ANTIOXIDANTS IN AMD

Free radicals Free radicals are chemically active atoms or molecular fragments that have a charge due to an excess or deficient number of electrons They scavenge body to grab or donate electrons, thereby damaging cell, proteins, and DNA

Free radicals formation Endogenous: form as a result of normal aerobic respiration, metabolism, and inflammation Exogenous free radicals form from environmental factors such as sunlight, X- rays, smoking and alcohol.

Free radicals Examples Examples: super oxide anion(O 2 - ), hydroxyl radical (OH - ),hydrogen peroxide (H 2 O 2 ), some metals such as iron and copper

Free radicals mechanism Some of the reactive species leak out of their enzyme-binding sites and may damage other components of tissues such as proteins, membrane lipids, and DNA if not captured by detoxifying enzymes

Mechanisms of Lipid Peroxidation auto-oxidation: Polyunsaturated fatty acids are susceptible to auto-oxidation because their allelic hydrogen is easily removed by several types of initiating radicals. Photo-oxidation: is a process by which oxygen is activated electronically by light to form singlet oxygen, which in turn reacts at a diffusion-controlled rate with unsaturated fatty acids or other cellular constituents

Free radicals & Retina Retina is vulnerable to damage from lipid peroxidation because of: high content of polyunsaturated fatty acids It is well established that polyunsaturated fatty acids are sensitive to peroxidation in proportion to their number of double bonds very rich in mitochondria Excellent oxygen supply retina and choroid showed at least a sevenfold higher rate of oxygen consumption per milligram of protein compared with all other tissues tested (except the adrenal gland) Light exposure may trigger photo-oxidative processes

What Are Antioxidants? antioxidants are substances that are capable of counteract damaging effects of the free radicals antioxidants are substances that are capable of counteract damaging effects of the free radicals

Types of Antioxidants nutrients (vitamins and minerals) (Vitamin E,Vitamin C, Beta-carotene selenium, manganese and zinc enzymes (superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx )

Vitamin E Refers to all entities that exhibit biological activity of the isomer tocopherol Alpha-tocopherol, the most widely available isomer, has strongest effect in the body It is fat-soluble and is in a unique position to safeguard cell membranes from damage by free radicals.

VITAMIN E AND AMD  17 studies have assessed association between vit E and AMD  10 of the 17 studies found no significant results (Blumenkranz et al., 1986;Cardinault et al., 2005; Cho et al., 2004; Christen et al.,1999; EDCCS (Eye Disease Case Control Study), 1993;Mares-Perlman et al., 1995c, 1996a; Sanders et al., 1993; Seddon et al., 1994a; Smith et al., 1997; van Leeuwen et al.,2005).  7 studies found significantly protective effects under certain circumstances (Belda et al., 1999; Delcourt et al., 1999; Ishihara et al., 1997; Simonelli et al.,2002; van Leeuwen et al., 2005; VandenLangenberg et al.,1998; West et al., 1994)

Vitamin C is a water-soluble vitamin. also known as ascorbic acid. it scavenges free radicals that are in an aqueous (watery) environment, such as inside cells Vitamin C works synergistically with vitamin E to quench free radicals.

VITAMIN C AND AMD  26 studies have assessed the association between vitamin C intake or supplement use and risk for ARM (Blumenkranz et al., 1986; Cho et al., 2004; Christen et al., 1999; Delcourt et al., 1999; EDCCS (Eye Disease Case Control Study), 1993; Flood et al., 2002; Goldberg et al., 1988; Ishihara et al., 1997; Mares-Perlman et al., 1996a; Seddon et al., 1994a; Simonelli et al., 2002; van Leeuwen et al., 2005; VandenLangenberg et al., 1998; West et al., 1994).  12 studies did not find significant association (Blumenkranz et al., 1986; Cho et al., 2004; Christen et al., 1999; Delcourt et al., 1999; EDCCS (Eye Disease Case Control Study), 1993; Goldberg et al., 1988; Ishihara et al., 1997; Mares- Perlman et al., 1996a; Seddon et al., 1994a; van Leeuwen et al., 2005; VandenLangenberg et al., 1998; West et al., 1994)  2 studies found significant results, but in opposite direction (Flood et al., 2002; Simonelli et al., 2002).

Carotenoids in retina Activity: carotenoids have been shown to make up the yellow pigment in the macula limiting chromatic aberration at the fovea protect the macula against short- wavelength visible light quenching of free radicals Beta Carotene is the precursor for vitamin A

Carotenoids in retina A mixture of the two carotenoids lutein and zeaxanthin presents in the macula zeaxanthin is concentrated in the fovea lutein is dispersed throughout the retina. Little beta-carotene is present in the human eye. carotenoids are present only in the retina and not at all in the RPE.

Beta-carotene and AMD  Of the 13 studies that have tried to relate beta- carotene to ARM 2 studies found significant results to support a protective role for beta- carotene on advanced AMD (Cardinault et al., 2005; Cho et al., 2004; EDCCS (Eye Disease Case Control Study), 1993; Flood et al., 2002; Mares-Perlman et al., 1995c, 1996a; Sanders et al., 1993; Seddon et al., 1994a; Simonelli et al., 2002; Smith et al., 1997; van Leeuwen et al., 2005; VandenLangenberg et al., 1998; West et al., 1994),

VITAMIN A AND AMD  12 studies related vitamin A or retinol to AMD, of these, only 3 studies found significant results (Blumenkranz et al., 1986; Cho et al., 2004; Delcourt et al., 1999; Flood et al., 2002; Goldberg et al., 1988; Ishihara et al., 1997; Knekt et al., 1992; Sanders et al., 1993; Seddon et al., 1994a; Simonelli et al., 2002; Vanden Langenberg et al., 1998; West et al., 1994).

Lutein / Zeaxanthin and AMD  14 studies have related lutein and zeaxanthin to ARM (Cardinault et al., 2005; Cho et al., 2004; EDCCS (Eye Disease Case Control Study), 1993; Flood et al., 2002;Gale et al., 2003; Mares-Perlman et al., 1995c, 1996a, 2001; Sanders et al., 1993; Seddon et al., 1994a; Simonelli et al., 2002; Snellen et al., 2002; van Leeuwen et al., 2005; Vanden- Langenberg et al., 1998).  5 studies indicated beneficial effects due to consuming higher level of lutein/zeaxanthin  9 studies, did not find significant results including four prospective studies from the Beaver Dam Eye Study (VandenLangenberg et al., 1998), the Blue Mountain Eye Study (Flood et al., 2002), the Nurses’ Health Study, the Health Professionals Follow-up Study (Cho et al., 2004), and the Rotterdam Study

ZINC Is the most abundant trace element in human eye It is a cofactor for several antioxidant enzymes including catalase & superoxide dismutase

ZINC AND AMD 8 studies related zinc to AMD, Of these 3 studies found significant results

Vit E Cataract & AMD Trial (VECAT) Aim: to evaluate effects of VE in prevention of early AMD Design: C-C, n=1193, FU=4y, Vit E 500 IU/d Result: no effect

EYE DISEASE CASE DONTROL STUDY (EDCCS) Aim: to evaluate effects of dietary intake of antioxidant in decrease risk of AMD Design: C-C, n= 876, Results: higher intake of carotenoids → decrease risk for AMD Intake of Vit E,C & A was not associated with risk of AMD

BAEVER DAM EYE STUDY (BDES) Aim: to evaluate association between antioxidant & zinc and AMD Design: questionnaire(10 y), n ≈ 5000 F/U=5y Results: modest inverse association between intake of pro Vit A & zinc and AMD

PHYSICIAN’S HEALTH STUDY (PHS) Aim: to evaluate association between antioxidant and AMD Design: cohort, n= 21120, F/A> 12y, supplementary antioxidant & multivitamin Results: no association between use of antioxidants & multivitamin and reduce of AMD

NHS & HPFS Aim: to evaluate effects of dietary intake of antioxidant in decrease risk of AMD Design: prospective F/U, n= 120,000, Results: consume of > 3 serving/d of fruits had significantly reduce risk of AMD did not find significant association between intake of vegetables, supplement antioxidants, multivitamin or carotenoids

AGE RELATRD EYE DISEASE STUDY (AREDS) Aim: to evaluate effects of vit C (500mg) vit E (400 IU) beta-carotene (15 mg) & zinc (80mg) /d in AMD Design: C-T, n ≈5000, in 4 groups, (no drusen, small, intermediate or large drusen) received antioxidant or zinc or both F/U>6y

AREDS STUDY (contd.) Patients divided into 4 categories: Category 1: little or no AMD -> randomized to antioxidants or placebo to determine any effect on lens changes Category 2: early AMD Category 3: intermediate AMD Category 4: advanced AMD in one eye Category 2, 3 and 4 randomized to receive: 1.Placebo 2.Antioxidants alone 3.Zinc alone 4.Antioxidants plus zinc

AREDS STUDY (contd.) Results For category 2, only 13% of patients progressed to advanced AMD. For categories 3 and 4 (who are at greater risk for developing advanced AMD), it was found that the combination of zinc and antioxidants were most effective in reducing the progression to advanced AMD.

Recommendations of AREDS Persons >55y should have dilated eye examination Those with Extensive intermediated size drusen At least one large drusen Non central geographic atrophy Visual loss due to AMD in one eye Should consider take supplement of antioxidants and zinc

Conclusions and considerations Oxidative stress and its sequelae are clearly involved in the etiology of AMD Data from the observational studies suggest beneficial effects of some specific antioxidants Data from the intervention trials are not totally consistent However, it is clear that good nutrition, coupled with healthy lifestyles which preclude known risk factors for eye diseases such as smoking, overweight, must be begun early in life in order to obtain the benefit of prolonged sight later in life

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