Optic Nerve Formula®

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.

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.