21.1Introduction

Natural compounds provide frontline pharmacotherapy for many millions of people worldwide. The transformation of traditional medicines derived from natural compounds into modern drugs has its origins in the archetypal examples of the antimalarial quinine and the antipyretic analgesic aspirin. Tens of thousands of these natural compounds, many of which are produced as secondary metabolites by the higher plants as a natural defense against disease and infection, have been found to be useful for ameliorating human diseases. Numerous reports describe studies that have been conducted to explore the beneÞt of nutraceuticals and botanicals on the prevention and treatment of several common retinal disorders, especially the chronic retinal illness such as age-related macular degeneration (AMD), diabetic retinopathy (DR), and retinitis pigmentosa (RP). There are many common insults and mechanistic compromises of the retina, such as chronic exposure to light and the higher oxidantstress environment with aging, that when combined with a personÕs genetic makeup and personal habits (such as smoking) are integral to these multifactorial chronic retinal diseases. From a mechanistic point of view, oxidative stress and inßammation have been the core for pathological development. Therefore, supplementation of natural compounds with known beneÞcial antioxidative and anti-inßammatory properties, started at right age, along with healthy lifestyles may provide some practical way to delay the onset of these chronic diseases and thus protect vision. The results from the Age-Related Eye Disease Study (AREDS) on AMD support this hypothesis. AMD is considered to be the major cause of irreversible blindness in the elderly population in Europe and the USA [1]. The role of oxidative stress in the pathogenesis of AMD is strongly supported by the AREDS, which found that dietary supplementation of antioxidants can signiÞcantly reduce the risk of progressing to advanced AMD by 25%, and the risk of moderate vision loss by 19% (http://www. nei.nih.gov/amd/). On the other hand, retinopathy associated with diabetes generally occurs 10 years after the onset of diabetes, which remains one of the leading risk factors of blindness worldwide [2]. Likewise, one of the crucial contributors in the pathogenesis of DR is oxidative stress, which also appears to be highly interrelated with other biochemical imbalances. This stress and other imbalances lead to structural and functional changes, accelerated loss of cells in the retinal microvasculature and ultimately result in to pathological DR [3]. DR can be prevented by maintaining healthy blood sugar levels but there are a number of natural compounds, which may also help delay or treat retinopathy by inhibiting protein glycosylation, stabilizing collagen, decreasing capillary permeability, and providing important antioxidant effects [4]. It is estimated that 1.5 million people have RP worldwide [5]. Unlike AMD, RP is a heterogeneous group of inherited retinal degenerative diseases. Since no generally accepted medical treatment can stop the course of this disease, there have been studies undertaken with the supplementing of natural compounds with the intent of improving RP patientsÕ visual function.

Natural compounds with potent antioxidative and anti-inßammatory properties hold the promise to be effective against these retinal diseases. Since these compounds

are mostly plant-derived and nontoxic, and mechanistic aspects are somewhat understood, identifying effective compounds using animal models should pave the path for future clinical trials. Hindering the development of natural compounds is the lack of awareness and interest by both the research community and by clinicians. Here, we summarize the evidence that natural compounds, including carotenoids, omega-3 long-chain polyunsaturated fatty acids (LC-PUFAs), polyphenols or phenolic ester, sulfur-containing chemicals, and vitamins, could have potential therapeutic beneÞts for major retinal diseases.

21.2Carotenoids in Retinal Diseases

More than 600 carotenoids have been identiÞed in nature [6]. Among them, lutein and its stereoisomer, zeaxanthin, have been studied widely and have shown diverse beneÞcial effects on improving eye health and especially for improving AMD [7, 8]. Although these two carotenoids are similar in structure to a- and b-carotene, they do not have provitamin A activity [9]. Lutein and zeaxanthin give the macula its characteristic Òyellow spotÓ appearance, and are the major components of macular pigment [8]. Lutein is found in higher concentrations in the central macula surrounding the fovea, while zeaxanthin concentrates in the fovea [10, 11]. Their antioxidant properties, as well as the ability to Þlter blue light, may help protect the outer retina and retinal pigmented epithelium (RPE) from oxidative stress and maintain cell membrane stability [8]. Lutein and zeaxanthin also appear to decrease the amount of lipofuscin and A2E formed, as well as attenuate photooxidative damage of RPE cells induced by lipofuscin [12, 13]. Results of some studies support the hypothesis of a connection between AMD and macular pigment optical density (MPOD), since low MPOD appears to be a potential cause of AMD [14Ð17]. The authors of the Carotenoids in Age-Related Eye Disease study (CAREDS) suggest that prospective studies are needed to further explore this relationship [18].

Several large-scale epidemiological trials, including AREDS, have examined the association between AMD risk and the supplementation of lutein and zeaxanthin [18Ð21]. In 2007, AREDS recruited 4,519 participants aged 60Ð80 years with prevalent AMD to evaluate the relationship of dietary carotenoids (including provitamin A carotenoids and lutein/zeaxanthin), vitamin A, vitamin E, and vitamin C. They concluded that the quintile of dietary intake of lutein/zeaxanthin was inversely associated with neovascular AMD, geographic atrophy, and extensive intermediate drusen, with 27, 35, and 55% lower probabilities, respectively. The other nutrients were not independently related to AMD [21]. CAREDS also found that lutein/ zeaxanthin-rich diets may protect against intermediate AMD. CAREDS data on carotenoids supplementation in 1,781 participants found a signiÞcant reduction in the risk of AMD by 43% in female patients younger than 75 years of age [20]. A recent trial from Blue Mountains Eye Study (BMES) in Australia demonstrated that increased dietary intake of lutein/zeaxanthin reduced the risk of incident AMD over 5- and 10-year periods [22].

Due to the information emerging about AMD, several small studies have been conducted to explore the effect of carotenoids on the pathogenesis of retinal degeneration diseases of RP and Usher syndrome [23Ð26]. However, the results were inconsistent with the expectations. Aleman et al. found that supplementing lutein for 6 months did not result in improvement of central visual function. However, there was a signiÞcant increase in MPOD for approximately half of the RP and Usher syndrome patients [24]. A randomized, double-masked, placebo-controlled trial demonstrated that lutein might slightly ameliorate the visual acuity in patients with RP [25]. Adackapara et al. also conducted a trial examining the effects of a 48-week period of supplementation with lutein to assess the effects of lutein on the retinal thickness of patients with moderately advanced RP. The study indicated that lutein did not exert a beneÞcial effect on the retinal thickness [26].

21.3Omega-3 Polyunsaturated Fatty Acid

In the past decades there has been much interest in two of the omega-3 LC-PUFAs, docosahexaenoid acid (DHA) and eicosapentaenic acid (EPA), due to their postulated effect in the development of various retinopathies. The retina is one of the few vertebrate tissues with abundant PUFA content [27]. Omega-3 LC-PUFAs and their potent mediators (eicosaoids, endocannabinoids, resolvins, lipoxins, docosatrienes, and neuroprotectins) may modulate the metabolic process related to retinal ischemia, chronic light exposure, oxidative stress, inßammation, cellular signaling mechanisms, and aging [28Ð30]. DHA is highly concentrated in the outer segment of photoreceptors, comprising approximately 50% of the total lipid [31Ð33]. Because of this, DHA is thought to play an important role in providing an environment for conformational rhodopsin changes and in modifying the activity of retinal enzymes in photoreceptors [34]. EPA is the parent fatty acid for a family of eicosanoids that have the potential to affect arachidonic acid (AA)-derived eicosanoids, which are implicated in abnormal retinal neovascularization, vascular permeability, and inßammation [28]. There is consistent epidemiological evidence to suggest that omega-3 LC-PUFAs may have a protective role against ischemia-, light-, oxygen-, inßamma- tory-, and age-associated pathology of the vascular and neural retina [28, 35].

Extensive epidemiologic evidence also shows an association between AMD and both dietary DHA and dietary EPA [28, 35Ð45]. A nested cohort study of an AREDS population (>1,800 participants) with moderate-to-high risk of advanced AMD demonstrated a 30% reduced incidence of advanced AMD over a 12 year period in patients reporting the highest consumption of omega-3 fatty acids [46]. Additionally, AREDS participants with the highest intake of omega-3 LC-PUFAs were approximately half as likely to have neovascular AMD at baseline. They were also less likely to progress from bilateral drusen to central geographic atrophy over a 6-year period [42, 47]. Recently, Chong et al. reported a meta-analysis with a total sample of 88,974 people, including 3,203 AMD cases (1,847 early and 1,356 late AMD cases) [41]; consumption of n-3 fatty acids may be associated with a lower risk of AMD