceuticals. These systems include inorganic nanoparticles, lipid-based carriers, polymeric formulations, and nanodiamonds. The bottom section highlights the combination of therapies with nutraceuticals for improved effectiveness. Gene therapy employs advanced technologies like the CRISPR/Cas system for in vivo gene editing, facilitating personalized medicine by correcting patient-specific mutations. Concurrently, nutraceuticals can mitigate related pathophysiological processes. Cell transplantation strategies aim to replace lost cells using autologous hiPSCs, retinal organoids, and 3D bioprinting to reconstruct retinal structures. Additionally, flavonoids can work synergistically with other flavonoids, pharmaceuticals, and natural compounds in NUT therapy, enhancing overall therapeutic outcomes. Created with BioRender.com. 3D: Three-dimentional; CRISPR: clustered regularly interspaced short palindromic repeats; hiPSC: human induced pluripotent stem cells.

Among different nanosystems applied to flavonoid encapsulation, one of the most reported strategies is referred to as colloidal carriers, such as lipid nanocarriers, including liposomes, nanoemulsions, nanostructured lipid carriers (NLC), and solid lipid nanoparticles. Liposomes are lipid vesicles with high biocompatibility and improved capability for encapsulating flavonoids into both internal aqueous compartments and lipid bilayers, protecting them from chemical degradation. Most articles discuss flavonoid-loaded liposomes designed for skin delivery (Chen et al., 2022), but the main limitations of their applications as nutraceuticals rely on physicochemical instability against pH variation throughout the gastrointestinal tract.

In an attempt to overcome those limitations, solid lipid nanoparticles and NLC were proposed for flavonoid delivery due to their ability to promote flavonoid permeation across the intestinal barrier. Interesting results were achieved by using NLC for delivering quercetin, naringenin, and hesperidin since the bioavailability of those compounds was higher after encapsulation in NLC when compared to solid lipid nanoparticles (Aditya et al., 2014). In fact, those promising results can be attributed to the adequate transition temperature of the lipids mixture (at physiological temperature) incorporated into the NLC core, which promotes the physico-chemical stability of the compound and, consequently, enhances the transepithelial permeation (Hu et al., 2021).

Other recently studied colloidal carriers are polymeric micelles. Most reasons for proposing micelles as flavonoid delivery systems rely on their capability to improve the aqueous solubility of molecules, even considering short circulation time of the micelle. In particular, their reduced dimensions (< 100 nm), compared to other nanocarriers, favor intestinal permeation, as well as their composition (natural polymers such as chitosan, pullulan, and cellulose-derivatives), determines adhesion and enhances the contact between the nanocarrier and intestinal mucosa (Kaushal et al., 2022).

Despite the therapeutic potential of colloidal carriers, factors inherent to gastrointestinal administration drive the main biopharmaceutical limitations to be overcome are: (i) their chemical integrity and colloidal stability even considering the pH changes from stomach to intestinal mucosa; (ii) the dilution processes that occur during intestinal peristalsis; (iii) the contact with mucin layer on the intestinal surface mucosa; (iv) targeted-cellular delivery modulated by nanocarriers components coating. Other strategies were developed, such as metallic nanoparticles silver, gold, and zinc. Similarly, quercetin and hesperidin are used, especially for colorectal cancer treatment. Another important point is the possibility of combining stimuli-responsive components (pH, temperature, and oxidative stress sensors) for coating metallic nanoparticles, expanding their applications for intestinal delivery (Sysak et al., 2023).

The synergy between two different therapeutic strategies occurs when the combined effect of both therapies is greater than the sum of their individual effects. This synergistic interaction can enhance the overall efficacy of treatment, reduce side effects, and address multiple pathways through complementary and supportive actions (Leena et al., 2020). Such integration is well-utilized in fields such as cancer therapy, where chemotherapy induces cell death and immunotherapy enhances the immune response (Di Napoli et al., 2023). Also seen in chronic diseases such as diabetes, where lifestyle interventions and pharmacology are combined (Wronka et al., 2022). Additionally, there is growing interest in the synergistic effects of polyphenols and flavonoids when combined with other dietary natural products (Ulrich-Merzenich et al., 2009; Hidalgo, Sánchez-Moreno and de Pascual-Teresa, 2010; Vue et al., 2015; Leena et al., 2020; Piano et al., 2022; Zhang et al., 2023b).

There is growing evidence that nutraceutical therapies, when used synergistically with other treatments, can contribute to more integrated and effective medical care (Yang et al., 2017; Hussain et al., 2020; Di Napoli et al., 2023; Li et al., 2024). Multi-target treatments could be more effective than single-drug treatments, especially for neurodegeneration like RP (Maneu et al., 2022). While NUT utilizing polyphenols and flavonoids appear to be a reliable treatment option for RP or other PR degenerative conditions, it may not be effective for severe or late-stage retinal degeneration. In these cases, it could be beneficial to combine NUT with other emerging therapies, such as genetic and cell-based therapies, like transplantation of autologous-reprogrammed retinal cells, incorporating retinal organoids and 3D bioprint for cell sheet transplantation (Voisin et al., 2023; Bovi Dos Santos et al., 2024). This approach aims to ameliorate the pathophysiology of retinopathies while addressing cell loss and suppressing the immunological response to avoid rejection (Hyon et al., 2006; Hodge et al., 2019). Finally, genetic therapy could be aligned with nutraceuticals – treating the pathogenesis (genetic mutations) and the pathophysiological process (neuroinflammation and oxidative stress).

Doses, Safety Assessments, and Potential Adverse Effects of Polyphenols and Flavonoids

Although polyphenols and flavonoids show significant potential in the nutraceutical management of photoreceptor degeneration, current literature highlights a substantial gap in detailed dose-response and safety data specific to retinal degeneration. Pre-clinical studies in retinal degeneration models have used doses ranging from 20 to 500 mg/kg (Additional Table 5), demonstrating neuroprotective effects without significant toxicity. However, these doses are relatively high when compared to typical dietary intake. For instance, the average daily consumption of total flavonoids is estimated to be between 300 and 1800 mg, varying according to the geographical region studied (Grosso et al., 2014; Escobar‐Cévoli et al., 2017; Anacleto et al., 2019; Del Bo et al., 2019; Hejazi et al., 2020; Huang et al., 2020; Kapolou et al., 2021; Carnauba et al., 2023). To illustrate, to achieve a therapeutic dose of 100 mg/kg of a specific polyphenol in a 70 kg adult, one would theoretically need to consume approximately 7 g of anthocyanins per day, a quantity 4 to 23 times higher than the normal dietary intake. In contrast, clinical trials that utilize polyphenol supplementation typically range from 10 to 1200 mg/day (Additional Tables 1–4), which is far less than the doses used in animal models – none of the pre-clinical nor clinical trials published/showed adverse effects of the doses implemented.

Moreover, the challenges related to bioavailability and metabolic processing further complicate the translation of these doses to human clinical applications – challenges that nanocarrier-based delivery systems may help overcome (Figure 3 and Additional Table 6). Therefore, rigorous clinical trials focusing on dose optimization, long-term safety, and monitoring of potential adverse events are essential to establish practical guidelines for their use in PR degenerating diseases like RP. However, extrapolation to clinical use requires caution, as these compounds may present adverse effects such as pro-oxidant activity, interference with cytochrome P450 enzymes, and reduced mineral absorption at high concentrations. In cases of overdose, their protective effects may be countered by toxicological consequences (Abotaleb et al., 2018; Andres et al., 2018; Del Bo et al., 2019; Kapolou et al., 2021; Cianciosi et al., 2022).

Although many studies have confirmed the safety of flavonoids, their potential toxicity remains an important area of research due to the highly complex mechanisms involved. Current evidence indicates that natural flavonoid glycosides act on multiple molecular targets, with their effects varying according to dose in both in vivo and in vitro experiments. While most flavonoids are considered safe, those marketed as food supplements must have their tolerable upper intake levels thoroughly assessed, as there have been reports of toxic effects associated with excessive intake. It is also important to note that, although the observed adverse effects of polyphenols have not shown significant impacts on neurons, caution is warranted. Some commercially available flavonoid supplements may pose public health concerns due to the limited information available on adverse side effects and drug interactions in both in vivo experimental settings and clinical trials (Abotaleb et al., 2018; Andres et al., 2018; Del Bo et al., 2019; Kapolou et al., 2021; Cianciosi et al., 2022).

Concluding Remarks

The complex nature of neurodegenerative diseases increases the difficulty of finding suitable treatments that benefit most diagnosed patients. Nutraceutical therapies aim to use natural food-based products with medicinal benefits to improve health, prevent chronic diseases, delay the aging process, and support the structure and function of the body. This review highlights the potential of nutraceutical therapies, particularly polyphenolic compounds such as flavonoids, in addressing neurodegeneration in the retina, focusing on RP. These bioactive compounds show promise due to their multi-targeted roles, including antioxidant, anti-inflammatory, and neuroprotective effects.

However, significant challenges remain, particularly in enhancing their bioavailability and developing reliable delivery methods with cellular-specific recognition. Integrating advanced delivery systems, such as nanoformulations and biomaterials, offers a promising avenue to overcome challenges inherent to nanocarrier design and intestinal mucosa barrier. Moreover, the synergistic use of nutraceuticals with other emerging therapies, such as genetic and cell-based treatments, could provide a more comprehensive approach to treating retinal degenerative diseases. Considering those advancements, nutraceuticals could become a viable and accessible option for patients suffering from RP and other retinal diseases, independent of the mutation displayed, ultimately improving their quality of life. Still, while flavonoids and polyphenols present a promising therapeutic option for RP, further research and clinical trials are essential to optimize their delivery systems and establish their efficacy.

Additional files:

Additional Table 1: Clinical trials based on dietary supplements or nutraceutical therapy for AMD.

Additional Table 2: Clinical trials based on dietary supplements or nutraceutical therapy for diabetic retinopathy.

Additional Table 2.

Clinical trials based on dietary supplements or nutraceutical therapy for diabetic retinopathy

Clinical data ID	Compounds	Methods	Results	Years
NCT00893724	Inosine; tocopherols, tocotrienol, CoQ10 combination capsule; niacinamide SR; vitamin C; N-acetyl cysteine; complete multivitamin with all minerals and minocycline	Group 1 (supplement): Oral administration of inosine [500 mg], tocopherols [200IU], tocotrienol [10 mg], CoQ10 [50 mg], niacinamide [750 mg] vitamin C [1000 mg], N-acetyl cysteine [600 mg], complete multivitamin with all minerals; Group 2 (supplement + minocycline): Oral administration of supplement + minocycline [50 mg]	Completed, no results published.	2009
NCT01646047	Multi-component nutritional supplement in capsule (vitamin C, mixed tocopherols/tocotrienols, vitamin D, fish oil, lutein, zeaxanthin, pine bark extract, benfotiamine, green tea extract, curcumin).	Two capsules containing nutritional supplements per day for 6 months.	Improvements in visual function, hsCRP and peripheral neuropathy in patients with diabetes, both with and without retinopathy, and without affecting glycaemic control.	2012
NCT01880372	Alpha lipoic acid.	600 mg oral administration of lipoic acid daily for 12 months.	Terminated, no results published.	2013
NCT03533478	Oral treatment Alzer and Diamel.	Alzer group: Oral administration of one 500 mg tablet 3 times a day (1500 mg daily) after breakfast, lunch and dinner for one year. Diamel group: Oral administration of two 660 mg capsules 3 times a day (3960 mg daily) before breakfast, lunch and dinner for one year.	No statistically significant, but clinical: severe macular edema did not progress in the alzer and diamel.	2018
NCT04117022	Carotenoid supplement of DVS formula [vitamins C, D3 and E (d-a tocopherol), zinc oxide, eicosapentaenoic acid, docosahexaenoic acid, a-lipoic acid (racemic mixture), coenzyme Q10, mixed tocotrienols/tocopherols, zeaxanthin, lutein, benfotiamine, N-acetyl cysteine, grape seed extract, resveratrol, turmeric root extract, green tea leaf, and pycnogenol (patented French	2 soft gels per day for 6 months.	In progress.	2019
NCT03866005	Maritime Pine Bark extract, sp Pinus pinaster, Horphag Research, Geneva, Switzerland)]. Diabetes Visual Function Supplement (DiVFuSS), containing the macular carotenoids lutein and zeaxanthin, as well as antioxidants (vitamins B1, B12, C, D, E, lipoic acid, coenzyme Q10, resveratrol), omega3 fatty acids (EPA/DHA) and botanical extracts (Pycnogenol™ [patented extract of French maritime pine bark, Pinus pinaster], grape seed and green tea extracts, curcumin).	Two DiVFuSS soft gels per day, during 24 months.	Unknown status, no results published.	2019
NCT04742829	INTRAVIT(2 tablets: Curcumin 380mg, artemisia dracunculus L. 160mg, bromelain 160 mg, pineapple comosus stem d.e.i. 40 mg, total bromelain activity 394 GDU, pipeline 3.8 mg).	2 tablets per day morning and evening before meals, 6 months.	6 months of a dietary complementary supplement additionally to the present therapy for the treatment of diabetes, improves CRT, BCVA, and VD in patients with mild DME.	2021
NCT06376240	Pyridoxamine	Treatment with A (either 300 mg pyridoxamine or placebo per day) in period 1 followed by treatment with B (either 300 mg pyridoxamine or placebo per day) in period 2.	Recruiting	2024

Additional Table 3: Clinical trials based on dietary supplements or nutraceutical therapy for glaucoma.

Additional Table 3.

Clinical trials based on dietary supplements or nutraceutical therapy for glaucoma

Clinical data ID	Compounds	Methods	Results	Years
NCT00476138	Epigallocatechin-gallate (EGCG).	Oral administration of EGCG treatment (200 mg/day) for 3 months.	Reduced intraocular pressure.	2007
NCT01254006	Forskolin, rutin and vitamins B1 and B2.	Oral administration of two tablets per day of a food supplement (15 mg forskolin, 200 mg of rutin, 0.7 mg of vitamin B1 and 0.8 mg of vitamin B2) for 30 days.	Reduced intraocular pressure fluctuations.	2010
NCT01630551	Omega-3 fatty acid.	90-day supply of daily oral administration of a fish oil nutritional supplement.	Withdrawn.	2012
NCT01930487	Optic Nerve Formula (composed of essential vitamins and minerals, omega-3poly unsaturated fatty acids, polyphenolic nutrients, amino acid, botanical extracts, and flax seed oil).	Oral administration of the antioxidants, for one- month of antioxidants administered - three-weeks washout period.	Increases in biomarkers of ocular blood flow within retinal and retrobulbar vascular beds.	2013
NCT02984813	GlaucoHealth (alpha lipoic acid, citicoline, Co-enzyme Q10, Ginkgo biloba extract, grape seed extract, N- acetyl-cysteine, curcumin, and green tea extract) & GlaucoSelect (curcumin, bilberry extract, and grape seed extract).	2 pills once daily in the morning for 3 months.	Terminated, no results published.	2016
NCT04088084	Palmitoylethanolamide	PEA 600 mg supplementation for 3 months.	Protective effect on ganglion cells.	2019
NCT04380025	Mirtogenol (bilberry with pycnogenol).	Daily dietary supplementation of mirtogenol and one drop of bimatoprost 0.01% for 24 weeks.	No results found.	2020
NCT04460365	Lutein, zeaxanthin and meso-zexanthin	Daily oral administration of one softgel capsule (10 mg Lutein, 2 mg zeaxanthin, 10 mg meso-zeaxanthin) for 18 months.	Macular pigment optical density alterations, an increase in mesopic contrast sensitivity under glare.	2020
NCT04676126	Lumega-Z	A macular pigment-containing medical food (Lumega-Z) was prescribed in combination with a topical carbonic anhydrase inhibitor.	No results. No subjects enrolled.	2020
NCT04846179	Ginkgo biloba extract.	Webber natural ginkgo biloba 120 mg soft gel, 1 tablet twice a day for 4 months.	No significant increase in perfusion density of the macula and optic nerve head.	2021
NCT05080153	Ocufolin forte.	1 capsule/day after RVP measurement, till 90 tablets are finished (3 months)	Significantly reduce retinal vascular pressure in the setting of glaucoma.	2021
NCT05527106	Citicoline and docosahexaenoic acid (DHA)	Oral administration for 3 months of citicoline and DHA vs. citicoline and DHA vs. vitamin C.	Improvement of visual field indices.	2022
NCT05695027	Nicotinamide and pyruvate	Oral administration for 87 wk (20 months).	Enrolling.	2023

DHA: Docosahexaenoic acid; EGCG: epigallocatechm-gallate.

Additional Table 4: Clinical trials based on dietary supplements or nutraceutical therapy for RP.

Additional Table 5: Pre-clinical data utilizing in vivo experimentation with retinal degeneration models and polyphenols as treatment.

Additional Table 6: Nanocarriers, compositions, advantages and limitations.

Funding Statement

Funding: AHK is grateful for grants from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, Brazil, #2020/11667-0) and Universidade Federal do ABC (UFABC, Brazil). The following authors were recipients of fellowships from FAPESP: THLV (#2021/11969-9 and #2024/00828-3), GBS (#2021/14227-3), and GMB (#2024/10858-7). The following authors were recipients of fellowships from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Brazil): MIM (Finance Code 001, #88887.597402/2021-00). The following authors were recipients of fellowships from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil.): GKD (#145164/2024-1), and DRA (#308819/2022-5). The funders had no role in study design, data collection and analysis, decision to publish, or manuscript preparation.

Data availability statement:

Not applicable.