Glaucoma

Glaucoma affects 3-4 million Americans according to the National Eye Institute. Worldwide, it affects about 90 million people and is the leading cause of irreversible blindness. The most common form, open-angle glaucoma, is often referred to as the "silent thief" because most people with undetected glaucoma don't suffer from symptoms until they begin to lose their peripheral vision. The term glaucoma really refers to a group of diseases that share a common problem: a gradual degeneration of the cells that make up the optic nerve.

The optic nerve is a bundle of over one million nerve fibers that conduct electrical signals from the light-sensing retina at the back of the eye to the brain. Also called the "nerve of sight", the optic nerve is an essential link between the eye and the brain that makes vision possible.

Damage to the Optic Nerve

In many cases of glaucoma, damage to the optic nerve is caused largely by increased pressure in the eye that results from fluid build-up. However damage can also occur even when eye pressure is normal. Many clinicians now view glaucoma as a neurodegenerative disease - one caused by damage to, and loss of nerve cells - rather than a disease of elevated eye pressure alone (1). Although it's not known exactly how the optic nerve is damaged in glaucoma, poor or disordered blood flow to the retina and optic nerve appears to play a role. When blood supply to the nerve is interrupted, it slows the delivery of vital oxygen and nutrients, leading to cell damage or death.

Ginkgo Biloba Improves Vision

The botanical Ginkgo biloba is popularly known for its beneficial effects on brain function and memory in older people (2). This herbal can enhance cerebral blood flow and provide antioxidant activity. Because ginkgo has also been shown to increase ocular blood flow (3), its effect on visual field damage in glaucoma patients with normal eye pressure was recently evaluated in a double-blind trial (visual field is the amount of space you can see without moving the eyes) (4).

In this study, twenty seven patients with visual field damage received 120 mg of supplemental ginkgo extract for 4 weeks, followed by 8 weeks of no supplementation, then 4 weeks of placebo treatment. Other patients underwent the same regimen, but took the placebo first and ginkgo last. Visual field tests, were performed at the beginning and at the end of each phase of the study. Significant improvement in visual field measurements was found only after the period when ginkgo was taken, and did not continue after supplementation was stopped.

A Clue to Glaucoma Cause: Antioxidants May Help

Oxidative damage to the eye's fluid drainage system has recently been shown to match up, or correlate, with higher eye pressure and visual field loss (5,6). This finding is important because in some cases of glaucoma, fluid drains too slowly from the eye resulting in elevated pressure. The researchers measured a biomarker for oxidative DNA damage in the fluid drainage region of the eye (known as the trabecular meshwork) from 42 glaucoma patients and 45 patients of similar age and sex without the disease. Oxidative damage to the genetic material in trabecular meshwork cells was found to be significantly higher in those with glaucoma.

The optic nerve is a bundle of over one million nerve fibers that conduct electrical signals from the light-sensing retina at the back of the eye to the brain. Also called the "nerve of sight", the optic nerve is an essential link between the eye and the brain that makes vision possible.

Not only do these findings shed light on one possible cause of this disease, they also raise the possibility that antioxidants could help reduce damage to the trabecular meshwork in addition to protecting nerve cells. A host of experimental studies suggest that antioxidants such as alpha lipoic acid, vitamins C and E and bioflavonoids are useful in quelling such oxidative damage. According to these authors, antioxidants are well worth more clinical study to evaluate their potential in preventing or treating open-angle glaucoma.

References

1. Ercoli L et al. Society for Neuroscience Meeting, New Orleans, November, 2003
2. Chung HS et al. Ginkgo biloba extract increases ocular blood flow velocity. J Ocul Pharmacol Ther 15:233-40, 1999.
3. Quaranta L et al. Effect of Ginkgo biloba extract on pre-existing visual field damage in normal tension glaucoma. Opthalmol 110:359-62 (discussion 362-4), 2003.
4. Schwartz M. Neuroprotection as a treatment for glaucoma. Eur J Ophthalmol Suppl 3:S27-41, 2003. .
5. Izzotti A et al. Oxidative deoxyribonucleic acid damage in the eyes of glaucoma patients. Am J Med 114:638-46, 2003.
6. Chen JZ et al. A new clue to glaucoma pathogenesis. Am J Med 114:697-8, 2003.

Optic Nerve Formula, providing 120 mg of Ginkgo biloba, omega-3 fatty acids, antioxidants, and other key nutrients to support optic nerve health, is now available from ScienceBased Health.

Spotlight on Taurine

Taurine: A Unique Amino Acid

Amino acids, when strung together, make up the proteins found in our diet. The bonds connecting these building blocks of protein are broken during digestion, releasing amino acids for absorption. Once absorbed, the amino acids can be re-assembled to form proteins of different shapes, sizes and properties that the body needs to repair tissue, form muscle, manufacture enzymes, produce immune cells and perform a host of other functions.

A few amino acids are also manufactured within the body in addition to being provided by the protein foods we consume. Taurine is one example. This amino acid occurs naturally in foods such as seafood, meats, poultry and eggs - although it can also be synthesized internally from two sulfur-containing amino acids, methionine and cysteine, in the presence of vitamin B6. Unlike most proteins, however, taurine is not incorporated into proteins or enzymes but is found as a free amino acid in body tissues. The chemical structure of taurine is also unique, making it well-suited to perform its physiologic functions.

Taurine "Wears Many Hats" in the Body

Taurine's role in the body is diverse: from working with bile acids to help digest and absorb fats, to its involvement in regulating water balance by helping to transport magnesium and potassium into cells. Taurine is found throughout the body, but is concentrated in muscle, where it is thought to help regulate heart beat and muscle contraction. Taurine has antioxidant activity, and is gaining attention for its potential clinical use in ischemia-reperfusion injury - the free radical damage that can occur when blood flow is restored to oxygen deprived tissue, such as after heart valve or coronary artery bypass surgeries. Researchers are also investigating taurine's involvement in mediating the inflammatory response.

Because taurine is needed for the development of retinal and nervous tissue, dietary sources are important for premature and newborn infants who can't manufacture sufficient amounts on their own and obtain taurine through breast milk. For those with chronic kidney, liver or heart failure, taurine is often considered a "conditionally essential" amino acid, which means that under certain conditions, diseases or injury, the body may not be able to make enough taurine to meet demands.

The Role of Taurine in the Eye

Taurine plays a role in the visual system of adults: it interacts with zinc to stabilize membranes and helps make photoreceptors (rods) in the retina, resistant to injury. Some also postulate a role for antioxidant taurine in helping to maintain clarity of the eye's lens, though this remains speculative.

In addition to taurine's function in the adult eye, new research has shed some light on how this amino acid helps to initially develop rod photoreceptors - the specialized light-gathering cells that line the retina. In the early 1990s, it was found that adding taurine to immature retinal cells could get more of them to turn into rods. Yet it was unclear what was making the cells susceptible to taurine's instructions. New findings from Harvard suggest that taurine works its transforming effects through neurotransmitter receptors, with similar findings reported by UC San Francisco researchers. According to the Harvard team, this discovery provides information that someday could lead to new methods of restoring or replacing these delicate cells, which are lost in various retinal diseases and decline with age.

Bibliography

1. Kingston R et al. The therapeutic role of taurine in ischemia-reperfusion injury. Curr Pharm Des 10:2401-10, 2004
2. Lourenco R and Camilo ME. Taurine: a conditionally essential amino acid in humans? An overview in health and disease. 17:262-70, 2002.
3. Militante J and Lombardini JB. (Review) Age-related retinal degeneration in animal models of aging: possible involvement of taurine deficiency and oxidative stress. Neurochem Res 29:151-60, 2004.
4. Militante JD and Lombardini JB. Taurine: evidence of physiologic function in the retina. Nutr Neurosci 5:75-90, 2002.
5. Renteria RC et al. Need rods? Get glycine receptors and taurine. Neuron 41:839-41, 2004.
6. Schuller-Lewis G. and Park E. (Review) Taurine: new implications for an old amino acid. FEMS Microbiol Letters 226:195-202, 2003.
7. Young TL and Cepko CL. A role for ligand-gated ion channels in rod photoreceptor development. Neuron 41:839-41, 2004.

Ginkgo May Slow Visual Field Loss in Normal Tension Glaucoma

Glaucoma and Altered Ocular Blood Flow

There are two leading theories to explain the mechanisms underlying glaucoma. The first, a mechanical theory, postulates that increased intraocular pressure (IOP) stretches the lamina cribrosa and damages retinal ganglion cell axons. The second theory suggests that an inadequate vascular supply, such as reduced blood flow to the optic nerve, results in ganglion cell damage.

Although there’s agreement that IOP reduction is a beneficial treatment in both high and normal tension glaucoma (NTG), the vascular theory may be more relevant in explaining NTG pathogenesis. In support of this idea is the observation that glaucoma continues to progress in many patients despite IOP reductions, and the fact that a reduction in blood flow often precedes optic nerve damage. Additionally, risk factors for NTG – such as low blood pressure, orthostatic hypotension, nighttime hypotension, migraine and sleep apnea – result in reduced blood flow to the brain.

Ginkgo biloba: Mechanisms & Research Findings

Ginkgo biloba leaf extracts have been used in Chinese traditional medicine for 5000 years. In recent times, Ginkgo has been reported to be neuroprotective for retinal ganglion cells in animal models of chronic glaucoma, and clinically shown to increase ocular blood flow and reduce visual field damage in NTG patients in the short term. Ginkgo has demonstrated antioxidant activity, and may increase blood flow by changes in blood viscosity and inhibition of platelet activating factor.

The current study (1) was conducted to evaluate the long-term effects of G. biloba extract on progression of visual field defects in patients with NTG.

Study Design

In this retrospective study, 42 eyes of 42 NTG patients were evaluated for more than a 4-year period before and 4 years after receiving 80 mg of Gingko biloba extract twice daily (total of 160 mg per day). Patients had at least 5 visual field (VF) tests in the 4 years prior to and after supplementation. The VF tests were routinely preformed at diagnosis, 3 months later, and every 6-12 months thereafter with the Humphrey VF Analyzer. The change of progression rate was evaluated using mean deviation, pattern standard deviation, and visual field index. The time course of mean total deviation in 10 zones corresponding to the glaucoma hemifield test was analyzed using a linear mixed effects model with unequal random effects variance.

Results

The mean follow-up period was 12.3 years. After Ginkgo treatment, the regression coefficients of the mean deviation (MD), pattern standard deviation (PSD) and visual field index (VFI) change improved significantly (p<0.001). Before and after treatment regression coefficient values were as follows:

• MD,  -0.619 and –0.379 dB/yr
• PSD, -0.626 and 0.342 dB/yr
• VFI change, -2.351 and -1.212 %

In zone 1, after Ginkgo biloba administration, visual field damage was significantly slowed (rate of the regression coefficient of mean total deviation change significantly increased; p<0.05).

Comment

The authors conclude that Ginkgo biloba extract slowed the progression of visual field damage in patients with NTG, especially in zone 1 which corresponds to the superior central field. A number of studies have shown that the superior central field is the main location of visual field defects in NTG, whereas high tension glaucoma defects tend to be more diffuse (2,3).

No ocular or systemic adverse effects were reported among patients during follow-up in this retrospective study cohort. This appears to be the first study to compare visual field progression in the same patients after Ginkgo supplementation, and the results suggest that Ginkgo biloba may be useful as a complementary treatment for glaucoma.

References

1. Lee J et al. Effect of Ginkgo biloba extract on visual field progression in normal tension glaucoma. J Glaucoma [Epub May 12, 2012].  
2. Ahrlich KG et al. Visual Field progression differences between normal-tension and exfoliative high-tension glaucoma.  Invest Ophthalmol Vis Sci 51:1458-63, 2010.
3. Araie M et al. Visual field defects in normal-tension and high-tension glaucoma. Ophthalmol 100:1808-14, 1993.

Low Antioxidant Status Seen in Glaucoma

Oxidative Stress & Development of Glaucoma

Primary open-angle glaucoma (POAG) is a chronic, slowly-progressing optic neuropathy characterized by a distinctive pattern of visual field defects. Psuedoexfoliation syndrome (PEX) is distinguished by abnormal extracellular fibrillar material that accumulates in the anterior segment of the eye and in other organs. PEX is the most common identifiable cause of open-angle glaucoma worldwide.

Oxidative stress – the presence of increased levels of reactive oxygen species relative to antioxidant defenses – may contribute to the development of both POAG and psuedoexfoliation glaucoma (PEG). Greater oxidative damage to trabecular meshwork cells has been reported in POAG and PEG vs. non-glaucoma patients (1), for example, and oxidative stress has been implicated as an underlying mechanism of retinal ganglion cell death (2).

In the present study, researchers examined the antioxidant status and established the presence of oxidative stress in patients with POAG and PEG3 (3).

Study Design

The study enrolled 23 POAG patients, 24 PEG patients, and 19 healthy control subjects; all 3 groups included men and women within the same age range.

As indicators of antioxidant status, the total antioxidant capacity of serum and total activity of superoxide dismutase were determined by spectrophotometry. Total antioxidant status represents the cumulative action of all antioxidants present in serum.

Total oxidant status, nitric oxide, protein carbonyl levels, and maldonaldehyde were also measured from blood sample by spectrophotometry as indicators of oxidative stress. Maldonaldehyde and protein carbonyl reflect the level of lipid peroxidation and protein oxidation, respectively.

Results

Antioxidant Status Indicators: Mean total antioxidant capacity in the POAG and PEG groups was about half that of controls (p = 0.001).

Mean superoxide dismutase levels were significantly higher in both glaucoma groups compared to the control group (p = 0.001). Concentrations of superoxide dismutase are known to rise as a consequence of oxidative stress, and in accordance with the degree of stress conditions.

Oxidative Stress Indicators: Mean total oxidant status was significantly higher in both glaucoma groups compared to controls (p = 0.001), as was maldonaldehyde (p = 0.001). The POAG group showed higher serum nitric oxide levels than controls (p = 0.005), although the PEG group did not.

Those with PEG had higher serum protein carbonyl levels than both the POAG and control groups (p = 0.001), while protein oxidation in the POAG group was no different from controls.

Comments

These results add to the growing body of evidence supporting a role for oxidative stress in POAG and PEG. The finding of lower antioxidant defense systems in the glaucoma patients are also consistent with reports from other researcher groups (4,5).

The relatively small number of subjects assessed can be considered a study limitation. However, the breadth of biomarkers measured is certainly one of the study’s strengths, since no one biomarker of antioxidant or oxidant status gives a full picture of the oxidative state. The consistency of results observed between the various biomarkers that were measured lends credence to the findings overall.

References

1. Izzotti A, et al. Mitochondrial damage in the trabecular meshwork occurs only in primary open-angle glaucoma and in pseudoexfoliative glaucoma. PloS 6(1)e14567, Jan, 2011.
2. Baltmr A, et al. Neuroprotection in glaucoma—Is there a future role? Exp Eye Res 91:554-66, 2010.
3. Erdurmus M, et al. Antioxidant status and oxidative stress in primary open angle glaucoma and pseudoexfoliative glaucoma. Curr Eye Res 36:713-718, 2011.
4. Ghanem AA, et al. Oxidative stress markers in patients with primary open-angle glaucoma. Cur Eye Res 35:295-301, 2010.
5. Engin KN, et al. Variability of serum oxidative stress biomarkers relative to biochemical data and clinical parameters of glaucoma patients. Mol Vis 16:1260-71, 2010.

Polyphenols Bolster Drug Effects in Ocular Hypertension

Ocular Hypertension and Risk of Glaucoma

Ocular hypertension is a leading risk factor for the development of primary open angle glaucoma (POAG), and is the only modifiable risk factor acknowledged at present.

It’s estimated that 4 to 7% of Americans over 40 years of age have ocular hypertension. The Ocular Hyper-tension Treatment Study (OHTS) clearly showed that lowering IOP is effective in delaying or preventing the onset of POAG in individuals with ocular hypertension. Recent results from a long-term study by the OHTS group indicates that those at high risk of POAG can benefit from early preventive treatment (1).

Spurred by previous findings that a combination of polyphenols (anthocyanins and procyanidins) could improve IOP and blood flow in ocular hypertension, the same researchers recently compared the effects of those polyphenols alone and with latanoprost in ocular hypertensive patients with no signs of POAG (2).

Study Design

The study recruited 79 men and women, mean age 49 yrs, with diagnosed elevated IOP (> 35 and < 40 mmHg). All subjects had complete eye exams, showing no signs of POAG. Patients were randomly divided into 3 groups to receive latanoprost (Xalatan, one drop per eye daily), one tablet of the polyphenol combination, or both.

The supplement tablet contained a daily dose of about 28 mg anthocyanins (Bilberry extract) and 28 mg procyanidins (French Maritime Pine Bark Extract). IOP was consistently measured at the same time in the a.m. by the same investigator, and in triplicate. High resolution color Doppler imaging was used to measure the peak systolic flow velocity, and the end diastolic flow velocity of the central retinal artery.

Results

• The polyphenol supplement alone lowered IOP from 38.1 at baseline to 29.0 mmHg after 16 weeks, with little further improvement during the following 8 weeks.
• Latanoprost rapidly lowered IOP from baseline 37.7 to 27.2 mmHg within 4 weeks, without further effects.
• The combined supplement and latanoprost lowered IOP from 38.0 to 27.3 mmHg after 4 weeks, and further reduced IOP to 24.2 mmHg after 6 weeks.
• After 24 weeks, IOP with the combination treatment (23.0 mmHg) was significantly lower than with the topical drug alone (27.2 mmHg). [See graph below]

• The supplement and latanoprost each gradually increased central artery blood flow in a comparable manner. From 12 weeks on, the diastolic component was higher with the combined vs. individual treatments.
  
  

Comments

The polyphenol and drug combination was more effective for lowering IOP, and the combination yielded better retinal blood flow. Evidence suggests that bilberry anthocyanins may act by countering increased permeability of blood capillaries, while the procyanidins may improve endothelial function. These promising results warrant further research with a larger patient group, according to the authors.

References

1. Kass MA, et al. Delaying Treatment of Ocular Hypertension. The Ocular Hypertension Treatment Study. Arch Ophthalmol 128:276-287, 2010.
2. Steigerwalt RD, et al. Mirtogenol® potentiates latanoprost in lowering intraocular pressure and improves ocular blood flow in asymptomatic subjects. Clinical Ophthalmol 4:471-6, 2010.

Serum Levels of Vitamin C & Uric Acid in Normal Tension Glaucoma

Oxidative Stress & Normal Tension Glaucoma

The occurrence of normal-tension glaucoma (NTG) varies worldwide. In the US, up to 15-25% of people with primary open-angle glaucoma (POAG) experience NTG. It is considerably more prevalent in Japan, with NTG comprising more than 70% of glaucoma cases.

In NTG, progressive damage can occur even with intraocular pressure (IOP)-lowering intervention. The cause of optic nerve damage in NTG is not fully understood, but oxidative stress is believed to be one contributing factor. Current evidence, for example, points to the association between oxidative stress and ganglion cell death without elevated IOP. In addition, there are some reports of lower levels of circulating antioxidants such as the major cellular antioxidant glutathione, in POAG patients.

These and other findings led Japanese researchers to examine serum levels of antioxidant vitamins A (beta-carotene), C and E, as well as folic acid and endogenous uric acid in NTG patients.

Beta-carotene and vitamin A are fat soluble antioxidants, while water soluble ascorbic acid and uric acid are strong reducing agents and potent antioxidants. In humans, over half the antioxidant capacity of plasma comes from uric acid, and vitamin C is highly concentrated in the aqueous humor. While not an antioxidant, folic acid insufficiency results in microvascular-damaging levels of homocysteine.

Study Design

Sixty patients with newly diagnosed POAG were consecutively screened for inclusion in this study. After diagnosis of POAG, patients underwent 24-hr IOP measurements, and 47 newly diagnosed consecutive NTG patients (18 males, 29 females; mean age 59.5 years) were enrolled. The control subjects were recruited from subjects who came to the clinic for annual refractive check-up. The 44 consecutive control subjects (16 males, 28 females; mean age 62.7 years) had no ocular diseases.

Serum levels of vitamins A, folic acid, C, E, and uric

acid were measured, and the values compared between the NTG and control groups by the Mann-Whitney U test.

Results

Serum levels of vitamin C were significantly lower in NTG patients than in normal healthy controls (P=0.04; NTG 4.6±4.0 µg/ml, and control 6.3±3.9 µg/ml).

Uric acid concentrations were significantly higher in NTG patients compared to controls (P=0.01; NTG 5.8±1.5 mg/dl, and control 4.9±1.4 mg/dl).

No statistically significant differences were observed in the other vitamins measured.

Comments

The results of this study indicate that uric acid levels were increased and vitamin C levels were decreased in NTG patients. The authors speculate that higher serum uric acid and lower serum vitamin C may change the trabecular meshwork physiology. In turn, this may decrease the outflow facility of aqueous humor, causing eventual IOP elevation and glaucomatous optic neuropathy.

The diurnal IOP of the NTG patients in this study was under 21 mmHg, yet significantly higher than that of the normal controls (P=0.001). According to the authors, low vitamin C levels may cause modest IOP elevation and optic neuropathy even in NTG patients.

Vitamin C is thought to play an important role in reducing reactive oxygen species in the trabecular meshwork. Recent studies suggest that oxidative stress accelerates trabecular meshwork cell death. Further, in vitro studies indicate that interactions between uric acid and vitamin C can change the viscosity of some glycosaminoglycans, which are found in the trabecular meshwork.

The authors call for placebo-controlled trials to investigate the effects of vitamin C on IOP and visual field change in patients with NTG.

Reference

Inflammation and Chronic Diseases

Inflammation is a complex series of reactions designed to prevent ongoing tissue damage and activate repair processes and defense mechanisms against infectious diseases. Prolonged inflammation, however, contributes to the pathogenesis of chronic such as Alzheimer's, diabetes, cancers, and CVD. Chronic inflammation is also believed to contribute to such eye diseases as AMD, dry eye, diabetic retinopathy and glaucoma.

Dampening inflammation may help retard the development of such diseases. Inflammatory injury may be mediated by reactive oxygen species (ROS) or their reaction products, and antioxidant therapy has been shown to prevent in vivo tissue injury during inflammation.

Role of NF-kB in the Inflammatory Response

The transcription factor nuclear factor-kB (NF-kB) controls expression of genes involved in the inflammatory response and is activated by oxidative stress and other pro-inflammatory stimuli. Activation of NF-kB results in coordinated expression of inflam-matory genes and secretion of pro-inflammatory chemokines and cytokines, which are associated with increased risk of disease and poor outcome of chronic inflammatory diseases. Thus, dampening NF-kB activation has been suggested as a strategy to prevent chronic inflammatory diseases.

Anthocyanins Dampen Inflammation

Anthocyanins are water-soluble red and blue flavonoid pigments responsible for the dark color of grapes, plums, black currants, blueberries and bilberries. The anthocyanins are effective antioxidant compounds in vitro, and have also been shown to suppress cancer, cataract, and neurodegeneration in animal models.

These data led researchers from the University of Oslo to examine whether bilberry and blackcurrant anthocyanins could inhibit NF-kB activation in vitro and in humans. The results of this study suggest that anthocyanin supplementation may have a role in pre-venting or treating chronic inflammatory diseases by inhibiting NF-kB trans-activation and deceasing plasma concentrations of pro-inflammatory chemokines, cytokines, and inflammatory mediators.

Study Design and Methods

The researchers studied whether anthocyanins inhibit LPS-induced NF-kB activation in cultured monocytes. Monocytes were pre-incubated with a combination of black currant and bilberry anthocyanins or placebo (dimethylsulfoxide). NF-kB activity was induced by LPS.

In the parallel-designed, placebo-controlled clinical study, 120 participants were randomly assigned to receive 300 mg of anthocyanins or placebo for 3 weeks. The amount of anthocyanins provided corresponded to 100 g of fresh bilberries. The subjects maintained their regular diet during the intervention period.

Blood samples from fasting at baseline and after the intervention period were collected and analyzed for cytokines [IL-1b, IL-1 receptor antagonist (IL-1Ra), IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, IL-17, TNFa, IFNa, IFNg, granolyte/macrophage colony-stimulating factor (GMCSF), and others were measured in plasma by a sandwich immunoassay-based protein array system.

Results

In the cultured cells incubated with anthocyanins, NF-kB activation was suppressed by 28% compared with cells incubated with vehicle only (p = 0.003). Anthocyanins also decreased the LPS-induced p65 DNA binding, another assay for NF-kB-activation, by 18% (p =.041).

In the clinical trial, differences were observed in several NF-kB related inflammatory mediators in the anthocyanin group compared to placebo.

Decreases from baseline in the NF-kB controlled pro-inflammatory chemokines IL-8, ''regulated upon activation, normal T cell expressed and secreted,'' and IFNa (an inducer of NF-kB activation) in the anthocyanin group differed significantly from those in placebos.

Similarly, decreases from baseline in IL-4 (60%) and IL-13 (38%) in the active group differed significantly from the slight decreases seen in placebos. Both of these cytokines mediate pro-inflammatory responses and activate NF-kB.

Reference
Karlsen A , et al. Anthocyanins Inhibit Nuclear Factor-kB Activation in Monocytes and Reduce Plasma Concentrations of Pro-Inflammatory Mediators in Healthy Adults. Journal of Nutriton. 137: 1951-1954, 2007.

Mitochondrial Dysfunction & Antioxidants

Primary open angle glaucoma (POAG) is generally associated with elevations in intraocular pressure (IOP) caused by abnormal resistance of aqueous outflow through the trabecular meshwork, a specialized tissue lining the eye's outflow pathway.

A key suspect in the progression of POAG is local oxidative stress. Oxidative free radicals and reactive oxygen species (ROS) are reported to trigger degeneration in the trabecular meshwork, subsequently leading to increases in IOP and glaucoma. There is mounting evidence that ROS play a fundamental role in reducing local antioxidant activities in the region of the trabecular meshwork. The mitochondria are the main source of cellular ROS and adenosine triphosphate (ATP), and are key regulators of mechanisms controlling cell survival and death. A spectrum of mitochondrial abnormalities in patients with POAG has recently been reported.

The authors of a newly published paper (1), now provide evidence that mitochondrial dysfunction is a possible mechanism for the loss of trabecular meshwork cells in POAG. They also report that the antioxidants vitamin E and n-acetyl cysteine (NAC), as well as mitochondrial permeability transition (MPT) inhibitors, can reduce the progression of this condition.

Study Design and Methods

Trabecular meshwork from patients with POAG and age-matched subjects without disease were obtained by standard surgical trabeculectomy. Primary cultures of trabecular meshwork were treated with 3 different respiratory chain inhibitors specific for Complex I, II and III. The protective effect of vitamin E, NAC and cyclosporine A was examined by adding these antioxidants or the MPT inhibitor to the cells 30 minutes before treatment with the respiratory chain inhibitors. Mitochondrial function was determined by changes in mitochondrial membrane potential and ATP production with fluorescent probes and a luciferin/luciferase-based ATP assay, respectively. ROS levels were determined by H2-DCF-DA, and cell death was measured by lactate dehydrogenase activity.

Results

The trabecular meshwork cells of patients with POAG exhibited senescence and degeneration compared with those of controls. There was spontaneous generation of ROS, decreased mitochondrial membrane potential, decreased ATP production, and loss of cell viability in primary cell cultures of patients with POAG compared with those of control subjects. ROS generation was associated with dysfunction at the level of mitochondrial complex I.

It was also determined that vitamin E, NAC (fig. A below), and the MPT inhibitor cyclosporine A protected POAG trabecular meshwork cells from cytotoxicity by attenuating ROS production and cytochrome c release from the mitochondria and by inhibiting the mitochondrial permeability transition opening.

Comments

Taken together, the results support the hypothesis that a defect in mitochondrial complex I contributes to progressive loss of tabecular meshwork cells in patients with POAG by promoting excessive mitochondrial ROS production. The finding of a protective effect of vitamin E and NAC (a key component of glutathione) adds to the growing evidence that antioxidants are beneficial in POAG and are worthy of further investigation.

(A) Reduction of ROS production in GTM cells by antioxidants Vit E and NAC. Treatment with antioxidants vitamin E (Vit E; 200 µM) or N-acetylcysteine (NAC; 10 mM) induced a decrease in ROS production in GTM cells. Pretreatment with Vit E or NAC for 30 minutes also significantly reduced ROT-induced ROS production in GTM cells. Data are expressed as a fold change in fluorescence levels of GTM to NTM. Results are expressed as the mean SE of six separate experiments performed in triplicate. *Significant differences from untreated control at P = 0.05.

Reference

1. Yuan He, et al. Mitochondrial Complex I defect induces ROS release and degeneration in trabecular meshwork cells of POAG patients: Protection by antioxidants, Invest Ophthalmol Vis Sci 49:1447-58, 2008.

Vitamin E: More Than an Antioxidant

Vitamin E is best known as the body's major fat-soluble antioxidant. Its main function is to intercept free radicals and prevent chain reactions of lipid destruction. However the discovery of complex molecules that control vitamin E metabolism such as tocopherol transfer protein, alpha tocopherol membrane receptors, and intracellular transfer proteins, triggered the idea that the activity of vitamin E extends beyond its antioxidant capacity.

Vitamin E is now known to affect the expression and activity of immune and inflammatory cells, to enhance vasodilation, and to inhibit the activity of the important cell signaling molecule protein kinase C (PKC).

Modulating the PKC pathway may be relevant in glaucoma. For instance, PKC inhibitors have been shown to relax the trabecular meshwork, and to affect matrix metalloproteinase and PGF2 alpha.

Vitamin E and PKC could also have a vaso-regulatory effect in the retina. In different experimental models, retinal vascular dysfunction due to hyperglycemia was reportedly prevented by vitamin E via the diacylglycerol-PKC pathway (1,2).

These findings prompted researchers at Istanbul University to evaluate the clinical potential of vitamin E in glaucoma patients. They report prevention of visual field loss in this preliminary study, and conclude that vitamin E deserves further attention in preventing glaucomatous damage (3).

Study Design and Methods

Thirty glaucomatous patients (60 eyes) with controlled IOP, were randomly divided into three groups. Group (A) received no vitamin E, while groups (B) and (C) were given a daily dose of 300 and 600 mg of vitamin E respectively, as d-alpha tocopheryl acetate for 12 months. Blood levels of vitamin E were measured via HPLC.

Disease progression for each subject was monitored via visual field measurements and color Doppler imaging of ophthalmic and posterior ciliary arteries at baseline, and at 6 and 12 months. Retinal blood flow of ophthalmic and posterior ciliary arteries was evaluated, and resistivity and pulsatility indexes were obtained. Mean deviation values for Fastpac visual fields were recorded at all time points, and the difference in mean deviation values calculated. The change in mean deviations of Groups (B) and (C) were compared with Group (A), and the Mann-Whitney U-test was employed for statistical analysis.

Results

There were no significant differences between the groups in mean ages, IOP, best corrected visual acuities of 10/10 ratios and disease etiologies. The average differences between the pulsatility indexes (PI) and resistivity indexes (RI) of both ophthalmic arteries and posterior ciliary arteries of both supplemented groups were significantly lower than those of the non-supplemented groups at 6 months and 1 year. RI decreases observed in posterior ciliary arteries at both time points, and PI decreases observed in ophthalmic arteries at the 6th month were statistically significant.

Compared with those receiving vitamin E, non-treated subjects showed a statistically significant reduction in visual field (change in mean deviation) at 6 and 12 months (Tables, below).

                                              Figure courtesy Eur J Ophthalmol

References

1. Kunisaki M et al. Vitamin E prevents diabetes-induced abnormal retinal blood flow via the diacylglycerol-protein kinase C pathway. Am J Physiol 269:239-46, 1995.
2. Lee IK et al. d-alpha tocopherol prevents hyperglycemia induced activation of the diacylglycerol (DAG)-protein kinase C pathwayin vascular smooth muscle cells by an increase in DAG kinase activity. Diabetes Res Clin Pract 45:183-90, 1999.
3. Engin KN et al. Clinical evaluation of the neuroprotective effect of alpha tocopherol in glaucomatous damage. Eur J Ophthalmol 17:528-33, 2007.

Systematic reviews and recent studies indicate that Ginkgo biloba is a promising herbal supplement for improving cognition and function in people with age-related dementia (1,2,3). Preliminary research also points to a role for ginkgo in some eye conditions. Small controlled trials report that Ginkgo improves pre-existing visual field damage in patients with normal tension glaucoma (4), and long distance visual acuity in AMD patients (5).

The beneficial effects of ginkgo are attributed to its antioxidant properties and ability to enhance cerebral blood flow. There have been reports linking Ginkgo use with spontaneous bleeding or increased bleeding post-surgically (6). However, it is not always clear from these observations whether ginkgo is contributory or simply associated with these occurrences. According to the conclusions of a recent independent and systematic review of the world's medical literature, the probability of ginkgo causing such bleeding is "unlikely" (7). However the use of Ginkgo at effective levels (120 mg. or higher) along with anti-coagulation or anti-platelet medications could raise the risk of increased bleeding (2) and likely should be monitored with occasional bleeding time tests. Some experts also believe that ginkgo, like aspirin, should be discontinued between 36 hours and 14 days before surgery.

Medical experts at the University of Exeter, England searched 5 medical databases for cases reports in which bleeding had been observed in patients who had been using some type of preparation containing ginkgo. The review was initiated in recognition that numerous published articles and reviews on ginkgo have acknowledged the theoretical possibility that use of ginkgo extract as a medicine or dietary supplement may result in bleeding due to ginkgo's well-documented mechanism of inhibiting platelet aggregation.

Twelve case reports met the authors' inclusion criteria. They examined each of these published reports and scored them according to a previously published scoring scale that rates the reliability of each report based on the amount of evidence. This scale classifies each study into one of 3 categories: "not able to evaluate" - the report contains inadequate information to assess the likelihood of a causal relationship; "possible" - the report provides some evidence for a causal relationship but there may be other causes of the event (e.g., the use of anti-coagulant drugs); and "likely" - the report is well documented and appears to provide reliable evidence for a causal relationship.

The authors concluded that the evidence in the reports was "far from compelling." In all but one of the cases the evidence for causality did not rate higher than "possible". They noted that with such widespread use of ginkgo - 5 million unit doses are sold each year in Germany alone - the number of case reports of bleeding was "extremely low."

The authors discuss the apparent contradiction in the case reports and the results from controlled clinical trials. The researchers concluded that since there have been no cases of bleeding observed in 9772 subjects in 44 controlled clinical trials that they reviewed, that the probability of such cases happening with ginkgo users was "unlikely."

"Case reports can rarely be conclusive," they write, "and under-reporting can significantly distort the picture. While the case reports suggest that [ginkgo] does affect blood coagulation, the controlled clinical trials do not support such a hypothesis. Weighing the conclusiveness of this evidence, it seems likely that the case reports are 'false positives' and that the controlled trials depict the true situation: Ginkgo biloba does not cause bleeding abnormalities."

References

• Birks J, et al. Ginkgo biloba for cognitive impairment and dementia. The Cochrane Database of Systematic Reviews Issue 4. Art. No.: CD003120. DOI: 10.1002/14651858.CD003120, 2002.
• Sierpina VS, et al. Ginkgo biloba.Am Family Physician 68:923-6, 2003.
• Ercoli L, et al. Society for Neuroscience Meeting, New Orleans, November, 2003
• Quaranta L, et al. Effect of Ginkgo biloba extract on preexisting visual field damage in normal tension glaucoma. Opthalmol 110:359-62, 2003.
• Fies P, et al. Ginkgo extract in impaired vision-treatment with special extract EGb 761 of impaired vision due to dry senile macular degeneration. Wien Med Wochenshr 152:423, 2002
• Fraunfelder FW. Ocular adverse drug reactions and the National Registry of Drug-induced Ocular Side Effects. Insight.29(2):7-11, 2004.
• Ernst E, et al. Does Ginkgo biloba increase the risk of bleeding? A systematic review of case reports. Perfusion 18-52-56, 2005.

Some SBH multi formulas include small amounts of ginkgo for the unique bioflavonoids it contributes. The potency of ginkgo in these multis represents 1/6-1/3 of the minimum clinical level - amounts highly unlikely to pose any safety risk. Optic Nerve Formula contains 120 mg of ginkgo - the amount that has been shown in research to support normal blood flow to the eyes. The label of this product notes: "Contains Ginkgo biloba, which may affect platelet aggregation. If you are taking anticoagulant or anti-platelet medication, ask your physician."

Introduction:

Glaucoma is the second leading cause of blindness in the world after cataracts. While research has identified non-pressure dependent risk factors for glaucoma, elevated intraocular pressure due to reduction in aqueous outflow remains a major causal factor. Several lines of evidence suggest that chronic oxidative stress is important in glaucoma pathogenesis: age-dependent clinical onset, constant exposure of the trabecular meshwork to H2O2 in the aqueous humor, and altered cellular and molecular responses to H2O2 exposure in vitro (1). Results of a recent investigation provide convincing evidence that oxidative damage to the trabecular meshwork is involved in glaucoma (2).

Study Design and Results:

Specimens of trabecular meshwork collected from 45 glaucoma patients and 45 controls of similar age and gender, were analyzed for levels of 8-hydroxy-2'-deoxyguanosine (8-OH-dG). Levels of 8-OH-dG, an indicator of oxidative DNA damage, were measured using a 32P post-labeling procedure. The researchers observed a more than three-fold increase in the amount of 8-OH-dG in the meshwork tissue of glaucoma patients. This increased DNA damage was found to correlate significantly (p= .0001) with clinical parameters such as intraocular pressure indexes and visual field losses (see Figure 1).

Because several metabolic pathways affect the cellular response to oxidative DNA damage, the investigators also evaluated the status of genes involved in detoxifying oxidative radicals - in particular GSTM1 and GSTT1. The enzymes encoded by these two genes catalyze the deactivation of reactive oxygen species by glutathione. The absence of GSTM1 was associated with primary-angle glaucoma.

Discussion:

Trabecular meshwork cells and the aqueous humor rely on antioxidant mechanisms for protection. In the meshwork for example, reduced glutathione protects against H2O2-induced oxidative damage, and it becomes depleted when the aqueous humor is under oxidative stress.

Figure 1. Correlation between visual field defects, expressed as Aulhorn and Karmeyer's visual defect score, and oxidative deoxyribonucleic acid damage (8-hydroxy-2'-deoxyguanosine) in trabecular meshwork cells from patients with glaucoma, including primary open-angle glaucoma (open circles), pseudoexfoliative syndrome (filled circles), juvenile glaucoma (open diamonds), and angle recession glaucoma (open triangles). The equation of the regression line is y=1.90 + 2.50x (r = 0.67, P = 0.0001).

"Our results may have implications for the prevention and treatment of glaucoma", the researchers stated. "Use of antioxidants may be worth studying for the prevention of primary open-angle glaucoma and psuedoexfoliative syndrome, and for treating overt cases". According to an accompanying article in the same journal, these findings shed new and important light on the molecular mechanisms involved in glaucoma, and also suggest a possible genetic predisposition to the disease (3).

References

• Green K. Free radicals and aging of anterior segment tissues of the eye: A hypothesis. Ophthalmic Res 27(S):143-49, 1995.
• Izzotti A et al. Oxidative deoxyribonucleic damage in the eyes of glaucoma patients. Am J Med 114:638-46, 2003.
• Chen JZ and Kadlubar FF. A new clue to glaucoma pathogenesis. Am J Med 114:697-98, 2003.

Optic Nerve Formula®, providing ocular antioxidants, DHA omega-3, and other key nutrients to support optic nerve health, is now available from ScienceBased Health

Introduction:

The botanical Ginkgo biloba has been extensively examined for its cognitive effects in patients with dementia. Recently, a six-month double blind trial conducted at UCLA found significant improvement in verbal recall among subjects with age-associated memory impairment (1). Using positron-emission tomography, the researchers reported that improved recall correlated with better function in key brain memory centers of those taking ginkgo supplements. The effects of ginkgo are attributed to its ability to enhance cerebral blood flow and provide antioxidant activity.

Over the past decade, research has identified non-pressure dependent risk factors for glaucoma, including cerebral and ocular ischemia. There is increasing awareness that the prevalence of normal-tension glaucoma (NTG) is greater than previously realized, and that progressive damage can occur even with IOP-lowering intervention. Since Ginkgo has been shown to increase ocular blood flow (2), the effects of a ginkgo extract on pre-existing visual field damage in normal tension glaucoma was evaluated in a prospective, randomized, double-blind crossover trial (3).

Trial Results:

Twenty seven patients with bilateral visual field damage resulting from NTG received 120 mg of ginkgo extract (40 mg, 3x daily) for 4 weeks, followed by a wash-out period of 8 weeks, then 4 weeks of placebo treatment. Other patients underwent the same regimen, but took the placebo first and ginkgo last. Visual field tests, performed at baseline and at the end of each phase of the study, were evaluated for changes in visual field and any ocular or systemic complications.

After ginkgo treatment, a significant improvement in visual field indices was observed.

No significant changes were found in intraocular pressure, blood pressure, or heart rate after placebo or ginkgo treatment. The investigators concluded that Ginkgo biloba is a useful therapy for some patients with NTG. An accompanying editorial in Ophthalmology points out that the mechanisms of ginkgo are plausible, and that the beneficial effects were not maintained in this study after discontinuation of ginkgo treatment. Both of these observations lend credence to the findings.

References

• Ercoli L et al. Society for Neuroscience Meeting, New Orleans, November, 2003
• Chung HS et al. Ginkgo biloba extract increases ocular blood flow velocity. J Ocul Pharmacol Ther 15:233-40, 1999.
• Quaranta L et al. Effect of Ginkgo biloba extract on preexisting visual field damage in normal tension glaucoma. Opthalmol 110:359-62 (discussion 362-4), 2003.

Optic Nerve Formula®, providing 120 mg of Ginkgo biloba, DHA, antioxidants, and other key nutrients to support optic nerve health, is now available from ScienceBased Health.