From: Subject: ANTIOXIDANTS IN OPHTHALMOLOGY Date: Mon, 23 Oct 2006 15:01:44 +0530 MIME-Version: 1.0 Content-Type: text/html; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: file://C:\WINNT\Profiles\Administrator\Desktop\material\IIIfolderonlearningmaterials19.10.2006\opthaqlomolgy\DNB%20ANTIOXIDANTSrecentadvances.htm X-MimeOLE: Produced By Microsoft MimeOLE V5.00.2314.1300 ANTIOXIDANTS IN = OPHTHALMOLOGY

ANTIOXIDANTS=20 IN OPHTHALMOLOGY

 

M R = Jain ,M. = R. J=20 Insttute & Jain Eye Hospital,=20 Jiapur =

 

 

INTRODUCTION

Free=20 radical chemistry began in 1900s when they were determined as cause for = fat=20 spoilage. Importance of free radicals in human diseases pathophysiology = was=20 first recognized in 1969 when McCord & Fridovich isolated the first=20 antioxidant enzyme superoxide = dismutase.1

 

The=20 controversy as regards the use of antioxidants, particularly = carotenoids, in=20 ophthalmic diseases seems to be resolving due to advances made in = measuring=20 their levels in foods and tissues. There is consistent experimental and=20 epidemiological evidence to substantiate the role of particularly lutein = and=20 zeaxanthin in prevention and, to a certain extent, cure of early = age-related=20 macular degeneration (ARMD) and cataract formation. Also clinical = observations=20 depending upon the recommended dietary modification and therapeutic=20 supplementation presently are encouraging.FREE=20 RADICALSDEFINITION

A=20 free radical is defined as any species (atom / molecule / molecular = fragment)=20 capable of independent existence and contains one or more unpaired=20 electrons.1

 

HOW=20 FREE RADICALS ARE FORMED?

The=20 various tissues in the human body are formed by innumerable molecules. = Each=20 molecule consists of two or more atoms joined together by chemical = bonds. An=20 atom, the smallest particle of an element, consists of a core which = contains=20 positively charged protons (or positrons) as well as neutral neutrons. = In the=20 orbit of each atom (referred to as orbital) are present the electrons = (or=20 negatrons). Each orbital can accommodate a maximum of two electrons both = of=20 which spin in opposite directions.

Most=20 molecules are non-radical since they contain a paired set of electrons. = But=20 oxygen is always electronegative. As a consequence, it pulls electrons = away from=20 other atoms (including oxygen itself) and renders these as free=20 radicals.

 

Oxygen-derived = free radicals have a lifespan of only a few microseconds.4 = Their=20 concentration at any single site is miniscule. However the danger lies = in their=20 ability to combine with another nonradical to render the latter as free = radical.=20 Normally,=20 bonds don=92t split in a way that leaves a molecule with an odd, = unpaired=20 electron. But when weak bonds split, free radicals are formed. Free = radicals are=20 very unstable and react quickly with other compounds, trying to capture = the=20 needed electron to gain stability.

 

Fig:=20 Serial formation of free radicals.

 

 

Generally,=20 free radicals attack the nearest stable molecule, thereby "stealing" its = electron. When the "attacked" molecule loses its electron, it becomes a = free=20 radical itself.  This = leads to a=20 process of chain reaction.1 Once such a process has started, = it can=20 cascade, finally resulting in the disruption of a living=20 cell.

 

Radicals can react =
with other molecules in a number of ways. If two radicals meet, they can =
combine their unpaired electrons symbolized by.) and join to =
form a covalent bond (a shared pair of electrons). The hydrogen atom, =
with one unpaired electron, is a radical and two atoms of hydrogen =
easily combine to form the diatomic hydrogen =
molecule:4
H. + H. =

 
Radicals react with =
nonradicals in several ways. A radical may donate its unpaired electron =
to a non-radical (a reducing radical) or it might take an electron from =
another molecule in order to form a pair (an oxidizing radical). A =
radical may also join onto a nonradical. Whichever of these three types =
of reaction occurs, the nonradical species becomes a radical. A feature =
of the reactions of free radicals with nonradicals is that they tend to =
proceed as chain reactions, where one radical begets =
another.

 

SOURCES=20 OF FREE RADICALS

Some=20 free radicals arise normally during metabolism.5 Sometimes = the body=92s=20 cells or it=92s immune system purposefully create them to neutralize = viruses and=20 bacteria. However, environmental factors such as pollution, radiation, = cigarette=20 smoke and herbicides can also generate free radicals. Free radicals = causing=20 structural damage (to proteins) resulting in aging changes such as = cataract and=20 ARMD.

 

An=20 adult utilizes 3.5 ml oxygen per kg body weight per minute. Assuming a = body=20 weight of 70 kgs, this works out to 352.8 liters per day. Even if 1% of = oxygen=20 is converted to free radicals, this amounts to 1.72 kg of free oxygen = radicals=20 per year!6

 

 

 

EXAMPLES=20 OF FREE RADICALS

Some=20 free radicals well studied free radicals=20 are:4,7,8

=A8      =20 SUPEROXIDE=20 ANION (O2.)

=A8      =20 HYDROXYL=20 RADICAL (OH.)

It=20 is important to note that free radicals such as hydroxyl radical differ = from=20 hydroxyl ions in their content of electrons.

 

 

 

REACTIVE=20 OXYGEN SPECIES

These=20 are partially reduced oxygen species which do not contain any unpaired electron. Examples of reactive oxygen = species=20 are:1,4,6

 

=A8      =20 HYDROGEN=20 PEROXIDE (H2O2)

=A8      =20 HYDROPEROXY=20 RADICAL (HOO-)

=A8      =20 HYPOCHLOROUS=20 ACID RADICAL (HOCl)

 

Under=20 certain conditions reactive oxygen species have potential to enter free = radical=20 reactions to form the more toxic free radicals. Another reactive oxygen = species,=20 which is not a free radical, is singlet oxygen (O). In this, a = rearrangement of=20 electrons has occurred which allows it to react faster with biological = molecules=20 - as compared to =91normal=92 oxygen.

 

 

ANTIOXIDANTS

DEFINITION

Antioxidants=20 can be defined as substances whose presence in relatively low = concentrations=20 significantly inhibits the rate of oxidation of the=20 targets.9

 

HOW=20 ANTIOXIDANTS WORK?

Antioxidants=20 serve as natural protectors in the body, mopping up free radicals and = reactive=20 oxygen species, which are potentially damaging. Antioxidants protect the tissues = in 4=20 ways:10

 

=A8      =20 Physically=20 separating the free radicals / reactive oxygen species from the = susceptible=20 molecules of the human body.

=A8      =20 Providing=20 molecules which effectively compete for oxygen.

=A8      =20 Rapidly=20 repair the damage caused by free radicals / reactive oxygen=20 species.

=A8      =20 Lyse=20 the free radicals / reactive oxygen species and rapidly remove=20 these.

 

 

 

CLASSIFICATION=20 OF ANTIOXIDANTS9,12

=EE     =20 ANTIOXIDANT=20 ENZYMES

=A8      =20 Superoxide=20 dismutase

=A8      =20 Catalase

=A8      =20 Glutathione=20 peroxidase

=EE     =20 PREVENTIVE=20 ANTIOXIDANTS

=A8      =20 Ceruloplasmin

=A8      =20 Transferrin

=A8      =20 Albumin

=EE     =20 CHAIN-BREAKING=20 ANTIOXIDANTS

r     =20 Water-soluble*

=A8      =20 Uric=20 acid (200-400 mmol/L)

=A8      =20 Ascorbate=20 (25-100 mmol/L)

=A8      =20 Thiols=20 (400-500 mmol/L)

=A8      =20 Bilirubin=20 (10-20 mmol/L)

=A8      =20 Flavanoids

r     =20 Fat-soluble*

=A8      =20 Tocopherols=20 (20-30 mmol/L)

=A8      =20 Ubiquinol-10=20 (<2 mmol/L)

=A8      =20 Beta-carotene=20 (1-2 mmol/L)

=A8      =20 Estrogens

*=20 optimal blood level given in brackets

 

 

 

The=20 most important antioxidants are three vitamins and three = minerals.7=20

 

r           = ;            =             &= nbsp;     =20 ANTIOXIDANT=20 VITAMINS

=A8      =20 CAROTENOIDS

=A8      =20 VITAMIN=20 E

=A8      =20 VITAMIN=20 C

r           = ;            =             &= nbsp;     =20 ANTIOXIDANT=20 MINERALS

=A8      =20 SELENIUM

=A8      =20 ZINC

=A8      =20 MANGANESE

=A8      =20 COPPER

carotenoids

Carotenoids=20 circulate in lipoproteins;11 53% of beta carotene occurs in = low=20 density lipoproteins.13 Besides the well known beta=20 carotene,=20 the other carotenoids of human importance are:

 

=A8      =20 Lutein

=A8      =20 Zeaxanthin

=A8      =20 Lycopene

=A8      =20 Alpha=20 carotene

=A8      =20 Beta=20 cryptoxanthin

 

As=20 far as the eye is concerned, lutein and zeaxanthin are exclusively = concentrated=20 in the macula, lens and iris. The retina and choroids additionally = contain=20 lycopene, alpha- and beta carotene. In the ciliary body, all the = carotenoids=20 taken in foodstuff or as dietary supplement get = accumulated.14=20

VITAMIN=20 E

Being=20 a fat soluble vitamin, alpha tocopherol is abundant in all cell = membranes as=20 well as in lipoproteins.1,15 In the eye, vitamin E is present = in=20 retina and choroids, and balance in iris and ciliary body.16 = It is=20 important in protection of rods and cones in retina, and also for = preventing=20 free radical damage to lens. Vitamin E acts synergistically with vitamin = C, beta=20 carotene and selenium for better functioning of=20 glutathione.17

VITAMIN=20 C

Vitamin=20 C is protective for the cytoplasm & is also most important for = plasma=20 defense.11,13 It also occurs in certain cells like muscle, = adrenals=20 and eye.18 Vitamin C has the capacity to regenerate vitamin = E. It is=20 more significant in combating free radicals formed due to pollution and=20 cigarette smoke. Vitamin C especially concentrates in ocular tissues and = is the=20 first antioxidant to tackle free = radicals.19

ZINC,=20 MANGANESE & COPPER

Zinc=20 (Zn), manganese (Mn) and copper (Cu) are constituents of superoxide = dismutase=20 (SOD) antioxidant enzyme.20 SOD is widely distributed in = tissues as=20 well as fluid compartments. CuZnSOD is present in cytoplasm and nucleus, = MnSOD=20 in operates mitochondria whilst CuSOD is most distributed in=20 plasma.21 SOD attacks free radicals like hydroxyl radical to = convert=20 these into hydrogen peroxide.1

 

Besides,=20 Zn serves an important structural role, whilst Cu is necessary for = functioning=20 of another antioxidant enzyme called as catalases.20 Hydrogen = peroxide is converted by catalases into harmless water and molecular=20 oxygen.1

 

In=20 the retina, SOD plays an important role by scavenging free radicals to = prevent=20 the oxidative damage which plays a role in the development of drusen, an = early=20 sign of ARMD.22 Catalases, on the other hand, are vital for = lens=20 protection.

SELENIUM

Selenium=20 (Se) is the most important dictator of glutathione peroxidase=20 activity.10,23-25 Glutathione peroxidase is concentrated in = various=20 tissues, besides blood and synovial fluid.11 In tisues, it = operates=20 in the cytoplasm and mitochondria principally.15 Like = catalases,=20 glutathione peroxidase breaks down hydrogen peroxide, besides reducing = lipid=20 peroxidation like vitamin E and beta carotene.1=20

 

Glutathione=20 peroxidase and related enzymes in the retina, plus the precursor amino = acids=20 (N-acetylcysteine, L-glycine, and glutamine and selenium) are protective = against=20 damage to human retinal pigment epithelium cells. Glutathione peroxidase = prevents free radical-induced apoptosis (cell suicide) and helps prevent = or=20 treat ARMD.26

 

 

 

CAROTENOIDS

DEFINITION

More=20 than 500 distinct compounds are today identified as naturally occurring=20 carotenoids.   They = include=20 cyclic hydrocarbon-carotenoids (carotenes), acyclic hydrocarbon = carotenoids=20 (lycopene), and oxygenated hydrocarbon carotenoids (xanthophylls like = lutein and=20 zeaxanthin).27

 

Handelman=20 and associates28 noted carotenoids concentration in the = macula to be=20 5-fold higher compared to peripheral retina and 500 times more than the=20 concentration in other tissues.29 Lutein is the major = carotenoid in=20 the peripheral retina, whereas zeaxanthin becomes more and more dominant = as the=20 foveal centre is approached. The proportion of lutein to zeaxanthin in = macula is=20 1:2 and the proportion is reversed in the peripheral = retina.30 The=20 distribution of xanthophyll carotenoids suggests a possible role of = lutein in=20 protecting the rods and for zeaxanthin in protecting the cones that are=20 concentrated in the central retina.31 The human lens = carotenoids=20 content is 10-20 ng/gm of wet tissue, and the ratio is 1.6:2.2 for = lutein and=20 zeaxanthin.29

 

Another=20 most important dietary antioxidant of ocular significance is lycopene, which is however, = conspicuous=20 by its absence in macula. Due to its presence in high concentration in=20 circulating blood in the eye, lycopene plays a prominent role in = prevention of=20 macular degeneration mainly by its very potent singlet oxygen = quenching=20 capacity.32

 

FOCUS=20 ON CAROTENOIDS IN ARMD

ARMD=20 - INTRODUCTION

In=20 developed countries, ARMD is the leading cause of blindness amongst the = elderly=20 (more than 60 years) with a prevalence ranging between 2 to 7% for = severe (wet)=20 form and a range of 12 to 30% for the dry form.33,34 The = disease=20 has caused irreversible visual impairment in an estimated 1.7 = million=20 Americans over the age of 65 years. The number of cases of ARMD has been = predicted to increase from 2.7 million in 1970 to 7.5 million by the = year=20 2030.

 

In=20 India, the incidence of ARMD affects approximately 4-5 per cent of the=20 population over the age of 50 years and may be affecting 19-20 per cent = of=20 people above 70 years of age.35 Early disease is = characterized by=20 yellowish-colored subretinal drusen. Late disease, which may be = =91dry=92 or =91wet=92,=20 may lead to significant loss of central vision. Wet form occurs only in = 10=20 percent of population.36

 

ARMD=20 - PATHOPHYSIOLOGY

The=20 light must pass the macular pigment, which contains abundance of = zeaxanthin and=20 lutein before striking the photoreceptors. If any damage to the rods and = cones=20 is to be prevented the short wave length of light rays (<500 nm = range) must=20 be filtered.37-39 This is accomplished as=20 follows:40

 

=A8      =20 5-286=20 nm wavelength (ultraviolet C rays): filtered by the earth=92s = ozone=20 layer.

=A8      =20 286-320=20 nm wavelength (ultraviolet B rays): filtered by=20 cornea.

=A8      =20 320-400=20 nm wavelength (ultraviolet C rays): filtered by=20 lens.

=A8      =20 400-500=20 nm wavelength (visible blue light): filtered by lutein / = zeaxanthin in=20 macula.

The=20 light entering the retina is between the wavelengths of 400 to 700=20 nm.41 The eye would be in perfect focus for daylight only at = 560 nm,=20 and even at night 500 nm wavelength of light is optimal for functioning = of=20 rods.42 Hence, filtering out 400-500 nm wavelength of light = prevents=20 damage to macula without affecting vision.

Thus=20 macular pigments represent a significant filtering element and hence = protect=20 against the light=96initiated cumulative oxidative damage.43 = The=20 macular pigment also removes much of the blurry, short wave blue and = blue-green=20 light that results from the eye=92s chromatic aberration.44 = Apart from=20 this the earth=92s atmosphere through which we view objects almost = always contain=20 small-suspended particles, which scatters short wave length light more = than=20 other wavelengths and results in a bluish veiling luminance.=20

The=20 eye and skin are the only structures which have dual exposure to oxygen = and=20 light.45,46 In presence of blue light (400-500 nm wavelength) = the=20 oxygen will be split into singlet oxygen which is one of the most deadly = reactive oxygen species as far as the eye is concerned. The blue light = has=20 potential to split molecular oxygen due to the high energy contained in=20 it.47 =20

 

The=20 singlet oxygen and other free radicals formed inside the eye initiate = lipid=20 peroxidation of photoreceptors. The polyunsaturated fatty acids in the = outer=20 membrane of rods and cones are attacked by free radicals and singlet = oxygen=20 species to result in damage of these photoreceptors. As a consequence, = there is=20 accumulation of lipofuscin = by retinal=20 pigment epithelium which then contributes in druse=20 formation.45,48-52

 

ARMD=20 - MEDICAL MANAGEMENT

The=20 damage to macula and formation of druse can be prevented by filtering = out the=20 damaging blue light of the visible spectrum. This is possible by the = macula, if=20 its content of lutein and zeaxanthin are adequate. The additional = available of=20 lycopene in adequate amounts is of paramount importance in tackling the = singlet=20 oxygen single this carotenoids is the best antioxidant known for = quenching this=20 reactive oxygen species. In addition, glutathione peroxidase and SOD too = have=20 been shown to have preventive benefit in ARMD.

 

FOCUS=20 OF CAROTENOIDS IN CATARACT

CATARACT=20 - INTRODUCTION

Cataract=20 is a multifactorial disease. Oxidative stress together with weakened = antioxidant=20 defense mechanism is attributed to the changes observed in human = diabetic=20 cataract.Oxidative=20 damage to the lens has been recognized as a primary event in the = pathogenesis of=20 many forms of cataract.53-56 Consistent with this view,=20 epidemiological reports have identified factors related to oxidative = process=20 that both increase (eg smoking and light exposure) and decrease (eg = antioxidant=20 intake) cataract risk.57,58

 

Epidemiological=20 studies provide evidence that nutritional antioxidants slow down the = progression=20 of cataract.59

CATARACT=20 - PATHOPHYSIOLOGY

Oxidative=20 stress is high in the eye due to ultraviolet rays which promote = liberation of=20 free radicals and singlet oxygen. The epidemiological evidence to = support the=20 possibility that lutein and zeaxanthin have an important role in = reducing the=20 risk of cataract is somewhat consistent, and justifies the belief in = free=20 radical & reactive oxygen species mediated damage to the=20 lens.60-62

 

Few=20 of the recent studies have stressed the significance of vitamin C, E and = selenium in the etiology of cataract. Role of vitamin E has been more=20 specifically stressed by several workers.57,60,61 Low blood = levels of=20 vitamin E are associated with approximately twice the risk of both = cortical and=20 nuclear cataracts, compared to median or high levels. Smokers are 2.6 = times=20 likely to develop posterior subcapsular cataracts more than=20 nonsmokers. Patients with senile cataracts were found to have = significantly=20 lower blood and intraocular levels of the mineral selenium than=20 control.

CATARACT=20 - MEDICAL MANAGEMENT

Lower=20 prevalence of nuclear cataract in women or men was associated with = intake of=20 lutein and zeaxanthin in high doses.60-62 Furthermore, in = prospective=20 cohort studies it was noted that people who consumed diet rich in lutein = and=20 zeaxanthin, had 20-25 percent lower risk of cataract extraction and 70 = percent=20 lower risk of cataract extraction under the age of 65=20 years.63-65

 

Experimental=20 study in human lens epithelial cells (HLEC) in culture was evaluated and = it was=20 concluded that addition of lycopene had a protective effect to prevent=20 vacuolization of epithelial cells. It was observed that there was as = positive=20 effect of retardation of lens opacities due to lutein and zeaxanthin in = the=20 aging lenses.

 

In=20 an 8 year prospective cohort study, Hankinson et al reported that an = elevated=20 intake of spinach, which is high in lutein and zeaxanthin (but low in = beta=20 carotene content) was most consistently associated with a lower risk of = cataract=20 extraction, whereas high beta carotene and vitamin E intakes alone had = no=20 beneficial effects against cataract prevention.60=20

 

This=20 study corroborated data from Jaques et al 1988 who demonstrated that = persons=20 with slightly elevated levels of plasma total carotenoids had a 25% = lower risk=20 for any type of cataract.58

 

 

 

ANTIOXIDANTS=20 IN RETINITS PIGMENTOSA

There=20 is possibility that lutein may slow degeneration of vision in retinitis=20 pigmentosa, a heterogeneous group of slow retinal degenerations. = However, only=20 preliminary data in a very small number of patients has been published = in which=20 lutein slowed vision loss associated with retinitis pigmentosa in=20 one.66

 

 

 

 

ANTIOXIDANTS=20 IN DIABETIC RETINOPATHY

Several=20 studies are in progress as regards role of antioxidants in diabetic = retinopathy=20 and=20 glaucoma=20 but as yet none is conclusive.

 

 

 

CONCLUSION

The=20 overwhelming body of evidence points to significant beneficial effects = of=20 nutritional supplementation for most degenerative eye conditions. =20 Important to remember is that most of the above studies used blood = levels and=20 food intakes associated with a normal diet. Taking supplements, = specifically=20 containing zeaxanthin, lutein and lycopene in adequate doses, which are=20 theorized to provide protection to macula and lens with adequate doses, = may have=20 a much more protective effect than dietary levels alone. With so = little=20 risk, and the other=20 potential health benefits from taking nutritional = supplements, it=20 would certainly seem prudent to try them, especially for macular = degeneration=20 where there are no real options.

 

Once=20 the damage is done it cannot be reversed (except to a small degree), so=20 prevention and early intervention is essential, especially if we have a = family=20 history of the disease. Of course, it's important to slow further=20 progression at any stage of development. Prevention of lens and = macula from=20 the ultraviolet rays and hazard of smoking, however, needs to be over = stressed.=20

 

 

REFERENCES

 

1.     =20 Richards=20 RT & Sharma HM. IJCP 1991; 7: 2: 15-26.

2.     =20 Yeolekar=20 ME & Nargund MP. Ind Pract 1994; XLVII: 5: = 377-390.

3.     =20 Halliwell=20 B. Drugs 1991; 42(4): 569-605.

4.     =20 Chandran=20 PV. Antiseptic 1992; 89:11: 615-616.

5.     =20 Parks=20 DA. Gut 1989; 30: 293-298

6.     =20 Halliwell=20 B. Nutr Rev 1994; 52: 8: 253-265.

7.     =20 Grey=20 KF et al. AJCN 1987; 45: 2: 1368-1377.

8.     =20 Lucchesi=20 BR. Am J Cardiol 1990; 65: 141-231.

9.     =20 Maxwell=20 SRJ. Drugs 1995; 49(3): 345-361.

10.  = Chow=20 CK. AJCN 1979; 32: 1066-1081.

11.  = Maxwell=20 SRJ & Lip GYH. Brit J Clin Pharmacol 1997; 44: 307-317.

12.  = Grey=20 KF. Bibl Nutr Dietat 1986; 37: 53-91.

13.  = Sommerburg=20 O et al. Br J Ophthalmol 1998; 82: 907-910.

14.  = Khachik=20 F et al. Exp Biol Med 2002; 227: 845-851.

15.  = Halliwell=20 B. Lancet 1994; 344: 721-724.

16.  = http://www.astro.northwestern.edu/~lin/VitE/VitE_Eye.html.=20 As read on 24th = March=20 2003.

17.  = http://www.dietsearch.com/health/eyediseases.html.=20 As read on 22nd = March=20 2003.

18.  = Suter=20 M & Rice-Evans C. Eastern Pharmacist 1995; XXXVIII: = 29-32.

19.  = http://216.239.33.100/search?q=3Dcache:pvj-7ut0tdYC:www.eyecareint= l.com/newsletters/vitamns2.doc+Free+radicals+AND+ARMD&hl=3Den&sta= rt=3D5&ie=3DUTF-8.=20 As read on 22nd = March=20 2003.

20.  = McCord=20 JM & Fridovich I. Ann Intern Med 1978; 89: = 122-127.

21.  = Heffner=20 JE & Repine JE. Am Rev Resp Dis 1989; 140: 531-554.

22.  = Mares-Perlman=20 JA & Klein R et al. Arch Ophthalmol 1996: = 114:991-997.

23.  = Rotruck=20 JT et al. Science 1973; 179: 588.

24.  = Flohe=20 L et al. FEBS Lett 1973; 32: 132.

25.  = Willett=20 WC et al. Lancet 1983; 2: 130-134.

26.  = Stemberg=20 DJ et al. Invest Ophthalmol Vis Sci.1993: 34(13)=20 3661-3668.

27.  = Oslon=20 JA. J Nutr 1989; 119: 94-95.

28.  = Handelman=20 GJ et al. Invest Ophthalmol Vis Sci 1988; 29: = 850-855.

29.