The discovery, development and marketing of food supplements, nutraceuticals and related products are currently the fastest-growing segments of the food industry (McCusker et al, 2016). Dietary supplements are defined as concentrated forms of vitamins, minerals, amino acids, herbs, botanicals or nutraceuticals. Unlike foods, these products are taken in specific dosages through capsules, tablets, pills, powders, soft gels or gel caps (Castro-Castañeda et al, 2022). Nutraceuticals are supplements derived from food sources. They contain specific bioactive agents in either higher concentrations than found in a balanced diet or equivalent amounts and contribute to enhancing pharmacological treatments, delaying, improving or even preventing diseases (Castro-Castañeda et al, 2022).
Supplements and nutraceuticals are commonly used in human ophthalmology for supportive treatment of age-related macular degeneration, glaucoma, cataracts, keratoconjunctivitis sicca and diabetic retinopathy (McCusker et al, 2016; Castro-Castañeda et al, 2022).
In veterinary medicine, nutraceutical products are primarily used as adjunctive treatment for feline herpesvirus infection (Stiles et al, 2002; Maggs et al, 2003). They are also widely used to slow down the progression of retinal degeneration and cataract development (Williams, 2006; Wang et al, 2016; Hopper et al, 2021). Unfortunately, there are numerous non-scientific reports on the ‘miracle’ treatment of ocular conditions; for example, the treatment of cataracts with nutraceuticals and other products. These are usually the result of misinterpretation of published reports or non-peer-reviewed claims made by individual companies. The result of these false claims is a possible negative conception by veterinarians regarding the use of nutraceuticals and/or supplements. This article reviews some of the positive effects of nutraceutical products and brings false claims regarding the use of some of these products to the reader's attention.
Nutraceuticals and supplements in ophthalmology: fiction
One of the most common false claims regarding the use of alternative treatment options is the use of the antioxidant L-carnitine for the treatment of cataracts in dogs. Williams and Munday (2006) reported that the use of a topical nutritional antioxidant formulation including N-acetyl carnosine improved lens opacification in eyes with immature cataracts or nuclear sclerosis, while less reduction was seen in eyes with mature cataracts or cataracts with associated intraocular inflammatory pathology (Williams and Munday, 2006). Unfortunately, this result was taken out of context and several companies claim the complete resorption of mature cataracts, which is not possible. There is a place for a product like N-acetyl carnosine if the expectation is to slow down the progression of cataract development and not complete reversal, eliminating the need for surgical removal of the lens. These claims by certain nutraceutical and pharmaceutical companies should be read with caution and peer-reviewed scientific proof should be sought (Figure 1).
Nutraceuticals and supplements in ophthalmology: facts
Products with positive ocular effects
This article is not a comprehensive review of every substance that benefits ocular health. Instead, it will focus on the most commonly commercially available products with proven eye-related improvements. Their effects and potential applications for treating three specific conditions (feline herpesvirus-associated disease, cataracts and retinal degeneration) will be explored.
Nutraceuticals and supplements with antiviral effects
Curcumin
Curcuma longa and its polyphenolic compound, curcumin spice, are known for their colour and ancient medicinal uses (Moghadamtousi et al, 2014). Traditionally used for its antimicrobial and insect-repellent properties, curcumin has been shown to possess a wide range of antibacterial, antiviral, antifungal and antimalarial activity (Moghadamtousi et al, 2014). The antiviral activity of curcumin manifests through several mechanisms:
Curcumin's therapeutic potential is hampered by its limited oral bioavailability and aqueous solubility, resulting in suboptimal absorption. This necessitates high, fortunately well-tolerated, doses or the implementation of nanocarrier systems, such as curcumin-loaded poly(lactic-co-glycolic acid).
Lysine
Lysine, an amino acid with potential antiviral properties, has been extensively studied for its effects on human herpes simplex virus-1 and feline herpesvirus. While numerous studies have investigated its efficacy, the results remain controversial, with reports of positive and negative outcomes (Stiles et al, 2002; Maggs et al, 2003; Rees and Lubinski, 2008; Bol and Bunnik, 2015; Thomasy and Maggs, 2016). The hypothesised mechanism of action involves lysine's competition with arginine, an essential amino acid for feline herpesvirus-1 replication (Stiles et al, 2002; Maggs et al, 2003).
Studies have yielded mixed findings. Stiles et al (2002) observed reduced conjunctivitis severity in lysine-treated cats, while Maggs et al (2003) reported decreased viral shedding. Conversely, Rees and Lubinski (2008) found no significant treatment effects. Bol and Bunnik (2015) further concluded that lysine supplementation does not have an inhibitory effect on feline herpesvirus-1 replication, is not effective in preventing cats from becoming infected with feline herpesvirus-1, does not decrease the chance of developing clinical signs related to active feline herpesvirus-1 infection or have a positive effect on the clinical course of its disease manifestations (Williams and Munday, 2006). They also concluded that the proposed mechanism of action of lysine-arginine antagonism resulting in lowering arginine levels can be undesirable for the cat (Bol and Bunnik, 2015).
Despite the lack of conclusive evidence, anecdotal reports suggest potential benefits of lysine in feline herpesvirus-1 management and lysine is still widely prescribed by veterinary ophthalmologists, in the authors experience. It is important to note that this summary is based on a limited selection of studies and does not constitute a comprehensive review of the literature. More research is needed to fully understand the potential role of lysine in feline herpesvirus-1 management.
Beta-glucans
Beta-glucans are glucose derivatives that are found in the cell walls of bacteria, fungi, yeasts, algae, lichens and plants such as oats and barley (Rahar et al, 2011; Urbancikova et al, 2020). Orally ingested beta-glucan exhibits distinct behaviour compared to other dietary components. Its inherent acid resistance allows it to traverse the stomach largely intact, reaching the intestinal lumen. At this point macrophages recognise and bind beta-glucan particles via dedicated receptors. This interaction prompts immediate macrophage activation, culminating in their enhanced functionality. Moreover, these activated macrophages actively migrate to nearby Payer's patches (lymph nodes within the intestine). This migration plays a crucial role in their antigen-presenting function (Rahar et al, 2011).
One study indicated that beta-glucans possess a range of potential health benefits, including anti-infective, antiviral, anti-tu-mour, and immunomodulatory properties, further extending to wound healing capabilities. Notably, their antiviral activity demonstrates promising efficacy against a broad spectrum of viruses impacting plants, animals and humans, with documented success against herpes simplex virus type 1 (Urbancikova et al, 2020).
Beta-glucans exhibit in vitro antiherpetic activity and inhibit viral adsorption, penetration and cell-to-cell spread, as well as increasing the macrophage proinflammatory cytokine response to herpes simplex virus-1 infection. Beta-glucans are indicated as potential prophylactic or treatment agents in herpes simplex virus-1 infection (Urbancikova et al, 2020). No specific information regarding the activity against feline herpesvirus is available.
Resveratrol
Resveratrol, a health-promoting stilbene, is found in various food sources like grapes, berries, peanuts and legumes (Annunziata et al, 2018). Resveratrol exhibits its inhibitory activity against herpes simplex virus replication primarily at the level of the transcriptional apparatus. This is achieved through the inhibition of ribonucleotide reductase, which consequently impairs the normal expression of essential viral proteins including immediate–early protein-4, a protein critical for viral replication. This cascade ultimately leads to the disruption of immediate–early, early and lategene activation within the infected cell. These effects are attributed to resveratrol's capability to suppress nuclear factor-κB activation (Docherty et al, 1999; Annunziata et al, 2018).
Compounded antiviral nutraceuticals and supplements
In veterinary medicine, these products serve primarily as an adjunctive treatment option for active feline herpesvirus and as a preventative measure against recrudescent disease. Nutraceuticals or supplements do not negate the need for antiviral drugs, such as idoxuridine, famciclovir and cidofovir (Thomasy and Maggs, 2016). Stress is a known contributor to feline herpesvirus reactivation, making it crucial that any preventative product does not itself induce stress, as this could paradoxically exacerbate the condition (Thomasy and Maggs, 2016). Consequently, palatability is paramount, and treatment non-compliance as a result of taste aversion necessitates discontinuation. Lysine exemplifies this challenge because of its extreme bitterness. Therefore, crushing human-based formulations or administering whole tablets is contraindicated.
Nutraceuticals and supplements with effects on the lens
Diabetic cataracts
Canine diabetes mellitus frequently coincides with the rapid development of bilateral, symmetrical cataracts (Beam et al, 1999; Shay et al, 2009; Kador et al, 2010). Elevated blood glucose levels translate to increased lens glucose concentration, saturating the hexokinase-mediated anaerobic metabolic pathway. This compels a metabolic shift towards an alternative pathway involving the enzyme aldose reductase. Aldose reductase catalyses the reduction of glucose's aldehyde form to sorbitol, leading to its accumulation within the lens. Osmotic forces then drive the influx of aqueous humour into the lens, inducing architectural changes characterised by fibre swelling, rupture, vacuole formation and ultimately, clinically apparent cataracts (Kador et al, 2010). Research has found that 50% of canine diabetic patients exhibit cataract formation within 170 days of diagnosis, rising to 80% by day 470 (Beam et al, 1999). While topical administration of the aldose reductase inhibitor Kinostat has been demonstrably effective in inhibiting cataract development in diabetic dogs (Kador et al, 2010), the product remains commercially unavailable.
Alpha-lipoic acid is a naturally occurring compound synthesised enzymatically in the mitochondrion from octanoic acid. Alpha-lipoic acid serves a critical role in mitochondrial energy metabolism (Shay et al, 2009). In addition to synthesis, alpha-lipoic acid is also absorbed intact from dietary sources, including red meat, carrots, beets, spinach, broccoli and potatoes. Alpha-lipoic acid is an aldose reductase inhibitor as well as a potent antioxidant, efficiently chelating metals and scavenging reactive oxygen species like hydroxyl radicals, hypochlorous acid and singlet oxygen. Additionally, alpha-lipoic acid facilitates the regeneration of reduced glutathione, contributing to its antioxidant potential (Shay et al, 2009; Williams, 2017). Williams (2017) demonstrated that daily administration of alpha-lipoic acid at 2 mg/kg in diabetic dogs delayed and potentially prevented cataract development by acting as an antioxidant and aldose reductase inhibitor.
Cataracts and refractive errors
The lens plays the crucial role of focusing light onto the retina throughout an individual's lifespan. However, this inherent function entails an unavoidable consequence, namely photo-oxidation of lens structures. Despite its outwardly inert appearance, the lens harbours adenosine triphosphate levels comparable to those found in muscle (Greiner et al, 1985). This underscores the critical role of oxidative metabolism in maintaining lens transparency. Unfortunately, the continuous exposure to light is compounded by constant oxygen immersion. Oxygen's reduction to water proceeds through the intermediary superoxide, radical, O–₂. Thus, the initially benign oxygen molecule transforms into a highly reactive free radical. Research using laboratory rodent models has demonstrated that heightened oxidative stress associated with increased reactive oxygen species accelerates cataract formation (Williams, 2006). Thiol groups in lens proteins can be oxidised by sunlight, leading to the formation of disulphide bonds. This can cause the proteins to clump together and form aggregates, contributing to the development of cataracts.
Presbyopia, an age-related refractive condition, impairs the ability to focus on near objects because of a gradual loss of accommodation. Two primary factors contribute to this decline: a progressive weakening of the ciliary muscles, and a reduction in lens elasticity (Castro-Castañeda et al, 2022). This myopic shift entails a diminished ability to focus on distant objects, potentially translating to significant functional implications for canine activities and performance, particularly those requiring visual acuity for target acquisition, such as retrieving objects (Wang et al, 2016).
Veterinary literature on antioxidants and the lens is limited and most of the current information is based on human medicine. Vitamin C has been established as a critical player in safeguarding the lens from oxidative damage (Hegde and Varma, 2004; Castro-Castañeda et al, 2022). Its multifaceted role in lens biology encompasses antioxidant activity and ultraviolet filtering capabilities when present in the aqueous humour. Notably, the lenses of diurnal animals exhibit naturally high concentrations of ascorbate, highlighting its physiological significance (Hegde and Varma, 2004).
Naturally-occurring xanthophyll pigments within the lens, such as xanthin, lutein and zeaxanthin, are currently the subject of investigations exploring their potential role in mitigating oxidative damage (Castro-Castañeda et al, 2022). However, current research interest primarily focuses on their protective role against age-related macular degeneration (Williams, 2006; Ma and Lin, 2010).
Curcumin exhibits antioxidant properties and has been shown to prevent cataract formation in various experimental models (Castro-Castañeda et al, 2022). Research suggests that the anticataractogenic effect of tomato extract might be attributed to the presence of the carotenoid lycopene (Williams, 2006). Grape-seed extract, which contains the potent antioxidant class of proanthocyanidins, has been shown to possess anticataractogenic effects in rats (Williams, 2006).
A 6-month study by Wang et al (2016) assessed the effectiveness of a specific antioxidant blend (20 mg lutein, 5 mg zeaxanthin, 20 mg beta-carotene, 5 mg astaxanthin, 180 mg vitamin C and 336 mg vitamin E) in slowing down refractive error development in dogs. The results demonstrated a statistically significant difference in refractive error change between the treatment and control groups, suggesting the potential benefits of antioxidant supplementation for canine vision health (Wang et al, 2016).
Neuroprotective agents for canine degenerative retinal and optic nerve diseases
Canine degenerative retinal and optic nerve conditions represent a significant cause of irreversible vision loss, encompassing conditions such as sudden acquired retinal degeneration syndrome, progressive retinal atrophy and retinal detachment. The increased intraocular pressure in glaucoma patients also leads to progressive retinal and in particular, retinal ganglion cell degeneration (Plummer et al, 2021). While treatment options exist for certain pathologies, excluding progressive retinal atrophy, the majority of these degenerative processes remain characterised by progressive and irreversible vision loss despite treatment efforts. This persistence likely stems from several inter-related factors, including oxidative stress, excitotoxicity arising from excessive release of excitatory amino acids like glutamate and aspartate, elevated intracellular calcium levels, neurotrophin deprivation and inflammatory processes (Hopper et al, 2021). In this context, neuroprotection can be defined as the strategic modulation of neurons and their surrounding microenvironment to promote their survival and functional integrity in adverse conditions (Hopper et al, 2021).
Acknowledging the current limitations and absence of rigorous clinical efficacy data, veterinary ophthalmologists nonetheless use presumed neuroprotective therapies in clinical practice to mitigate vision decline. Hopper et al (2021) administered a survey to veterinary ophthalmologists in the US to gauge their use of neuroprotective agents for these conditions in dogs. Notably, 85% of the respondents indicated having been prescribing such therapies for at least one of the four main pathologies: 69% for glaucoma, 31% for sudden acquired retinal degeneration syndrome, 70% for progressive retinal atrophy and 30% for retinal detachment (Hopper et al, 2021).
The main neuroprotective strategy recommended by veterinary ophthalmologists consisted of inhibiting oxidative stress. The most commonly prescribed by the cohort of US veterinary ophthalmologists was Ocu-GLO Vision Supplement for animals, which contains 12 antioxidants including grape seed extract, lutein, omega−3 fatty acids, vitamin A, vitamin C, alpha-lipoic acid, coenzyme Q10 and lycopene from tomato extract. Coenzyme Q10 is not licensed for use in the UK. Other commonly prescribed products in this study also contained similar, as well as additional, agents including zeaxanthin and astaxanthin (Hopper et al, 2021).
Lutein and zeaxanthin are oxygenated carotenoids with 40-car-bon chains and nine conjugated double bonds. Zeaxanthin differs from lutein only in the location of a single double bond within a hydroxyl group, potentially conferring unique biological functions. Compared to hydrocarbon carotenoids, they are more hydrophilic and polar, enabling efficient quenching of singlet oxygen in aqueous environments. Their absorption bands in the blue-vi-olet spectrum make them ideal filters for blue light, as confirmed by fluorescence emission studies (Ma and Lin, 2010). Wang et al (2016) demonstrated that nutritional factors, including lutein and zeaxanthin, can prevent age-related retinal decline and potentially preserve visual function in dogs.
Fatty acids are considered short-chain (<8 carbons in length), medium-chain (8–12 carbons) or long-chain (>12 carbons). The number of carbons in the chain gives the fatty acid different properties in terms of digestion, absorption and usage. They are further defined by the number of double bonds: saturated fats contain no double bonds, monounsaturated fats contain one double bond and polyunsaturated fats contain two or more double bonds. Dogs and cats require omega-6 and omega-3 fatty acids in their diet because they cannot produce these essential fatty acids on their own. The omega-3 essential fatty acids are alpha-linolenic acid, eicosapentaenoic acid and docosahexaenoic acid. Eicosapentaenoic acid and docosahexaenoic acid are found primarily in marine sources, including fish oil as well as phytoplankton and other marine plants. Among one of the most important functions of omega-3 fatty acids is its participation in the reduction of inflammation through competitive inhibition with arachidonic acid and important enzymes like 5-lipoxygenase and cyclo-oxygenase (Lenox, 2016). A diet rich in long omega-3 fatty acids may be beneficial to humans with age-related macular degeneration (Castro-Castañeda et al, 2022). There is no conclusive literature on the positive effects of omega-3 fatty acids and retinal degeneration in canine patients.
Conclusions
Within the domain of veterinary ophthalmology, nutraceuticals have demonstrated promising potential as therapeutic agents, exhibiting safety and efficacy in various clinical assays for diverse ocular pathologies. It is crucial to emphasise that, similar to their application in other medical fields, the use of nutraceuticals in ophthalmic contexts is intended as an adjunctive therapy to complement the primary treatment regimen. While these substances have displayed considerable therapeutic potential in addressing specific ocular conditions, a significant knowledge gap persists regarding their precise mechanisms of action and potential adverse effects across different types of ocular pathologies. This necessitates extensive further research to ensure their safe and efficacious implementation in ophthalmic care.