Complementary and Alternative Therapy for Glaucoma



Complementary Therapy for the Treatment of Glaucoma

A Perspective

Robert Ritch, MD

Complementary Medicine for Glaucoma

for

New Developments in Ocular Pharmacology and Therapeutics

Ophthalmology Clinics of North America

Robert Ritch, MD

From the Departments of Ophthalmology, The New York Eye and Ear Infirmary, New York, NY, and The New York Medical College, Valhalla, NY,

Supported in part by the Joseph and Marilyn Rosen Research Fund of the New York Glaucoma Research Institute

Corresponding author: Robert Ritch, MD, Glaucoma Associates of New York, The New York Eye and Ear Infirmary, 310 East 14th Street suite 304, New York, NY, 10003

Tel: 212-477-7540 Fax: 212-420-8743 ritchmd@

Glaucoma is a progressive optic neuropathy characterized by a specific pattern of optic nerve head and visual field damage. Damage to the visual system in glaucoma is due to the death of the retinal ganglion cells, the axons of which comprise the optic nerve and carry the visual impulses from the eye to the brain. Glaucoma represents a final common pathway resulting from a number of different conditions that can affect the eye, many of which are associated with elevated intraocular pressure (IOP). It is important to realize that elevated IOP is not synonymous with glaucoma, but rather is the most important risk factor we know of for the development and/or progression of glaucomatous damage.

Other risk factors for glaucomatous damage besides elevated IOP have only begun to be explored in the past decade. Much remains to be discovered, so that new approaches to treatment can be devised. We can refer to these other risk factors as non-pressure-dependent risk factors, and the damage they cause as non-IOP-dependent damage. The most intensively investigated cause of non-pressure-dependent glaucomatous damage is the possibility of an insufficient blood supply to the optic nerve head and adjacent retina. Risk factors for this include low blood pressure, orthostatic hypotension, nocturnal hypotension, atrial fibrillation, migraine, Raynaud’s phenomenon, abnormally low intracranial pressure, autoimmune phenomena, and sleep apnea. Other hemorheologic (flow properties of blood) abnormalities, such as increased erythrocyte agglutinability (tendency for red blood cells to stick to each other), decreased erythrocyte deformability (ability of the red blood cells to change shape so that they can squeeze into capillaries), increased serum viscosity, or increased platelet aggregability may also play a role.

Neuronal death may be viewed as occurring in three steps: 1) axonal injury, 2) death of the injured neuron, and 3) injury and death of previously intact neurons through secondary degeneration. The concept of secondary degeneration is based on the finding that neuronal damage in the central nervous system may progress even when the primary cause of damage is alleviated. Neuroprotection refers to the postinjury protection of neurons that were initially undamaged or only marginally damaged by a particular insult, but are at risk from toxic stimuli released by damaged cells which cause secondary degeneration. Secondary degeneration refers to the spread of degeneration to apparently healthy neurons that escape the primary insult, but are adjacent to injured neurons and are thus exposed to the degenerative milieu that the latter create. Neural rescue refers to the restoration of viability to neurons which are already damaged. Neuroprotection is useful even when the exact cause of a disorder is undefined, as the therapy occurs at the level of the dying cells and not at the initial injury. The aim of neuroprotection in glaucoma would be to limit and prevent damage by blocking the mechanisms which lead to retinal ganglion cell death. Numerous categories of compounds have been reported to have neuroprotective action. These include antioxidants, NMDA antagonists, calcium channel blockers, and nitric oxide pathway inhibitors. The lack of availability of specific neuroprotectants in the United States and the lack of clinical trials examining the benefits of neuroprotective agents for glaucoma limit the use of these agents at the present time.

Neuroprotection is an area of rapidly expanding research and has been a focus of numerous conferences and symposia, notwithstanding the absence to date of any proven clinically effective neuroprotective agent for the treatment of glaucoma. This interest is due to the fact that neuroprotection represents a new avenue of therapy for a frustrating disease that often progresses despite lowering of intraocular pressure (IOP) to “acceptable” or “normal” levels. As neuroprotective strategies and pharmaceutical agents have been initiated in the treatment of numerous disorders of the central and peripheral nervous systems, including trauma, epilepsy, stroke, Huntington’s disease, amyotrophic lateral sclerosis, and AIDS dementia, it is logical that their use in the treatment of glaucoma should be explored.

From a practical, clinical point of view with regard to the treatment of glaucoma, neuroprotection is more appropriately defined as the prevention or retardation of the loss of functional integrity of retinal ganglion cells, their axons, and their axonal connections in order to maintain and stabilize the patient’s vision for as long as possible. Proving the efficacy of a neuroprotective agent depends upon our ability to measure differences meaningfully and reliably. Such measurement has been relatively imprecise and to some degree inferential, as when achromatic automated perimetry is used as an end point. The advent of more precise modalities of assessment, particularly refinement of advanced imaging devices which will allow us to investigate quantitative morphological aspects of the retinal ganglion cell layer, will promote better assessment of agents tested for their neuroprotective activity in vivo.

Retinal ganglion cells die in glaucoma by apoptosis, or programmed cell death. The aim of neuroprotection in glaucoma is to limit and prevent damage by blocking the mechanisms which lead to RGC death. Many categories of both natural and synthetic compounds have been reported to have neuroprotective activity. These include not only antioxidants, NMDA receptor antagonists, inhibitors of glutamate release, calcium channel blockers, polyamine antagonists, and nitric oxide synthase inhibitors, but cannabinoids, aspirin, melatonin, and vitamin B-12. The lack of availability of specific neuroprotectant compounds in the United States and the lack of clinical trials examining the benefits of neuroprotective agents for glaucoma limit the use of these agents at the present time. As a result, treatment of non-IOP-dependent risk factors for glaucomatous damage remains limited, yet very much needed.

There are, however, presently available compounds which have been shown to have many actions which would be beneficial in the treatment of glaucoma and offer the possibility of neuroprotective activity at the present time. These include elements of traditional medical systems, such as Chinese traditional medicine and Ayurvedic medicine, which are included in the umbrella rubric of “complementary and alternative medicine”, and specific compounds, including vitamins and supplements, which have antioxidant and potentially other neuroprotective activity.

There has been a tendency throughout the 20th century to denigrate nonpharmaceutical, single-compound preparations for treatment of disease. However, we should keep in mind that for millenia, medicine consisted of just these, and many valuable compounds still used in medicine were originally isolated from plants. These include vitamin C from citrus, digitalis from foxglove, quinine from cinchona bark, salicylic acid from willow bark, taxol from yew bark, and pilocarpine itself. Nutritional supplements have been shown to slow progression of age-related macular degeneration in a prospective randomized study which has received much attention.1 In the absence of clinical trials, it devolves upon us to attempt to make the best possible guess as to what might or might not be effective in glaucoma. The most studied of these is Ginkgo biloba extract (GBE).

GINKGO BILOBA EXTRACT

Leaf extracts of the ginkgo tree were described in the earliest known texts of Chinese medicine from about 3000 BC for treating asthma and bronchitis. GBE appears to have many neuroprotective properties applicable to the treatment of non-IOP-dependent risk factors for glaucomatous damage.2-5 It contains over 60 known bioactive compounds, half of which are found nowhere else in nature. The standardized extract used most widely in clinical research, EGb 761 (Dr Willmar Schwabe GmbH & Co, Karlsruhe, Germany), contains 24% ginkgo flavone glycosides (flavonoids), 6% terpene lactones (ginkgolides and bilobalide), approximately 7% proanthocyanidines, and other, uncharacterized compounds. In the United States, it is freely available as a nutritional supplement. GBE has been claimed effective in a variety of disorders associated with aging, including cerebrovascular disease, peripheral vascular disease, dementia, tinnitus, bronchoconstriction, and sexual dysfunction.

GBE exerts significant protective effects against free radical damage and lipid peroxidation in various tissues and experimental systems. Its antioxidant potential is comparable to water soluble antioxidants such as ascorbic acid and glutathione and lipid soluble ones such as alpha-tocopherol and retinol acetate.6 GBE preserves mitochondrial metabolism and ATP production in various tissues and partially prevents morphologic changes and indices of oxidative damage associated with mitochondrial aging.7-11 It can scavenge nitric oxide12 and possibly inhibit its production.13

Substantial experimental evidence exists to support the view that GBE has neuroprotective properties in conditions such as hypoxia/ischemia, seizure activity, cerebral edema, and peripheral nerve damage.14 GBE can reduce glutamate-induced elevation of calcium concentrations15 and can reduce oxidative metabolism in both resting and calcium-loaded neurons.16 Neurons in tissue culture are protected from a variety of toxic insults by GBE.17, 18 GBE inhibits apoptosis.19-21 Ginkolide B, one of the most active components of GBE and a powerful inhibitor of platelet activating factor, inhibited neurotoxicity of prions and amyoid-beta1-42, a neurotoxic protein fragment in nanomolar concentrations.22

GBE improves both peripheral and cerebral blood flow. Is improves symptoms of intermittent claudication and peripheral arterial occlusive disease.23-25 It protects myocardium against hypoxia and ischemia-reperfusion injury.26, 27 There is convincing evidence for functional improvement in patients with Alzheimer’s-type and multi-infarct dementias.28, 29

In the eye, GBE may have a protective effect against the progression of diabetic retinopathy30 and reduces ischemia-reperfusion injury in rat retina.31 In patients with type 2 diabetes and retinopathy, it reduced blood viscosity, erythrocyte malondialdehyde levels, and fibrinogen levels, while improving erythrocyte deformability and retinal capillary blood flow rate.32 and reduced platelet malondialdehyde levels, leading the authors to suggest that patients with type 2 diabetes might benefit from GBE as a dietary supplement.33

GBE protects retinal photoreceptors against light-induced damage.34 Chloroquine-induced ERG changes were prevented by simultaneous treatment with GBE.35 In a rat model of central retinal artery occlusion, GBE reduced edema and necrosis and blocked the reduction in b-wave amplitude.36

GBE has been reported to be neuroprotective for retinal ganglion cells in a rat model of chronic glaucoma.37 GBE may has been reported to improve automated visual field indices.38, 39 In one clinical cross-over study of low-dose, short-term treatment in normal volunteers, GBE increased ophthalmic artery blood flow by a mean of 24%.40

OTHER PLANT AND THEIR EXTRACTS

ANGELICA SINENSIS (DANG GUI ROOT; DONG QUAI)

More than 60 species of medicinal plants belong to the genus Angelica. Active principles isolated from these plants mainly include various types of coumarins, acetylenic compounds, chalcones, sesquiterpenes and polysaccharides.41 Traditionally used in Chinese medicine for enhancing cardiovascular function, extracts of Angelica sinensis are anti-atherogenic, inhibit LDL oxidation, and protect vascular endothelium from the effects of oxidized LDLs.42 In mice with immunologically injured liver, Angelica polysaccharides markedly reduced Bax and iNOS levels and increased Bcl-2 and cNOS levels.43 The anti-atherogenic effect of angelica has been suggested to result from decreasing serum triglyceride concentrations and its effects on hemorheology.44

ARCTIGENIN AND OTHER LIGNANS

Isolated from the bark of the tree Torreya nucifera, arctigenin and demethyltraxillagenin, dibenzylbutyrolactone lignans, are phenylpropanoid metabolites with antioxidant and anti-inflammatory activities.45 Lignans may regulate immune responses in activated macrophages and lymphocytes. Arctigenin inhibits TNF-alpha and nitric oxide production46 and protects cultured neurons against glutamate toxicity.47

ASPILIA SPP

A perfect example of how medicine evolved along with the evolution of animals and of learned behavior in prehuman animals, these plants stimulate uterine contraction and are eaten primarily by female chimpanzees when pregnant. They also contain thiarubrine A, a valuable fungicidal and nematocidal agent, which was discovered because of anthropologists in the field observing chimpanzee behavior. An anticoagulant factor in Aspilia prolongs partial thromboplastin time and prothrombin time, while decreasing plasma fibrinogen.48

CRATAEGUS SPP (HAWTHORN)

Crataegus oxycantha has been used traditionally as a cardiac tonic and current uses include treatment for angina, hypertension, arrhythmias, and congestive heart failure, while nimal studies have also indicated that Crataegus extracts may also have potential use as anti-ischemic and lipid-lowering agents.49 Oral administration in gerbils protected against hippocampal cell loss from ischemia-reperfusion injury.50 To my knowledge, no studies on ocular effects have been reported.

COLEUS FORSKOLII

Forskolin has been heavily touted on the Internet for its antiglaucoma properties. It was investigated in the 1980s for its ability to reduce aqueous secretion, but never pursued further.51, 52 A few human single-dose studies suggested that topical application lowers IOP.53-55 It is believed that rapid tachyphylaxis developed, preventing its longer term use.

GINSENG (PANAX GINSENG; REN SHEN)

Next to GBE, ginseng, a highly valued herb in the Far East, is the most studied plant compound. A major problem with elucidating the effects of ginseng is that, not only can its properties vary from species to species, but within species depending on the soil, environment, and time of year. Panax ginseng is one of the most widely used herbs in traditional Chinese medicine. The major active components of ginseng are ginsenosides, a diverse group of steroidal saponins, which demonstrate the ability to target a myriad of tissues, producing an array of pharmacological responses.56 Of greatest interest are the ginsenoside saponins RB1 and Rg3, which attenuate or inhibit responses that lead to the apoptotic cascade, including glutamate-induced neurotoxicity, calcium influx into cells in the presence of excess glutamate, and lipid peroxidation.

Ginsenosides Rb1 and Rg3 exert significant neuroprotective effects on cultured cortical cells,57 and against 3-nitropropionic acid-induced motor impairment and cell loss in the striatum,58 and apparently act by inhibiting N-methyl-d-aspartate (NMDA) receptor activity.59 Central infusion of ginsenoside Rb1 in a gerbil model after forebrain ischemia protects hippocampal CA1 neurons against lethal ischemic damage.60 Ginsenoside Rb1 has been reported to enhance peripheral nerve regeneration in vitro.61 Ginsenosides suppress tumor necrosis factor-alpha production in vitro and may have potential therapeutic efficacy against TNF-alpha mediated disease.62 Another compound from ginseng, ginsenoside Re, induced angiogenesis and enhanced tissue regeneration, supporting the concept of therapeutic angiogenesis in tissue-engineering strategies.63

GRAPE SEED EXTRACT AND RED WINE

Alcohol consumption did not begin with humans, but is found as far down the evolutionary scale as fish, which become inebriated after eating overripe fruit falling into the water. Grape seed proanthocyanidins have been reported to possess a broad spectrum of pharmacological and medicinal properties against oxidative stress. Grape seed proanthocyanidin extract (GSE) provides excellent protection against free radicals in both in vitro and in vivo models.64 GSE significantly prevented and postponed development of cataract formation in rats with hereditary cataracts65 and radiation-induced cataract.66 Improvement in myocardial ischemia-reperfusion injury in vitro has been reported.67-69 Activin, a new generation antioxidant derived from grape seed proanthocyanidins, reduced plasma levels of oxidative stress and adhesion molecules (ICAM-1, VCAM-1 and E-selectin) in patients with systemic sclerosis.70 Supplementation of a meal with GSE minimizes postprandial oxidative stress by decreasing oxidants and increasing the antioxidant levels in plasma, and, as a consequence, enhancing the resistance to oxidative modification of low density lipoproteins.71 Grape seed proanthocyanidins have also been reported to have activity against HIV-1 entry into cells.72

Resveratrol is found largely in the skins of red grapes and came to scientific attention as a possible explanation for the low incidence of heart disease among the French, who eat a relatively high-fat diet. Many studies suggest that consuming alcohol (especially red wine) may reduce the incidence of coronary heart disease (CHD). Grape juice, which is not a fermented beverage, is not a significant source of resveratrol.

Several studies have demonstrated that resveratrol is an effective antioxidant.73-75 It inhibits lipid peroxidation of low-density lipoprotein (LDL), prevents the cytotoxicity of oxidized LDL, and protects cells against lipid peroxidation.73 Its antiapoptotic activity has led to the suggestion that resveratrol may make a useful dietary supplement for minimizing oxidative injury in immune-perturbed states and human chronic degenerative diseases.76 Levels of Intracellular heme (iron-protoporphyrin IX), a pro-oxidant, increase after stroke, and, in neuronal cell cultures, resveratrol induces heme oxygenase 1, suggesting that increased heme oxygenase activity is a unique pathway by which resveratrol can exert its neuroprotective actions.77

Epidemiological evidence suggests that moderate wine consumption may protect against age-related macular degeneration (AMD), and resveratrol can reduce oxidative stress and hyperproliferation of retinal pigment epithelial cells in vitro.78 In a rabbit model of spinal cord ischemia, resveratrol decreased oxidative stress, increased nitric oxide release, and protected spinal cord from ischemia-reperfusion injury.79 In a mouse model, orally administered proanthocyanidin significantly inhibited laser-irradiation induced thrombus formation in the carotid artery, perpahs through a direct inhibitory effect on platelets.80

GREEN TEA CATECHINS

Tea contains a number of bioactive chemicals and is particularly rich in catechins, of which epigallocatechin gallate (EGCG) is the most abundant81 and is an extremely potent antioxidant.82 Catechins and epicatechins are important constituents in human nutrition and have neuroprotective properties.83 Oxidative alterations of low density lipoproteins, scavenging of oxygen free radicals, and inhibition of glutamate toxicity are properties of catechins.84 There is a concentration-dependent correlation between these compounds and modulation of cell survival/cell death-related gene pathways in vitro.85 Catechins reduce mitochondrial damage during ischemia-reperfusion injury.86

Green tea extract scavenges free radicals and nitric oxide87 and have been reported to counteract the oxidative insult from cigarette smoke88 and to retard the progression of experimental cataract.89

PYCNOGENOL

Pycnogenol, an extract of French maritime pine bark (Pinus pinaster), primarily composed of procyanidins and phenolic acids, is a potent antioxidant which has strong free radical-scavenging activity against reactive oxygen and nitrogen species. Procyanidins are biopolymers of catechin and epicatechin subunits which are recognized as important constituents in human nutrition.90 Pretreatment with pycnogenol reduces smoke-induced platelet aggregation.91 Pycnogenol significantly reduces LDL-cholesterol levels.92, 93 In patients with chronic venous insufficiency, circumference of the lower legs and symptoms of pain, cramps, night-time swelling, feeling of "heaviness", and reddening of the skin were reduced.93 In an animal model using a branding iron on rats, pycnogenol accelerated wound healing and reduced scar formation.94

Glutamate-induced cytotoxicity in HT-4 neuronal cells has been demonstrated to be due to oxidative stress caused by depletion of cellular glutathione (GSH). Extracts of Gingko biloba (EGb 761) and French maritime pine bark (Pycnogenol) were effective inhibitors of this cytotoxicity.95 Pycnogenol can protect vascular endothelial cells from Aß-induced injury, suggesting that it may be useful for the prevention and/or treatment of vascular or neurodegenerative diseases associated with Aß toxicity.96 PYC not only suppresses the generation of reactive oxygen species, but also attenuates caspase-3 activation and DNA fragmentation, suggesting protection against Aß-induced apoptosis.97

Pycnogenol has also been reported to have angiotensin-converting enzyme (ACE) inhibiting activity, and the ability to enhance the microcirculation by increasing capillary permeability.98 Pycnogenol inhibits the progression of diabetic retinopathy.99, 100 It also showed strong inhibitory effects on the activities of MMP-1, MMP-2, and MMP-9, suggesting a basis for its use in prophylaxis and therapy of disorders related to imbalanced or excessive MMP activity.101 In another interesting study, Pycnogenol treatment was effective in decreasing the number of deep and superficial vein thromboses in moderate-to-high risk subjects during long-haul flights.102

SALVIA MILTIORRHIZA

Salvia miltiorrhiza, also known as Asian red sage or Dan shen, is a traditional Chinese medicine and has long been used for treating liver and heart diseases in China. It contains salvionolic acid B, a potent water-soluble, polyphenolic antioxidant with anti-inflammatory and anti-atherosclerotic properties isolated from Salvia miltiorrhiza.103, 104 It has been reported to reduce brain damage in cerebral infarction105, 106 and mitochondrial damage in ischemia-reperfusion injury.107 Retinal ganglion cell damage in glaucomatous damage was markedly reduced by intravenous treatment with S. miltiorrhiza.108 It has been claimed in one report to stabilize the visual field in patients with glaucoma.109 Data demonstrate that it inhibits TNF-(-induced activation of NF(( and in the rabbit model of glaucoma, protects against retinal ganglion cell loss. NMDA receptor antagonist activity may underlie its neuroprotective effects.110 Salvianic acid A scavenges superoxide anions in a dose-dependent manner, inhibits lipid peroxidation as effectively as Vitamin E, and inhibits mitochondrial swelling secondary to oxidative damage.111

SCROPHULARIA BUERGERIANA

These plants contain iridoid glycoside and E-p-methoxycinnamic acid. They inhibit calcium influx into cells and have been reported to inhibit glutamate-induced neurotoxicity in cultured cortical neurons.112, 113

VACCINIUM MYRTILIS (BILBERRY)

Highly touted in the lay press and Internet, and included in many eye vitamin preparations, bilberry was supposedly used by pilots in the Royal Air Force during World War II to improve their night vision. Most randomized controlled trials have found no advantage of bilberry on night vision or night contrast sensitivity and there is a virtual absence of research on patients with pathologically impaired night vision.114

TURMERIC

A staple of Indian cuisine, it is also used in herbal remedies. Turmeric extracts have strong antioxidant activity and inhibit lipid peroxidation.115 It also has anti-cancer, anti-inflammatory, and anti-angiogenesis activfities.116 Antiulcer activity of curcumin is primarily attributed to MMP-9 inhibition, one of the major path-ways of ulcer healing.117 Most recently, turmeric has been reported effective against the development of diabetic cataract in rats.118

SINGLE COMPOUNDS

CARNITINE

Carnitine, an amino acid derivative found in high energy demanding tissues (skeletal muscles, myocardium, liver), is essential for the intermediary metabolism of fatty acids. Carnitine prevents glutamate neurotoxicity in primary cultures of cerebellar neurons.119 It has been reported to prevent retinal injury following ischemia-reperfusion injury.120

CARNOSINE

Carnosine (beta-alanyl-L-histidine) and related dipeptides such as anserine are naturally-occurring histidine-containing compounds which possess strong antioxidant activity.121 Carnosine also inhibis the formation of advanced glycation end products and can inhibit the intracellular formation of reactive oxygen species and reactive nitrogen species.122 In diabetic mice, carnosine significantly decreased plasma glucose, fibronectin and triglyceride levels and enhanced catalase and gluathione peroxidase acivity, suggesting its potential as a protective agent for diabetic complications prevention or therapy.123 Carnosine also strongly suppresses ischemia-reperfusion injury in the kidney.124 Most of the work with this compound for ophthalmology has been performed by a single group in Russia and at a private company in Delaware. This group has claimed carnosine to protect the lens from oxidative stress-induced damage, cause regression of posterior subcapsular lens opacities, reduce glare, and improve visual acuity when applied topically.125-128

COENZYME Q10

Tissues which are highly dependent on oxygen such as muscle, the central and peripheral nervous system, kidney, and insulin-producing pancreatic beta-cell are especially susceptible to defective oxidative phosphorylation, which plays an important role in atherogenesis, in the pathogenesis of Alzheimer's disease, Parkinson's disease, diabetes, and aging.129 Pretreatment of cultured neuronal cells and astrocytes with coenzyme Q10 inhibited cell death due to glutamate neurotoxicity.130 It also exhibits anti-apoptotic effects, apparently by stabilizing mitochondrial depolarization.131 Oral Q10 supplementation is effective in treating cardiomyopathies and in restoring plasma levels reduced by the statin type of cholesterol-lowering drugs.129 Supplementation with Coenzyme Q10 has been reported to slow the development of Parkinson’s disease.132 Patients with open-angle glaucoma have an increased prevalence of Parkinson’s disease.133

FATTY ACIDS and FISH OIL

Omega-3 fatty acids, such as docosahexaenoic acid (DHA) and eicosapenteneoic acid (EPA) have been shown to have major health benefits. DHA has been thought to play an important role in providing an adequate environment for conformational rhodopsin changes and in modifying the activity of retinal enzymes in photoreceptor cells. Decreased retinal DHA content affects visual function in the monkey.

In the eye, they have been investigated most extensively with regard to age-related macular degeneration (AMD). In the Nurses' Health Study and the Health Professionals Follow-up Study, DHA intake had a modest inverse relation with AMD and more than 4 servings of fish weekly was associated with a 35% lower risk of AMD compared with 3 servings or less per month.134 In a prospective multi-institutional study, diets high in omega-3 fatty acids and fish were inversely associated with risk for AMD when intake of linoleic acid was low.135

DHA is effective intraperitoneally in protecting the retina against transient retinal ischemia induced by elevated intraocular pressure.136 Oral DHA can partially counteract retinal neurotoxicity induced by kainic acid.137 In ischemia-reperfusion injury, DHA protects against cell death probably by inhibiting the formation of hydroxyl radicals.138 In patients with retinitis pigmentosa who were beginning vitamin A therapy, addition of 1200 mg/day DHA slowed the course of disease for 2 years.139

METHYLCOBALAMIN (Vitamin B12)

In patients with glaucoma, studies have shown possible improvement or stabilization in visual field performance with oral B12 supplementation.140, 141 Methylcobalamin protects cultured retinal ganglion cells against glutamate-induced neurotoxicity142 and reduces retinal ganglion cell death after optic nerve crush injury in rats.143

QUERCETIN

This flavonoid antioxidant, found in Ginkgo biloba extract and in red wine, inhibits release of nitric oxide144 and tumor necrosis factor alpha,145 which may be an important factor in the initiation of glaucomatous damage. Quercetin is neuroprotective against oxidative injury in cortical cell cultures, inhibiting lipid peroxidation and scavenging free radicals,146 and hepatoprotective against ischemia-reperfusion injury when given orally.147 Apoptosis-promoting substances, including TNF-alpha secreted by activated glial cells after exposure to stress, contribute directly to neuronal cytotoxicity.148 Quercetin inhibits lipid peroxidation in the mammalian eye149 and has been reported to slow the progression of selenite-induced cataract in rats.150

CONCLUSIONS

Although neuroprotective strategies and pharmaceutical agents have been initiated in the treatment of numerous disorders of the central and peripheral nervous systems, including trauma, epilepsy, stroke, Huntington’s disease, amyotrophic lateral sclerosis, and AIDS dementia, none have yet been applied to the treatment of glaucoma. A prospective, placebo-controlled, multi-institutional trial of memantine is still underway. One would not expect the treatment modalities which form the bases of nonpharmaceutical, traditional medical systems to be used to lower IOP. Glaucoma was unknown when these medicinal treatments were developed over the centuries. Their primary use is in improving the cardiovascular and immune systems and in what we now call neuroprotection. Rather than single compounds, which target a specific receptor and have demarcated side effects in other systems, plant products are a blend of many compounds and, according to those most versed in them, achieve a balanced therapy, helping in specific symptomatic complexes while reducing side effects through ameliorating effects in other areas. It is not insignificant that, now that the rain forests are rapidly dwindling, along with their inhabitants and the knowledge of medicinal plants, especially in South America, the pharmaceutical companies are spending large amounts of money in a sudden, almost frantic attempt to gather up the knowledge about rain forest plants before all has been completely lost. Proof of effects clinically in a chronic disease such as glaucoma remains largely lacking, and controlled trials are unlikely to be initiated, except perhaps through the NIH, since these compounds, in general, have been in the public domain for many years. Perhaps those as yet unknown or unrecorded are patentable and perhaps these include those drugs known only to small surviving communities of hunter-gatherers, which would explain the pharmaceutical interest in these areas. When more accurate and rapid means of assessment of progression of glaucomatous damage than perimetry and optic nerve head photography are eventually developed, and trials can be reduced either in time, number of subjects, or even the use of nonhuman subjects for the bulk of studies, studies could be done for verification of effect of various compounds and also comparative studies. At the present time, Gingko biloba extract is the most well documented of all the complementary medicinal agents and appears to have the greatest potential value.

Gingko biloba extract has numerous properties which theoretically should be beneficial in treating non-IOP-dependent mechanisms in glaucoma. Its multiple beneficial actions, including increased ocular blood flow, antioxidant activity, platelet activating factor inhibitory activity, nitric oxide inhibition, and neuroprotective activity combine to suggest that GBE could prove to be of major therapeutic value in the treatment of glaucoma.

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