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Natural compounds: evidence for a protective role in eye diseaseRobert Ritch, MD, FACS, FRCOphth

Glaucoma is a progressive optic neuropathy charac-terized by a specific pattern of optic nerve head and

visual field damage. Damage to the visual system in glau-coma is due to the death of the retinal ganglion cells(RGCs) by apoptosis. Glaucoma represents a finalcommon pathway of a number of different conditionsthat can affect the eye, many of which are associated withelevated intraocular pressure (IOP). Elevated pressure isnot, however, synonymous with glaucoma, but rather isthe most important risk factor we know for the develop-ment and progression of glaucomatous damage. Indeed,glaucoma often progresses despite lowering of IOP toacceptable or normal levels. Therefore, a need exists fortherapies that prevent or limit the damage due to glau-coma, independent of therapies that simply lower IOP.

Other risk factors for glaucomatous damage besideselevated IOP have only begun to be explored. Risk

factors for decreased perfusion at the level of the opticnerve head include low blood pressure, orthostatichypotension, nocturnal hypotension, atrial fibrillation,migraine, Raynaud’s phenomenon, abnormally lowintracranial pressure, autoimmune phenomena, andsleep apnea. Other hemorheologic abnormalities, such asincreased erythrocyte agglutinability, decreased erythro-cyte deformability, increased serum viscosity, orincreased platelet aggregability, may also play a role.

The aim of neuroprotection in glaucoma is to retardprogression by blocking the mechanisms that lead toapoptosis. Many categories of both natural and syntheticcompounds reported to have neuroprotective activityinclude not only antioxidants, N-methyl-D-aspartate(NMDA) receptor antagonists, inhibitors of glutamaterelease, calcium channel blockers, polyamine antago-nists, and nitric oxide synthase inhibitors but also

From the Einhorn Clinical Research Center, The New York Eye and EarInfirmary, New York, N.Y., and New York Medical College, Valhalla, N.Y.

Presented at the International Ocular Neuroprotection Symposium inToronto Oct. 14, 2006

Originally received Dec. 16, 2006. Revised Jan. 27, 2007Accepted for publication Jan. 30, 2007

Correspondence to: Robert Ritch, MD, Glaucoma Associates of NewYork, The New York Eye and Ear Infirmary, 310 East 14th St., Ste. 304,New York NY 10003; [email protected]

This article has been peer-reviewed. Cet article a été évalué par les pairs.

Can J Ophthalmol 2007;42:425–38doi: 10.3129/can j ophthalmol.i07-044

Natural compounds—Ritch 425

ABSTRACT • RÉSUMÉ

Glaucoma often progresses despite lowering of intraocular pressure (IOP) to acceptable or normal levels; itcan also develop at normal or even low IOP on the basis of non-IOP–dependent risk factors.Therefore, a needexists for therapies limiting damage due to glaucoma that are independent of therapies that simply lower IOP.The aim of neuroprotection in glaucoma is to slow progression by blocking the mechanisms that lead toapoptosis. Many compounds have been described as neuroprotective, but the lack of availability of specificneuroprotectant compounds and the lack of clinical trials examining the benefits of neuroprotective agents forglaucoma limit their current therapeutic use.There are, however, many available natural compounds that offerthe possibility of neuroprotective activity.This review summarizes the potential benefits of natural compoundsin the treatment of eye disease.

Il arrive souvent que le glaucome progresse malgré la baisse de la pression intraoculaire (PIO) à des niveauxacceptables ou normaux; la maladie peut aussi se développer malgré un niveau de PIO normal ou même faibleà cause de facteurs de risque ne relevant pas de la PIO. Il faut donc mettre au point des thérapies permettantde limiter les dommages du glaucome qui ne dépendent pas des thérapies visant simplement à abaisser la PIO.Dans le glaucome, la neuroprotection a pour but de ralentir la progression de la maladie en bloquant lesmécanismes menant à l’apoptose. On a décrit le caractère neuroprotecteur de plusieurs composés, mais lemanque de disponibilité de composés neuroprotecteurs spécifiques et l’insuffisance d’essais cliniques visant àétablir les avantages des agents neuroprotecteurs contre le glaucome limitent actuellement l’utilisation de cescomposés thérapeutiques. Toutefois, plusieurs composés naturels comportent déjà une possibilité d’activiténeuroprotectrice. La présente revue résume le potentiel de ces composés naturels pour traiter les maladiesoculaires.

cannabinoids, acetylsalicylic acid, melatonin, andvitamin B12. The lack of availability of specific neuro-protectant compounds and the lack of clinical trialsexamining the benefits of neuroprotective agents forglaucoma limit the current use of these agents.

There are, however, many available natural com-pounds with actions that offer the possibility of neuro-protection. There has been a tendency throughout the20th century to denigrate nonpharmaceutical extractsand preparations. However, this was the nature of medi-cine for millennia, and many valuable compounds stillused were originally isolated from plants, includingvitamin C from citrus, digitalis from foxglove, quininefrom cinchona bark, salicylic acid from willow bark,taxol from yew bark, and pilocarpine itself. In theabsence of clinical trials, we must attempt to develop thebest possible working hypothesis of what might or mightnot be effective in glaucoma.

NATURAL COMPOUNDS

α-Lipoic acidα-Lipoic acid is a cofactor in mitochondrial dehydro-

genase complexes. When administered exogenously, ithas powerful antioxidant properties, which include freeradical scavenging, metal chelation, and regeneration ofother antioxidants. Lipoic acid decreases iron uptakefrom transferrin and reduces the size of the highly reac-tive iron pool in the cytoplasm of cells of the lens,changes associated with increased cell resistance to oxida-tive damage.1 α-Lipoic acid may help to prevent or slowthe progression of cataracts.2,3

Increases in leukostasis, or monocyte adhesion to thecapillary endothelium, and decreased retinal blood floware implicated in the pathogenesis of diabetic retinopa-thy. In diabetic rats, antioxidant treatment with α-lipoicacid normalized the amount of leukostasis but not theretinal blood flow, whereas treatment with d-α-toco-pherol prevented both the increase in leukostasis and thedecrease in retinal blood flow.4

Fish oil and omega-3 fatty acidsOmega-3 fatty acids, such as docosahexaenoic acid

(DHA) and eicosapentaenoic acid (EPA) have majorhealth benefits. DHA is thought to play an important rolein providing an adequate environment for conformationalrhodopsin changes and in modifying the activity of retinalenzymes in photoreceptor cells. Decreased retinal DHAcontent affects visual function in the monkey.5

Oxidative damage induces apoptosis in retinal neuronsduring their early development in culture and suggeststhat the loss of mitochondrial membrane integrity is

crucial in the apoptotic death of these cells. DHA acti-vates intracellular mechanisms that prevent this loss and,by modulating the levels of pro- and antiapoptotic pro-teins of the Bcl-2 family, selectively protects photorecep-tors from oxidative stress.6 DHA is enriched in retinalpigment epithelial cells and is the precursor of neuro-protectin D1 (NPD1), which inhibits oxidative-stress–mediated proinflammatory gene induction andapoptosis and consequently promotes survival of retinalpigment epithelial cells.7 NPD1 bioactivity demon-strates that DHA is the precursor to a neuroprotectivesignalling response to ischemia–reperfusion, thusopening newer avenues of therapeutic exploration instroke, neurotrauma, spinal cord injury, and neurode-generative diseases such as glaucoma with the aim ofupregulating this novel cell-survival signalling.8

DHA was effective intraperitoneally in protecting theretina against transient retinal ischemia induced by ele-vated IOP.9 Oral administration of DHA partially coun-teracted retinal neurotoxicity induced by kainic acid.10

In ischemia–reperfusion injury, DHA protected againstcell death, probably by inhibiting the formation ofhydroxyl radicals.11

With respect to the eye, fish oil has been investigatedmost extensively with regard to age-related macular degen-eration. In large studies, including the Nurses’ HealthStudy and the Health Professionals Follow-up Study,increased dietary fish consumption was associated with a35% lower risk of age-related macular degeneration.12,13

Another prospective, multicentre study found that higherintake of specific types of fat, including vegetable,monounsaturated, and polyunsaturated fats and linoleicacid, rather than total fat intake, may be associated with agreater risk of advanced macular degeneration, whereasdiets high in omega-3 fatty acids and fish were inverselyassociated with risk of macular degeneration when intakeof linoleic acid was low.14 Recently, it has been reportedthat increasing dietary omega-3 fatty acids leads to a lowerIOP and greater outflow facility in aging rats comparedwith controls, suggesting that dietary manipulation mayprovide a modifiable factor for IOP regulation.15

A combination of DHA, vitamin E, and vitamin Bwere reported to improve both visual field indices andretinal contrast sensitivity in patients with glaucoma.16

Intramuscular injections of fish oil containing EPA andDHA significantly lowered IOP in rabbits.17 Intraperi-toneal injection of DHA protected against transientretinal ischemia caused by elevation of IOP,9 and dietarysupplementation with DHA protected against retinaldegeneration caused by kainic acid10 and N-methyl-N-nitrosourea.18 DHA exerted a protective effect againstacute light-induced retinal toxicity.11,19

Natural compounds—Ritch

426 CAN J OPHTHALMOL—VOL. 42, NO. 3, 2007

α-Tocopherol (vitamin E) and tocotrienolIn nature, 8 substances have been found to have

vitamin E activity: α-, β-, γ-, and δ-tocopherol, and α-,β-, γ-, and δ-tocotrienol. In diabetic rats, treatment withthe antioxidant α-lipoic acid normalized the amount ofleukostasis but not retinal blood flow, whereas treatmentwith d-α-tocopherol prevented increase in leukostasisand decrease in retinal blood flow.4

α-Tocopherol has been reported to protect againstretinal phototoxicity20 and against ischemic injury of thecentral nervous system.21–23 α-Tocopherol has beenreported to inhibit human Tenon’s capsule fibroblastproliferation24 and to improve the results of filteringsurgery in rabbits.25 Vitamin E appeared to protectagainst cataract formation and progression in animalmodels and in humans.26–29

Tocotrienols possess powerful neuroprotective, anti-cancer, and cholesterol-lowering properties that are oftennot exhibited by tocopherols. At nanomolar concentra-tion, α-tocotrienol, not α-tocopherol, prevented neu-rodegeneration.30 α-Tocotrienol increased neuronalresistance to glutamate and homocysteine-induced toxi-city.31 Among the vitamin E analogs, α-tocotrienolexhibited the most potent neuroprotective actions in ratstriatal cultures.32 Tocotrienols showed a cardioprotec-tive effect in ischemia–reperfusion injury.33

CarnitineCarnitine, an amino acid derivative found in high

energy-demanding tissues (e.g., skeletal muscles,myocardium, liver) is essential for the intermediarymetabolism of fatty acids. It plays an important role inthose tissues of the eye, such as the ciliary body, wheremuscle cells are present, and it may represent an impor-tant energy reserve.34

Carnitine prevented glutamate neurotoxicity in primarycultures of cerebellar neurons.35 It has been reported toprevent retinal injury after ischemia–reperfusion injury.36

In streptozotocin-diabetic rats, carnitine loss in the lenswas an initial and important event and may be related tocataract development.34 Considerable evidence suggeststhat mitochondrial dysfunction and oxidative damageplay a role in the pathogenesis of Parkinson’s disease andthat acetyl-L-carnitine is beneficial in animal models ofthe disease.37 Recently, carnitine has been shown toprotect against selenite-induced cataract.38

CiticolineCiticoline (exogenous cytidine diphosphocholine) is a

nontoxic and well-tolerated drug used in pharmaco-therapy for cerebrovascular insufficiency and some otherneurological disorders, such as stroke, brain trauma, and

Parkinson’s disease.39 Once administered, it undergoesrapid transformation to cytidine and choline, which arebelieved to enter brain cells separately and provide neu-roprotection by enhancing phosphatydylcholine synthe-sis. Citicoline activates biosynthesis of structural phos-pholipids of neuronal membranes, increases brainmetabolism, and acts upon the levels of different neuro-transmitters.40 Citicoline has also been shown to inhibitapoptosis associated with cerebral ischemia in certainneurodegeneration models and to potentiate neuroplas-ticity mechanisms.40

A similar effect may be expected to occur in glauco-matous RGCs, but the precise effect of citicoline ondamaged RGCs remains to be explained. In RGC tissueculture, citicoline reduced apoptosis and increased thenumber of regenerating neurites.41 Citicoline mayinduce an improvement of retinal and visual pathwayfunctions in patients with glaucoma: treatment with citi-coline induced a significant (p < 0.01) improvement ofvisual evoked potential and pattern electroretinography(ERG) parameters.42–44 Both citicoline and lithium pro-tected RGCs and their axons in vivo against delayeddegeneration triggered by optic nerve crush injury andalso against retinal cell damage induced by kainic acid.45

The retinoprotective action of both drugs may involvean increase in Bcl-2 expression.46 Citicoline was as effec-tive as methylprednisolone, previously the only agenthaving clinically proven beneficial effects on spinal cordinjury, in preventing neurodegeneration.47

Coenzyme Q10Coenzymes are cofactors upon which the compara-

tively large and complex enzymes depend absolutely fortheir function. Coenzyme Q10 is the coenzyme for atleast mitochondrial and other enzymes. In its reducedform, it is a potent antioxidant. Tissues that are highlydependent on oxygen, such as muscle, the central andperipheral nervous systems, kidney, and insulin-produc-ing pancreatic β-cells, are especially susceptible to defectsin oxidative phosphorylation, the terminal process of cel-lular respiration. Defective oxidative phosphorylationplays an important role in atherogenesis and in thepathogenesis of Alzheimer’s disease, Parkinson’s disease,diabetes, and aging.48 Pretreatment of cultured neuronalcells and astrocytes with coenzyme Q10 inhibited celldeath due to glutamate neurotoxicity.49 Coenzyme Q10also exhibited antiapoptotic effects, apparently by stabi-lizing mitochondrial depolarization.50 Oral coenzymeQ10 supplementation was effective in treating car-diomyopathies and in restoring plasma levels reduced bythe statin type of cholesterol-lowering drugs.48

Supplementation with coenzyme Q10 has been reported


CAN J OPHTHALMOL—VOL. 42, NO. 3, 2007 427

to slow the development of Parkinson’s disease.51

Patients with open-angle glaucoma have an increasedprevalence of Parkinson’s disease.52

Coenzyme Q10 was beneficial in animal models ofneurodegenerative diseases and has shown promisingeffects in clinical trials of Parkinson’s disease,Huntington’s disease, and Friedreich’s ataxia.37

CurcuminCurcumin is an antioxidant extracted from the plant

Curcuma longa, or turmeric, an important spice in SouthAsian cuisine. It is also used in herbal remedies and isreported to possess therapeutic properties against avariety of diseases ranging from cancer to cystic fibrosis.

Turmeric extracts inhibit lipid peroxidation, haveshown beneficial effects in experimental studies of acuteand chronic diseases characterized by an exaggeratedinflammatory reaction, and have strong antioxidantactivity.53 Turmeric also has anticancer and antiangio-genesis activities.54 The antiulcer activity of curcumin isattributed primarily to matrix metalloproteinase 9(MMP-9) inhibition, one of the major pathways of ulcerhealing.55 MMP-9 is the gelatinase B gene, which is acti-vated during angiogenesis by fibroblast growth factor-2(FGF-2). Curcumin targets the FGF-2 angiogenic sig-nalling pathway and inhibits expression of gelatinase Bin the angiogenic process.56

Al-Omar et al57 evaluated the neuroprotective effect ofcurcumin on the neuronal death of hippocampalneurons after transient forebrain ischemia in the rat.Treatment reduced neuronal damage and increased glu-tathione, catalase, and superoxide dismutase to normallevels. Numerous other publications have provided evi-dence of the neuroprotective activity of curcumin.58,59

Curcumin inhibited chloroquine-resistant Plasmodiumfalciparum growth in culture and reduced blood levels ofPlasmodium berghei in mice, suggesting its possible use asan antimalarial compound.60 It accelerates cutaneouswound healing and increases wound tensile strength.61

In the rat eye, curcumin is effective against the devel-opment of diabetic cataract,62 galactose-inducedcataract,63 and naphthalene-induced cataract.64 In dia-betes, there is a decline in the chaperone-like activity ofeye lens α-crystallin. Curcumin, at levels close to thoseof dietary consumption, prevented the loss of chaper-one-like activity of α-crystallin vis-à-vis cataractogenesisdue to diabetes in rat lens.65 In rat retinal cultures, cur-cumin reduced NMDA-mediated excitotoxic celldamage and decreased apoptosis.66

Dan shen (Salvia miltiorrhiza)Salvia miltiorrhiza, also known as Asian red sage or

Dan shen, contains salviolonic acid B, a potent water-soluble, polyphenolic antioxidant with antiinflamma-tory and antiatherosclerotic properties.67,68 It has beenreported to reduce brain damage in cerebral infarc-tion69,70 and mitochondrial damage in ischemia–reper-fusion injury.71

RGC damage in glaucomatous damage was markedlyreduced by intravenous treatment with S. miltiorrhiza.72

It has been claimed in one report to stabilize the visualfield in patients with glaucoma.73 Data demonstrate thatit inhibited tumour necrosis factor-α (TNF-α)-inducedactivation of nuclear factor-kappa B (NF-κB) and in therabbit model of glaucoma, protected against RGC loss.NMDA receptor antagonist activity may underlie itsneuroprotective effects.74

Folic acidFolate is required for DNA replication and is necessary

for the production and maintenance of new cells. It alsohelps break down homocysteine in the body.Hyperhomocysteinemia may damage coronary arteriesand has been associated with central retinal vein occlu-sion and exfoliation syndrome (XFS). Mild hyperhomo-cysteinemia is an independent risk factor for prematurevascular disease,75 myocardial infarction,76 and stroke.77

Significantly elevated homocysteine levels have also beenfound in patients with Alzheimer’s disease and patientswith vascular dementia.78 Homocysteine can inducealterations in the extracellular matrix and neuronal celldeath, which are characteristic findings in glaucoma.Folate supplementation reduces hyperhomocysteinemia.

Culturing embryonic cortical neurons and differenti-ated human neuroblastoma cells (cell line SH-SY5Y) infolate-free medium was shown to induce neurodegener-ative changes characteristic of those observed inAlzheimer’s disease.79 A significant increase in homocys-teine was detected after folate deprivation, whichdecreased the reduced form of glutathione, indicating adepletion of oxidative buffering capacity.79 A recentstudy demonstrated that folic acid (400 μg) associatedwith vitamin B6 and B12 can reduce homocysteine levelsby 30%.80 XFS is the most common recognizable causeof open-angle glaucoma overall worldwide.81 XFS is cor-related positively with a history of hypertension, angina,myocardial infarction, or stroke, suggestive of the vascu-lar effects of the disease.82 An increased incidence of XFShas been found in patients with Alzheimer’s disease.83

Plasma homocysteine levels are elevated in patientswith XFS both with and without glaucoma when com-pared with controls who have no ocular disease andpatients with normal-tension glaucoma.84,85 Both XFSand hyperhomocysteinemia share common associations



with various disorders. Hyperhomocysteinemia might bea modifiable risk factor for XFS. Homocysteine levelsand the frequency of heterozygous methylenetetrahydro-folate reductase C677T mutation are also increased inprimary open-angle glaucoma.86

The Blue Mountains Eye Study found a strong pro-tective influence on cortical cataract from the use offolate or vitamin B12 supplements.26

Ginkgo biloba extractGinkgo biloba extract (GBE) contains over 60 known

bioactive compounds. The standardized extract usedmost widely in clinical research, EGb 761 (Dr. WillmarSchwabe Pharmaceuticals, Karlsruhe, Germany), con-tains 24% ginkgo flavone glycosides (flavonoids), 6%terpene lactones (ginkgolides and bilobalide), approxi-mately 7% proanthocyanidines, and other, uncharacter-ized, compounds.87 In Canada and the United States, itis freely available as a nutritional supplement. GBE hasbeen claimed to be effective in a variety of disorders asso-ciated with aging, including cerebrovascular disease,peripheral vascular disease, dementia, tinnitus, bron-choconstriction, and erectile dysfunction. GBE appearsto have many properties applicable to the treatment ofnon-IOP–dependent risk factors for glaucomatousdamage.88

GBE exerts significant protective effects against freeradical damage and lipid peroxidation in various tissuesand experimental systems. Its antioxidant potential iscomparable to water-soluble antioxidants, such as ascor-bic acid and glutathione, and lipid-soluble ones, such asα-tocopherol and retinol acetate.89 GBE preserves mito-chondrial metabolism and adenosine triphosphate (ATP)production in various tissues and partially prevents mor-phologic changes and indices of oxidative damage associ-ated with mitochondrial aging.90–92 It can scavenge nitricoxide93 and possibly inhibit its production.94

Substantial experimental evidence exists to support theview that GBE has neuroprotective properties in condi-tions such as hypoxia or ischemia, seizure activity, cere-bral edema, and peripheral nerve damage.95,96 GBE canreduce glutamate-induced elevation of calcium concen-trations97 and can reduce oxidative metabolism in bothresting and calcium-loaded neurons.98 Neurons in tissueculture were protected from a variety of toxic insults byGBE, which inhibited apoptosis.99–101

GBE improves both peripheral and cerebral bloodflow. It has been reported to protect myocardium againsthypoxia and ischemia–reperfusion injury.102,103 There isconvincing evidence for functional improvement inpatients with Alzheimer’s-type and multi-infarct demen-tias.104,105

In the eye, GBE may have a protective effect againstthe progression of diabetic retinopathy106; in rat retina,it reduced ischemia–reperfusion injury.107 GBE pro-tected retinal photoreceptors against light-induceddamage.108 Chloroquine-induced ERG changes wereprevented by simultaneous treatment with GBE.109 In arat model of central retinal artery occlusion, GBEreduced edema and necrosis and blocked the reductionin b-wave amplitude.110

GBE has been reported to improve automated visualfield indices.111,112 In one clinical crossover study of low-dose, short-term treatment in normal volunteers, GBEincreased ophthalmic artery blood flow by a mean of24%.113

Ginseng Rb1 and Rg3Ginseng (Panax ginseng) is a highly valued herb in the

Far East, second only to GBE as the most studied plantcompound and one of the most widely used herbs in tra-ditional Chinese medicine. The major active compo-nents of ginseng are ginsenosides, a diverse group ofsteroidal saponins, which demonstrate the ability totarget a myriad of tissues and produce an array of phar-macological responses.114 Of greatest interest are the gin-senoside saponins Rb1 and Rg3, which attenuate orinhibit responses that lead to the apoptotic cascade,including glutamate-induced neurotoxicity, calciuminflux into cells in the presence of excess glutamate, andlipid peroxidation.

Ginsenosides Rb1 and Rg3 exerted significant neuro-protective effects on cultured cortical cells,115 and appar-ently act by inhibiting NMDA receptor activity.116

Central infusion of ginsenoside Rb1 in a gerbil modelafter forebrain ischemia protected hippocampal CA1neurons against lethal ischemic damage.117 GinsenosideRb1 has been reported to enhance peripheral nerveregeneration in vitro.118 Ginsenosides suppressed TNF-αproduction in vitro and may have potential therapeuticefficacy against TNF-α–mediated disease.119

L-GlutathioneGlutathione is one of the most important antioxidants

in the body. Oxidative DNA damage is significantlyincreased in the trabecular meshwork of glaucomapatients, and glutathione S-transferase M1 (GSTM1)gene deletion, which has been associated with anincreased risk of cancer at various sites and molecularlesions in atherosclerosis, predisposes to more severedamage.120

In a study to identify retinal proteins that are thetargets of serum autoantibodies in patients with glau-coma, serum antibodies against glutathione S-transferase



antigen were recognized in 34 (52%) of 65 patients withglaucoma and 5 (20%) of 25 age-matched controls (p <0.05).121 These findings indicate that glutathione S-transferase is targeted by the serum antibodies detectedin some patients with glaucoma.121

A significant association of the GSTM1 polymorphismwith primary open-angle glaucoma has been reported.The risk of developing glaucoma was even higher inGSTM1-positive patients than in patients whosmoked.122 The level of sulfhydryl groups was reported tobe significantly lowered in the anterior chamber aqueoushumor of patients with open-angle glaucoma.123

Grape seed extractGrape seed proanthocyanidins have a broad spectrum

of pharmacological and medicinal properties againstoxidative stress. Proanthocyanidin-rich grape seedextract (GSE) provides excellent protection against freeradicals in both in vitro and in vivo models.124 GSE sig-nificantly prevented and postponed development ofcataract formation in rats with hereditary cataracts.125

Improvement in myocardial ischemia–reperfusion injuryin vitro has also been reported.126–128 Activin, a new-gen-eration antioxidant derived from grape seed proantho-cyanidins, reduced plasma levels of oxidative-stress andadhesion molecules (ICAM-1, VCAM-1, and E-selectin)in patients with systemic sclerosis.129 Supplementationof a meal with GSE minimized postprandial oxidativestress by decreasing oxidants and increasing the antioxi-dant levels in plasma, and, as a consequence, enhancedthe resistance to oxidative modification of low-densitylipoproteins (LDLs).130 Grape seed proanthocyanidinshave also been reported to have activity against humanimmunodeficiency virus (HIV)-1 entry into cells.131

Green tea catechinsGreen tea contains a number of bioactive chemicals and

is particularly rich in catechins, of which epigallocatechingallate (EGCG) is the most abundant132 and an extremelypotent antioxidant.133 Catechins and epicatechins areimportant constituents in human nutrition. There is aconcentration-dependent correlation between these com-pounds and modulation of cell survival (or cell death)-related gene pathways in vitro.134 Catechins reduced mito-chondrial damage during ischemia–reperfusion injury.135

Green tea extract scavenged free radicals and nitricoxide136 and has been reported to counteract the oxidativeinsult from cigarette smoke and to slow the progression ofcataract.137,138 Oxidative alterations of LDL, scavenging ofoxygen free radicals, and inhibition of glutamate toxicityare properties of catechins.139 Intraocular injections ofEGCG with sodium nitroprusside had a protective effect

on the retinal photoreceptors, suggesting that EGCG maybenefit individuals suffering from retinal diseases in whichoxidative stress is implicated.140

Lutein and zeaxanthinLutein, found in many fruits and vegetables that are

frequently consumed, is one of the most widely distrib-uted carotenoids. Distribution of lutein among tissues issimilar to that of other carotenoids, although lutein andzeaxanthin are commonly referred to as macular pig-ments because they are found selectively at the centre ofthe retina. Lutein and zeaxanthin may protect themacula and photoreceptor outer segments throughoutthe retina from oxidative stress and may play a role in anantioxidant cascade that safely disarms the energy ofreactive oxygen species.

Age-related macular degeneration is the leading causeof blindness in the developed world. One hypothesis ofits etiology involves the intrinsic vulnerability of theretina to damage through oxidation. This has promptedinterest in the role of antioxidants, particularly thecarotenoids lutein and zeaxanthin, in prevention andtreatment of macular degeneration. There is ample epi-demiological evidence that the amount of macularpigment is inversely associated with the incidence of age-related macular degeneration. Dietary supplementationwith lutein and zeaxanthin increase macular pigmentdensity.141

Several large, randomized, controlled trials, includingthe highly publicized Age-Related Eye Disease Study(AREDS), have examined the role of supplements con-taining lutein, vitamins C and E, zinc, and copper onmeasures of visual function in people with and withoutage-related macular disease and have observed a beneficialeffect.142 The amplitudes of focal electroretinograms wereimproved in patients with age-related macular degenera-tion who received supplementation with lutein, vitaminE, and nicotinamide.143 Zeaxanthin has been reported toprotect retinal photoreceptors from acute light-inducedtoxicity.144 Lutein and zeaxanthin may26,145,146 or maynot147 also retard cataract progression.

MethylcobalaminOf the several forms of vitamin B12, only methyl-

cobalamin, which donates methyl groups to the myelinsheath that insulates nerve fibres and regeneratesdamaged neurons, is used in the central nervous system.In patients with glaucoma, studies have shown possibleimprovement or stabilization in visual field performancewith oral B12 supplementation.148,149 Methylcobalaminprotected cultured retinal ganglion cells against gluta-mate-induced neurotoxicity.150



N-acetyl-L cysteineThe N-acetyl derivative of the amino acid L-cysteine is

a precursor in the formation of the antioxidant glu-tathione. The thiol (sulfhydryl) group confers antioxi-dant effects and is able to reduce free radicals. In diabeticretinopathy, apoptosis in retinal microvessels is associ-ated with an increase in cellular ceramide and diacyl-glycerol levels, the production of which is inhibited byN-acetyl-L-cysteine.151 Protein carbonylation, a nonen-zymatic modification that occurs in conditions of cellu-lar oxidative stress, was also inhibited by N-acetyl-L-cys-teine.152 In cultured neurons from embryonic mousecortex and striatum, N-acetyl-L-cysteine increased theneuronal cell survival rate.153

PycnogenolPycnogenol, an extract of the bark of the maritime pine

(Pinus pinaster) primarily composed of procyanidins andphenolic acids, is a potent antioxidant that has strongfree-radical–scavenging activity against reactive oxygenand nitrogen species. Procyanidins are biopolymers ofcatechin and epicatechin subunits that are recognized asimportant constituents in human nutrition.154

Pretreatment with pycnogenol reduced smoke-inducedplatelet aggregation.155 Pycnogenol significantly reducedLDL-cholesterol levels.156,157 In patients with chronicvenous insufficiency, the circumference of the lower legsand symptoms of pain, cramps, nighttime swelling,feeling of “heaviness”, and reddening of the skin werereduced.157 Pycnogenol was effective in reducing symp-toms in patients with venous microangiopathy158 or dia-betic microangiopathy,159 and it accelerated healing inpatients with ulcerations of the leg secondary to chronicvenous insufficiency160 and diabetes.161

After oral administration of pycnogenol, plasmasamples significantly inhibited both MMP-9 releasefrom human monocytes and NF-κB activation, indicat-ing that bioavailable active principles of pycnogenolexert antiinflammatory effects by inhibition of proin-flammatory gene expression.162 Glutamate-inducedcytotoxicity in neuronal cells (cell line HT4) has beendemonstrated to be the result of oxidative stress causedby depletion of cellular glutathione. More recently, pyc-nogenol has been shown to inhibit cyclooxygenases 1and 2.163 Extracts of Gingko biloba (EGb 761) and mar-itime pine bark (pycnogenol) were effective inhibitors ofthis cytotoxicity.164 Pycnogenol can protect vascularendothelial cells from amyloid-β peptide (Aβ)-inducedinjury, suggesting that it may be useful for the preven-tion and (or) treatment of vascular or neurodegenerativediseases associated with Aβ toxicity.165 Pycnogenol notonly suppresses the generation of reactive oxygen species,

but also attenuates caspase-3 activation and DNA frag-mentation, suggesting protection against Aβ-inducedapoptosis.166

Pycnogenol has also been reported to have the abilityboth to inhibit angiotensin-converting enzyme and toenhance the microcirculation by increasing capillary per-meability.167 Pycnogenol inhibited the progression ofdiabetic retinopathy168 and may reduce the risk of for-mation of both diabetic retinopathy and cataract.169

QuercetinThis flavonoid antioxidant, found in Ginkgo biloba and

in red wine, inhibits release of nitric oxide170 and TNF-α,171

which may be an important factor in the initiation of glau-comatous damage. Quercetin is neuroprotective againstoxidative injury in cortical neuron cell cultures, inhibitinglipid peroxidation and scavenging free radicals,172 and it ishepatoprotective against ischemia–reperfusion injury whengiven orally.173 Apoptosis-promoting substances, includingTNF-α secreted by activated glial cells after exposure tostress, contribute directly to neuronal cytotoxicity.174

Quercetin inhibited lipid peroxidation in the mammalianeye175 and has been reported to slow the progression ofselenite-induced cataract in rats.176

ResveratrolResveratrol is found largely in the skins of red grapes

and came to scientific attention as a possible explanationfor the low incidence of heart disease among the French,who eat a relatively high-fat diet. Many studies suggestthat consuming alcohol (especially red wine) may reducethe incidence of coronary heart disease. Grape juice,which is not a fermented beverage, may not be a signifi-cant source of resveratrol found in red grapes.

Resveratrol has previously been shown to increase the lifespan of the yeast Saccharomyces cerevisiae, the nematodeCaenorhabditis elegans, and the fruitfly Drosophilamelanogaster. Life-span extension is dependent on sirtuin2, a conserved deacetylase enzyme that has been linked tothe benefits of caloric restriction, which also extends thelife span. It has recently been shown to extend the life spanof the short-lived fish Nothobranchius furzeri.177

Resveratrol has now been shown to significantly increasethe health and survival of mice on a high-calorie diet,pointing to a new approach to treating diseases of aging.178

Several studies have demonstrated that resveratrol is aneffective antioxidant.179–181 It inhibited lipid peroxidationof LDL, prevented the cytotoxicity of oxidized LDL, andprotected cells against lipid peroxidation.179 Resveratrolprotected against the degeneration of neurons afteraxotomy.182 A single infusion of resveratrol can elicit neu-roprotective effects on cerebral-ischemia-induced neuron



damage through free radical scavenging and cerebralblood elevation due to nitric oxide release.183 Its anti-apoptotic activity has led to the suggestion that resvera-trol may make a useful dietary supplement for minimiz-ing oxidative injury in immune-perturbed states andhuman chronic degenerative diseases.184

Levels of intracellular heme (iron-protoporphyrin IX),a pro-oxidant, increase after stroke, and in neuronal cellcultures, resveratrol induces heme oxygenase 1, suggest-ing that increased heme oxygenase activity is a uniquepathway by which resveratrol can exert its neuroprotec-tive actions.185

In the eye, resveratrol suppressed selenite-inducedoxidative stress and cataract formation in rats.186 Thisprotective effect was supported by higher glutathioneand lower malonyl dialdehyde levels in the lens. Theauthors suggested that the presence of oxidative stress inselenite cataract development and its prevention byresveratrol support the possibility that high natural con-sumption of resveratrol in food can help prevent humansenile cataract.

TaurineTaurine is a free amino acid particularly abundant in

the retina. Visual dysfunction in both humans andanimals results from taurine deficiency, which can bereversed with nutritional supplementation. The distribu-tion of taurine is tightly regulated in the different retinalcell types during the development of the retina. Theexact function or functions of taurine in the retina arestill unresolved. Nevertheless, taurine depletion results insignificant retinal lesions, and taurine release and uptakehas been found to employ distinct regulatory mecha-nisms in the retina.187

Taurine supplementation in diabetic rats significantlydecreased lipid peroxidation and preserved ATPase activ-ity.188 Taurine protected against low level radiation-asso-ciated protein leakage.189 In studies of neuritic outgrowthfrom postcrush goldfish retinal explants, the highest neu-ritic outgrowth was observed in the presence of fetal calfserum, under which conditions taurine increased thelength and density of neurites.190 Treatment with taurine,diltiazem, and vitamin E had the beneficial effect ofdecreasing the rate of visual field loss in patients withretinitis pigmentosa, likely through a protective actionfrom free radical reactions in affected photoreceptors.191

CONCLUSION

Alternative medicine comprises a wide range of cate-gories, from long-standing, widely accepted, and well-tested approaches to spurious and quack remedies.

Plants have been used for medicinal purposes by virtu-ally every society since before recorded history. Chinesetraditional medicine is helpful in improving blood flowand circulation, strengthening the immune system, andproviding neuroprotection, all areas that could be ofbenefit in the treatment of glaucoma. Nutritional sup-plements have been shown to slow the progression ofage-related macular degeneration. In the absence of clin-ical trials, it devolves upon us to attempt to make thebest possible educated guess as to what might or mightnot be effective in glaucoma. The most studied of theseis Ginkgo biloba extract, which has several biologicalactions that combine to make it a potentially importantagent in the treatment of glaucoma: improvement incentral and peripheral blood flow and antioxidant activ-ity, reduction of vasospasm and serum viscosity, andinhibition of platelet-activating factor, apoptosis, andexcitotoxicity. Interest in these compounds by themedical establishment is fortunately being taken muchmore seriously now than in the past.

Supported in part by the Norman and Sandra Pessin ResearchFund of the New York Glaucoma Research Institute.

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Key words: complementary medicine, alternative medicine,ethnopharmacology, neuroprotection, glaucoma, apoptosis



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