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

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