**4. Lutein and AMD**

#### **4.1. AMD**

electrons are available in the polyene chain, thus cannot induce oxidation of lipid, protein and DNA in cells. Second, lutein and zeaxanthin insert themselves into the cell membrane to pair the single electron in ROS, making the lipid bilayers more rigid. Lutein was found to insert into the biological membranes in perpendicular and parallel orientation, while zeaxanthin follows the perpendicular orientation in the lipid membrane [28]. It is the transmembrane alignment of MPs that reduce the susceptibility of lipid bilayers to oxidative injury and main-

ROS is directly or indirectly involved in the most pathological processes observed in the retina, including inflammation, neuron degeneration, angiogenesis, or cell apoptosis. In the process of inflammation, excessive generation of ROS has been found to simulate many pro-inflammatory pathways. Moreover, oxidative injury is also associated with certain downstream signaling pathways in inflammation. Our research team has evaluated the anti-inflammatory effects of lutein in mouse model of ischemia/reperfusion and demonstrated that several proinflammatory factors, including nuclear factor-kappa B (NF-κB), interleukin 1β(IL-1β), and cyclooxygenase-2 (Cox-2), from Müller cells were significantly decreased in lutein-treated group when compared with control group, suggesting protection effects of lutein in retinal ischemia/reperfusion damage was achieved by its anti-inflammatory property [34]. Similarly, supplementation of lutein and zeaxanthin decreased NF-κB activity, while increased levels of erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1), which are the key factors to initiate phase II antioxidant protection to eliminate oxidative stress, in rats fed with high

In addition to the functions mentioned above, lutein also plays an important role in maintaining other visual performance. A huge number of studies have shown that lutein and/or zeaxanthin, or in combination with other antioxidants have improved visual acuity and contrast sensitivity in healthy, young adults, in subjects with AMD at early and/or advanced stage, and in people with diabetes. High levels of MPs have been reported to decrease the influence of bright lights via quick recover from bright lights and improvement of ability to see in glare conditions. Daily uptake of lutein (20 mg/day) for a year increased visual contrast and glare sensitivity in healthy Chinese drivers, thus benefiting driving or other vision-related tasks performed at night [17]. Furthermore, MPs are able to speed conversion of photic impulses into electrical impulses in retina as well as the transmission to the visual cortex in the brain by

Furthermore, lutein has been shown to have neuroprotective effects in the retina. We have reported that in mouse model of ischemia/reperfusion, lutein decreased the expression of nitrotyrosine, and nuclear poly(ADP-ribose) (PAR) in GCL and INL, which are the markers for oxidative stress; thus exhibited protection effects on cell loss and cell apoptosis in inner retinal neurons [37]. Similar results were observed in the cerebral ischemia/reperfusion injury [38]. We further used the in vitro model of oxidative stress and hypoxia to evaluate the neuroprotective function of lutein in retinal ganglion cells. Our data revealed that

O2


(cobalt

tain the integrity and rigidity of biological membranes [33].

fat diet [35].

*3.2.3. Other functions*

178 Progress in Carotenoid Research

keeping neurons in healthy state [36].

lutein could protect ganglion cells from either H2

AMD is the leading cause of visual impairment in people 65 years and above in developed countries. It is a slowly progressive disease that affects the central retina or macula. As estimated by the United Nations, approximately 20–25 million people are affected by AMD across the world, and the prevalence inevitably rises with the increasing of aged populations. By the end of 2020, it is expected that only in the USA, the number of AMD patients will reach to almost 3 million [42].

AMD is a complicated, multifactorial ocular disease, and the exact etiology still remains unclear. However, a number of risk factors are thought to be related to the pathogenesis of AMD. Of all those factors, age is the most obvious risk factor. Both the incidence and prevalence of AMD increase with age. Many investigators revealed that the family members of AMD patients were more prone to develop this disease, demonstrating the genetic factors in the genesis of AMD. Furthermore, the incidence in Caucasians is higher than that in other ethnic populations. There is no apparent sex preference in AMD patients, although some studies have indicated that women may be more susceptible [43]. In addition to the unmodified factors mentioned above, several other factors that can be modified are also involved in the pathogenesis of AMD. Smoking is considered as a frequent environmental risk factor, which is proved to double the AMD risk through increasing the oxidative stress in the macula [44]. Excessive exposure to the sunlight can lead to lipid peroxidation on cell membranes. Hypertension, overweight or obesity, poor nutrition status, and cardiovascular diseases are also correlated with AMD.

AMD is classified into a non-exudative or atrophic (dry) form, accounting for 90% of AMD, and an exudative (wet) form, accounting for only 10% of AMD. The atrophic form is characterized by the accumulation of drusen under the macula formed by photo-oxidation of lipids plus proteins, and progressive degeneration of RPE cells in the macula, affecting central vision to varying degrees. The exudative form is associated with choroidal neovascularization (CNV) in the submacular area and subsequent retinal hemorrhage, leading to severe central vision loss.

The most destructive type of AMD is the exudative or wet form because of the sudden loss of vision. Therapies for the wet form of AMD mainly focus on halting the progression of CNV, of which intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) drugs have been widely adopted by ophthalmologists as a standard treatment due to the up-regulation of VEGF in the development of CNV. Although it has been proved that anti-VEGF compounds can restrict growth of abnormal blood vessels, therefore making vision stabilized or even improved, the cost of each injection is relatively high and monthly intravitreal injection may be required for some patients. In contrast, the current treatments for non-exudative AMD are very limited. Hitherto, no medicine has yet approved for dry AMD in the world. Hence, strategies to delay the onset of this severe visual loss have been focused on the decrease of modified risk factors. Among these modified risk factors, oxidative stress is recognized as one of the major contributing factors in AMD. Since lutein is a powerful antioxidant that is highly concentrated in the retina, the effects of lutein on AMD have been widely investigated.

*4.2.2. Observational studies (MPs levels in the retina)*

*4.2.3. Interventional studies (supplementation of lutein)*

by increasing MPOD.

of MPs.

In addition to dietary intake and serum concentration of lutein and zeaxanthin, MPs level in the retina was also inversely associated with the risk of AMD. In a case-control study, the actual amounts of lutein and zeaxanthin in donor retinas with and without AMD were measured. Levels of lutein and zeaxanthin in three concentric areas (inner, medial, and outer) centered on the fovea were markedly lower in AMD donor retinas than these in control donor retinas, especially in the outer area, where logistic regression analysis suggested that donors in highest quartile of MPs levels had an 82% lower risk for AMD when compared with those in the lowest quartile after adjustment of age and sex [51]. This is the first report showing the decreased retinal levels of lutein and zeaxanthin in AMD patients, which was consistent with above findings concluded from diet and serum xanthophylls concentrations. Subsequently, MPOD, an indicator for MPs levels in retina in vivo, has been widely studied between healthy individuals and AMD patients. There was a MPOD decline in healthy eyes as the individuals aged, and MOPD in healthy eyes at high risk of AMD was significantly lower than those at no such risk [52, 53]. Moreover, Bernstein and his co-workers [54] evaluated MPs levels in relation to the incidence of AMD using noninvasive resonance Raman spectroscopy, and found 32% reduction of retinal lutein and zeaxanthin levels in AMD versus normal participants. However, it was notable that lower MPOD has also been linked with other risk factors for AMD, such as smoking and family history of this disease [55]. This result further supported the hypothesis that lutein and zeaxanthin could prevent or delay the development of AMD

Lutein and the Aging Eye

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http://dx.doi.org/10.5772/intechopen.79604

Observational results in relation to AMD have triggered a mass of interests in assessing effects of lutein supplementation on the risk of AMD. The supplementation trial was first reported in the Lutein Antioxidant Supplementation Trial (LAST) study [56]. This was a prospective, double-masked, placebo-controlled, randomized study to evaluate supplementation of lutein alone or lutein with other antioxidants, vitamins, and minerals in 90 atrophic AMD patients. After 12 months, higher MPOD, improved visual acuity and contrast sensitivity were observed in both of these groups than in placebo group. However, longer duration of the study, larger number of samples, and both genders are needed to examine the long-term effects of lutein or the combination of lutein with other nutrients in the treatment of dry AMD. Three years later, LASTII was performed to further analyze the specific factors that affected MPOD, including age, baseline levels of MPs, and combination of lutein and other antioxidants [57]. There was an increase in MPOD with supplementation, while a moderate reduction of MPOD was observed without supplementation. Patients with lowest baseline MPOD value were most likely to have a dramatic increase in MPOD than those with medium to high baseline MPOD during one-year supplementation of lutein or lutein with other nutrients. The reason might be the saturation mechanism that had an impact on the retinal transportation and stabilization

In the Combination of Lutein Effects in the Aging Retina (CLEAR) study, Murray et al. [58] supplemented the patients at early stage AMD with 10 mg lutein esters per day for up
