Antioxidants for Ocular Health
Today’s dogs seem far more predisposed to cancer and other immune-mediated diseases than dogs in decades past. Conditions like these result from an excess of oxidative stress that cannot be counteracted by the endogenous antioxidant systems of the cells, or by the typical diet. The causes are likely numerous but certainly the quest for the perfect dog in a specific breed has led to many of the genetic diseases we see in veterinary medicine – and ophthalmology. The hybrid or designer breeds now popular are not immune even though the intent was to diminish the genetic issues; unfortunately, this did not entirely happen.
The most common genetic diseases we see in veterinary ophthalmology practice include cataracts, retinal degenerations and glaucoma.1-3 Each breed or group of breeds likely have various mutation(s) that predispose that dog to one or more of these diseases. And unfortunately, you cannot change your genes. Thanks to the Dog Genome Project, the mutations for these diseases are already identified for some breeds, and many more will continue to be identified.
The new disciplines of nutrigenomics and nutrigenetics have helped cement nutrients as ways in which to modulate health. Nutrigenomics refers to genetic variation and its dietary response.1 Nutrigenetics refers to the evolutionary aspects of diet and the role of nutrients in gene expression.1 While the impact of diet and nutritional supplementation may not appear to affect inherited ophthalmic diseases in dogs, we might learn that genes that become involved in any of these diseases may be affected by what a dog eats. Likewise, this same concept of genetic variation and gene-nutrient interaction is important in drug metabolism and adverse reactions to drugs.1 That said, an intake of certain nutrients may directly or indirectly modulate genes, including those that affect eye diseases.
While inherited cataracts in dogs are unlikely to be prevented or inhibited by nutriceutical supplementation, antioxidants will improve the environment of the lens cells and possibly reduce secondary sequellae to the ensuing oxidative stress caused by cataractogenesis. Some examples of nutrients shown to have aprotective effect on lens epithelial cells and/or cataract development include grapeseed extract, lutein/zeaxanthin, lycopene, zinc and coenzyme Q10.
Proanthocyanidins are powerful antioxidants found in grapeseeds, tea, nuts, pine bark and other plant extracts. They have a variety of effects, including free radical scavenging and anti-inflammatory, anti-viral and antimicrobial activities. They also potentiate the function of vitamins C and E.5-7 A strain of rats (ICR/f) predisposed to hereditary cataracts due to lipid peroxidation were fed a diet containing grapeseed extract (GSE). Cataracts were slowed in progression and active glutathione (GSH) was higher in GSE-fed rats as compared to unsupplemented control rats.2 Selenite-induced cataracts, a form of toxin-induced cataract, were also significantly slowed or prevented by GSE.3 In vitro studies on lens epithelial cells found that GSE reduced oxidative stress-induced reactive oxygen species production and attenuated stress-induced cell-signaling markers and NF-kB.4, 5
Lutein and its coexistent isomer, zeaxanthin, are oxycarotenoids with two hydroxyl groups on either side of the molecule. They protect ocular tissues against photooxidative stress, quench and scavenge ultraviolet radiation-induced reactive oxygen species, inhibit lipid peroxidation, and filter blue light.6 They are the only carotenoids found in the retina and lens (Bomser, unpublished results in dogs).7 Lutein and zeaxanthin are potent antioxidants that inhibit lipid peroxidation. Though the literature strongly supports their role in protection against age-related cataracts in humans, there are no published reports investigating their inhibition of specific inherited or toxic cataracts in rodent models or other species. However, lutein and zeaxanthin may improve the lens environment during cataractogenesis through their anti-inflammatory activity.8 Cataractogenesis, regardless of the stage in dogs, causes inflammation9, 10 and chronic uveitis can cause cataractogenesis.11 Therefore, one can exacerbate the other.
Other plant extracts with protective effects against cataracts include lycopene and curcumin. Lycopene is a potent carotenoid found in tomatoes. Lycopene protects against selenite-induced cataracts as well as galactosemia-induced cataracts.12, 13 In vitro, lens epithelial cells exposed to selenite improved antioxidant activity and glutathione levels when supplemented with lycopene, compared to unsupplemented control cells. Curcumin is the chief phenolic compound found in turmeric (Curcuma longa).14 Curcumin’s anti-inflammatory and antioxidant effects are due to its ability to induce antioxidant enzymes, decrease production of pro-inflammatory cytokines, sequester free radicals, inhibit neutrophil and macrophage function, and inhibit lipid peroxidation.15-20 All cataractogenic processes have an imbalance in calcium, and curcumin may have anticataractogenic effects by preventing free radical-mediated accumulation of calcium in the lens.21 Calcium (Ca2+) is elevated in cortical, but not nuclear cataracts,22 and excessive Ca2+can be detrimental to lens cells. Calcium is tightly regulated in the lens and its imbalance is associated with changes occurring during cataractogenesis.23
Inherited degenerative or dystrophic retinal diseases have been a focus of research beginning in 1955. This research evaluated red Irish setters using the electroretinogram,24 and was followed in 1965 by the description of a photoreceptor abiotrophy in the elkhound.25 Since then, hundreds of publications have characterized and described the various forms of retinal dystrophy and degenerations in numerous breeds of dogs. With our improved understanding of gene cloning and the establishment of the Dog Genome Project, mutational analysis has identified specific mutations for these diseases in many breeds. As a result of this research, DNA testing is now available for 67 breeds so far.
Lutein and zeaxanthin selectively accumulate in the retina and lens.3-5 Recovery of electroretinographic function in dogs with Progressive Retinal Atrophy (PRA) has been demonstrated following nutritional supplementation; these findings suggest the progression of canine PRA is inhibited by antioxidant supplementation, including lutein and zeathanthin.26 Regardless of the mutation causing retinal dystrophy or degeneration, there is cell death and oxidative stress. Since rods are the major source of oxygen utilization in the retina, their death results in deleterious oxygen levels and photoreceptor damage.27, 28 Once the rods die, the cones gradually follow. It is hypothesized that cone death is due to oxidative damage possibly secondary to increased oxygen levels in the outer retina.27, 28
A combination of antioxidants including alpha-tocopherol, ascorbic acid and alpha lipoic acid, reduced oxidative stress. Individually, alpha-tocopherol and alpha lipoic acid, both lipid soluble antioxidants, showed significant increases in cone numbers compared with the other groups.27 Therefore, as long as enough cones survive in retinas with degenerative or dystrophic diseases, vision may be maintained or prolonged by the use of antioxidants.
Oxidative stress is an important part of glaucoma.29, 30 One theory is that an unstable ocular blood flow leads to repeated mild reperfusion events.31 Elevations in intraocular pressure (IOP) damage retinal ganglion cells with secondary excitotoxicity and free radical generation.32 Coenzyme Q10 has been shown to delay apoptosis in retinal ganglion cells resulting from high IOP.33 Much of the information, thus far, pertains to humans with open angle glaucoma, and rodent models; therefore, confirmation of oxidative stress events and evaluation of the effects of antioxidants in canine glaucoma are warranted. Other antioxidants, including polyphenols (grapeseed extract) and EGCG (green tea extract), may help slow the progression of the damage occurring in glaucoma.31
In summary, all diseases — including inherited ophthalmological conditions — have oxidative stress in their pathogenesis. The body’s numerous endogenous antioxidant systems fight the daily free radical damage that occurs with normal body functions, including digestion and metabolism and growth in young animals. However, an excess of oxidative stress, occurring with chronic lifelong situations such as inherited ophthalmic disease, depletes the endogenous antioxidant systems, and any antioxidants available from the diet. This likely exacerbates the progression of these diseases. Therefore, the use of antioxidant supplements as a complement to traditional therapy is likely beneficial.
1. Simopoulous AP. Nutrigenetics/Nutrigenomics. Ann Review Pub Health. 2010;31:53-68.
2. Yamakoshi J, Saito M, Kataoka S, Tokutake S. Procyanidin-rich extract from grape seeds prevents cataract formation in hereditary cataractous (ICR/f) rats. J Agric Food Chem. 2002;50:4983-4988.
3. Durukan AH, Everklioglu C, Hurmeric V, et al. Ingestion of IH636 grape seed proanthocyanidin extract to prevent selenite-induced oxidative stress in experimental cataract. J Cataract Refract Surg. 2006;32(6):1041-1045.
4. Barden CA, Chandler HL, Lu P, Bomser JA, Colitz CMH. The effect of grape polyphenols on oxidative stress in canine lens epithelial cells. Am J Vet Res. 2008;69:94-100.
5. Jia Z, Song Z, Zhao Y, Wang X, Liu P. Grape seed proanthocyanidin extract protects human lens epithelial cells from oxidative stress via reducing NF-кB and MAPK protein expression. Mol Vis. 2011;17:210-217.
6. Lutein and zeaxanthin. Alternative Medicine Review. 2005;10(2):128-135.
7. Yeum KJ, Taylor a, Tang G, Russell RM. Measurement of carotenoids, retinoids, and tocopherols in human lenses. Invest Ophthalmol Vis Sci. 1995;36:2756-2761.
8. Jin X-H, Ohgami K, Shiratory K, et al. Inhibitory effects of lutein on endotoxin-induced uveitis in Lewis rats. Invest Ophthalmol Vis Sci. 2006;47:2562-2568.
9. Gelatt KN, MacKay EO. Secondary glaucoma in the dog in North America. Vet Ophthalmol. 2004;7(4):245-259.
10. Leasure J, Gelatt KN, MacKay EO. The relationship of cataract maturity to intraocular pressure in dogs. Vet Ophthalmol. 2001;4(4):273-276.
11. Davidson MG, Nelms SR. Diseases of the Canine Lens and Cataract Formation. In: Gelatt KN, ed. Veterinary Ophthalmology. Vol 2. 4 ed. Ames: Blackwell; 2007:859-887.
12. Gupta SK, Trivedi D, Srivastava S, Joshi S, Halder N, Verma SD. Lycopene attenuates oxidative stress induced experimental cataract development: an in vitro and in vivo study. Nutrition. 2003;19(9):794-799.
13. Pollack A, Oren P, Stark AH, Eisner Z, Nyska A, Madar Z. Cataract development in sand and galactosemic rats fed a natural tomato extract. J Agric Food Chem. 1999;47:5122-5126.
14. Manikandan R, Thiagarajan R, Beulaja S, Sudhandiran G, Arumugam M. Effect of curcumin on selenite-induced cataractogenesis in Wistar rat pups. Curr Eye Res. 2010;35(2):122-129.
15. Kunchandy E, Rao MNA. Oxygen radical scavenging activity of curcumin. Int J Pharmaceut. 1990;58:237-240.
16. Sreejayan M, Rao N. Nitric oxide scavanging by curcuminoids. J Pharm Pharmcol. 1997;49:105-107.
17. Srivastava R. Inhibition of neutrophil response by curcumin. Agents Actions. 1989;28:298-303.
18. Joe B, Lokesh BR. Role of capsaicin, curcumin and dietary n-3 fatty acids in lowering the generation of reactive oxygen species in rat peritoneal macrophages. Biochim Biophys Acta. 1994;1224:255-263.
19. Chan MMY, H.I. H, Fenton MR, Fong D. In Vivo inhibition of nitric oxide synthase gene expression by curcumin, a cancer preventive natural product with anti-inflammatory properties. Biochem Pharmacol. 1998;55:1955-1962.
20. Reddy AC, Lokesh BR. Effect of dietary turmeric (Curcuma longa) on iron-induced lipid peroxidation in the rat liver. Food Chem Toxicol. 1994;32:279-283.
21. Manikandan R, Thiagarajan R, Beulaja S, Sudhandiran G, Arumugam M. Curcumin prevents free radical-mediated cataractogenesis through modulations in lens calcium. Free Radic Biol Med. 2010;48(4):483-492.
22. Duncan G, Bushnell AR. Ion analyses of human catractous lenses. Eye Research. 1975;20:223-230.
23. Rhodes JD, Sanderson J. The mechanisms of calcium homeostasis and signalling in the lens. Exp Eye Res. 2008;88:226-234.
24. Parry HB, Tansley K, Thomson LC. Electroretinogram during development of hereditary retinal degeneration in the dog. Br J Ophthalmol. 1966;39(6):349-352.
25. Cogan DG, Kuwabara T. PHOTORECEPTIVE ABIOTROPHY OF THE RETINA IN THE ELKHOUND. Pathol Vet. 1965;106:101-128.
26. Umeda Y, Maehara S, Wakaiki S, et al. Electroretinographic, evaluation of supplementation including lutein for canine progressive retinal atrophy. Paper presented at: Annual Meeting of the American College of Veterinary Ophthalmologists, 2004.
27. Komeima K, Rogers BS, Lu L, Campochiaro PA. Antioxidants reduce cone cell death in a model of retinitis pigmentosa. Proc Natl Acad Sci USA. 2006;103(30):11300-11305.
28. Shen J, Yang X, Dong A, et al. Oxidative damage is a potential cause of cone cell death in retinitis pigmentosa. J Cell Physiol. 2005;203(3):457-464.
29. Zanon-Moreno V, Garcia-Medina JJ, Gallego-Pinazo R, Vinuesa-Silva I, Moreno-Nadal MA, Pinazo D, M.D. Antioxidant status modifications by topical administration of dorzolamide in primary open-angle glaucoma. Eur J Ophthalmol. 2009;19(4):565-571.
30. Izzotti A, Sacca SC, Longobardi M, Cartiglia C. Sensitivity of ocular anterior-chamber tissues to oxidative damage and its relevance to glaucoma pathogenesis. Invest Ophthalmol Vis Sci. 2009;Epub ahead of print.
31. Mozaffarieh M, Grieshaber MC, Orgul S, Flammer J. The potential value of natural antioxidative treatment in glaucoma. Surv Ophthalmol. 2008;53:479-505.
32. Russo R, Cavaliere F, Rombola L, et al. Rational basis for the development of coenzyme Q10 as a neurotherapeutic agent for retinal protection. Prog Brain Res. 2008;173:575-582.
33. Nucci C, Tartaglione R, Cerulli A, et al. Retinal damage caused by high intraocular pressure-induced transient ischemia is prevented by coenzyme Q10 in rat. Int Rev Neurobiol. 2007;82:397-406.