Anti-oxidant Phytochemicals as Potential Treatments for Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is responsible for a substantial proportion of severe visual impairment and blindness in people over 50 years of age. Current treatments for AMD are not effective in all patients and a proportion of patients who respond well to the treatment will still eventually develop central visual impairment. Despite all efforts to develop safe and efficient medications for AMD, as yet pharmacological approaches have failed to provide fully effective treatments for this condition. Various lines of evidence attest to the contributions of oxidative stress in the etiology of AMD. Anti-oxidant nutrients may be valuable preventive or therapeutic agents however complementary therapies can become widely adopted without sufficient knowledge of the real advantages and liabilities. This review considers the interventional potential of some common phytochemicals for treating AMD, primarily focusing on clinical and epidemiological evidence of potential public health relevance. DOI : 10.14302/issn.2471-2140.jaa-14-616 Address for correspondence: Prof. Liz Milward, School of Biomedical Sciences and Pharmacy MSB, University of Newcastle, Callaghan, NSW 2308, Australia. Tel.: +61 2 4921 5167; Fax: +61 2 4921 7903, Email: Liz.Milward@newcastle.edu.au


Introduction
Age-related macular degeneration (AMD) is a disease of the elderly, especially those of European ancestry, in which there is irreversible central vision loss and ultimately blindness [1][2][3]. As lifespans increase, AMD poses an increasingly serious issue for the aging population [4] and is now a well-recognized public health problem with substantial social and economic impact [5]. Epidemiological studies have identified AMD as the leading cause of blindness in the demographic of individuals 55 years and over in industrialized countries [6][7][8]. There is a strong need for greater understanding of the underlying pathology and molecular mechanisms to guide the development of effective therapies.
As shown in Fig. 1, the macula, from the Latin macula lutea, macula meaning spot and lutea yellow, is located near the centre of retina. The pathological processes in AMD lead to damage and degeneration of photoreceptors within this region [9], causing impaired sight in the centre of the visual field.
AMD can be divided into two stages: early AMD, where there is mild pathology but no obvious vision abnormalities, and late AMD, which manifests as severe vision loss [10]. The pathology of early AMD is characterised by drusen, extracellular deposits of cellular debris between the retinal pigment epithelium (RPE) and Bruch's membrane ( Fig. 1) that range in colour from yellow to white under ophthalmoscopy [11]. While early AMD itself does not manifest as noticeable vision loss in affected individuals, it is associated with a significant risk of progression to late AMD, where substantial loss of visual function is often reported [9]. Late AMD is classified into two forms, wet and dry, based on whether there is choroidal neovascularisation. Both forms have drusen but whereas dry AMD is non-neovascular and characterised by geographic atrophy that extends to the centre of the macula, in contrast wet AMD is  increased vessel fragility and permeability [12].
While the etiology and pathophysiology of AMD are still incompletely defined, it has been proposed that oxidative processes play a contributory role [13,14].
Although a wide array of clinical and experimental drugs using anti-oxidant components is currently applied in degenerative diseases [15], it is hypothesized that there are certain diet-based compounds with the capacity to strengthen defence systems in response to oxidative stress and inflammation [16,17]. In fact, the potential benefits of nutrient supplementation for age-related eye diseases have been recognized for some time [18]. This review presents evidence for putative roles of natural dietary anti-oxidants as preventative or interventional compounds in AMD. required to determine the optimal dosage of these phytochemicals.

Curcumin
(1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6heptadiene-2,5-dione), derived from the yellow curry spice turmeric, possesses potent antioxidant properties, as reviewed previously [48,49]. Results from animal models suggest that it may have protective effects in the retina. Although curcumin has poor oral bioavailability, which may limit its therapeutic utility in the retina, it has been reported that bioavailability can be increased by encapsulating curcumin in liposomes [50,51].
Protective effects of curcumin have been reported in rats with diabetes-induced oxidative stress and inflammation in the retina [24], supporting other studies suggesting that curcumin is able to cross the blood-retina barrier [52] and may assist the anti-oxidant defence system by scavenging free radicals. Similarly, protective preconditioning effects have been reported in a rat model of light-induced retinal degeneration [53]. Wistar albino rats exposed to damaging light after two weeks of curcumin supplemented diet (0.2%) were found to be inflammation and oxidative stress [53].
As far as we have been able to determine, there has been no human study investigating the role of curcumin in prevention, delay or treatment of AMD. Further studies will be needed to assess the effectiveness of curcumin supplementation in preventing or treating AMD.

Ginkgo biloba
Therapeutic and drought on plants, as reviewed previously [56].
Interestingly, the Chinese wolfberry, which is high in anthocyanin, has been considered for centuries to be beneficial for the eyes and is used to treat eye conditions in traditional Chinese medicine, as reviewed elsewhere [57]. RNAs [70]. Similarly, in mice, dietary supplementation with crocetin for five days (100 mg/kg/day) following bright light exposure (8000 lux for 3 h) has been reported to attenuate retinal photoreceptor damage and inner retinal dysfunction [71].
Researchers are now beginning to investigate the effects of saffron in AMD patients. Results from one pioneering study of short-term supplementation of 20 mg/day saffron for 90 days in twenty-five patients with early AMD has provided evidence for improvement in retinal flicker sensitivity in response to light over this period [72]. This challenges the traditional idea that antioxidants are beneficial for AMD only after long-term applications [73]. Another study by Marangoni and colleagues [75] assessed the association between major risk genotypes for AMD and the effects of saffron. The study recruited Although neuroprotective mechanisms of saffron are still to be worked out in full [70], these studies suggest saffron may have therapeutic value in degenerative conditions such as AMD.

Conclusion
Since the initiation and progression of AMD may be considerably influenced by exposure to oxidative factors, the anti-oxidant properties of phytochemicals make them excellent candidates for the prevention or treatment of AMD. The capacity to scavenge free radicals is proposed to be the main mechanism by which phytochemicals may protect against AMD. The functional characteristics of phytochemicals, in conjunction with their low-toxicity, commercial availability and ability to cross the blood-retina barrier, make these naturally derived substances an attractive option for combatting AMD. In