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@earthlink.net
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 nonIOP-dependent damage. The most intensively investigated cause of non-pressuredependent 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-IOPdependent 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 glutamateinduced 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.2325 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 Nmethyl-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 immuneperturbed 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 ischemiareperfusion 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, nighttime 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 longhaul 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 openangle 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 agerelated 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 multiinstitutional 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 ischemiareperfusion 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 huntergatherers, 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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