Evidence of oxidative stress damage in glaucoma

FERREIRA S; REIDES C; LERNER F; LLESUY S

The Mystery of glaucoma

Intech

Año: 2011; p. 3 - 18

Oxidative stress has been implicated as a risk factor at several levels in the pathophysiology of glaucoma (Ferreira et al., 2004, 2009, 2010) as well as neurodegenerative diseases (Famulari et al., 1996); growing evidence supports the role of oxidative stress in glaucomatous neurodegeneration (Tezel, 2006). Reactive oxygen species are involved in signalling pathways during retinal ganglion cells death by acting as second messengers and/or modulating protein functions (Neufeld et al., 1999). Evidence of oxidative and nitrative processes was found in glaucoma in terms of activity of antioxidant enzymes, levels of low-molecular weight antioxidants and markers of lipid peroxidation (Aslan et al., 2008). Moreover it has been reported that nitric oxide may be an important mediator in retinal ganglion cells death in glaucoma (Neufeld et al., 1997). In the glaucoma eye, an altered oxidant/antioxidant balance may result in a number of molecular changes that contribute to the development of this ocular disease. Glaucoma is a disease characterized by a specific pattern of optic nerve head and visual field damage in which if it is not controlled may lead to blindness. Although it has been traditionally associated with high intraocular pressure (IOP), glaucoma is now considered as a multifactorial disease. In this context, IOP is the most important known risk factor for the development of glaucomatous optic nerve damage. Even in normal-pressure glaucoma, reducing IOP can be beneficial in terms of halting visual field damage progression. However, lowering IOP may not be enough in every case, since different mechanisms that may or may not depend on the IOP level could contribute to this damage. Proposed mechanisms include ischemia (Lander, 1982), obstruction of axoplasmic flow (Anderson & Hendrickson 1974) and deprivation of one or more trophic factors (Quigley et al., 1995), excitoxicity (Vorwerk et al., 1997) and oxidative stress damage (Ferreira et al., 2004, 2009, 2010). IOP is not elevated in all the eyes that exhibit characteristics of glaucomatous neurodegeneration but experimental elevation of IOP induces oxidative stress in the retina. Aqueous humor is known to contain several active oxidative agents such as hydrogen peroxide and superoxide anion. Low molecular weight antioxidants, such as glutathione (GSH), and ascorbate, together with molecules with free radicals scavenging properties like cysteine and tyrosine, have been identified in the aqueous. Ascorbate is present at high concentrations in it (1-2 mM) (Richer & Rose, 1998) and antioxidant enzymes such as superoxide dismutase (SOD), catalase and glutathione peroxidase have been reported in aqueous humor (Garland, 1991; Varma, 1987). It has been suggested that a chronic oxidative stress insult induced by this agents can compromise the trabecular meshwork function, the major route for aqueous outflow from the anterior chamber. The trabecular meshwork (TM) is exposed to chronic oxidative stress over the course of lifetime and therefore it has a sophisticated defense mechanism against ROS. Previous studies estimated that the rate of loss of cells of the TM is linear and approximately 0.58 % per year from birth through 81 years old (De la Paz & Epstein, 1996). Exfoliation syndrome (XFS) is a clinically significant systemic disorder, involving abnormal production or turnover of extracellular matrix material or a combination of both processes (Ritch & Schlötzer-Schrehardt, 2001). The exact etiology of this syndrome remains unknown; the most accepted theory postulates that it is an age-related process of buildup of an abnormal elastotic material (Schlötzer-Schrehardt & Naumann, 2006). XFS is the most common cause of secondary open-angle glaucoma (Ritch, 1994). It is a generalized agerelated disorder of the extracellular matrix with abnormalities in the basal membranes. Exfoliation syndrome: The clinical diagnosis is made by the presence of exfoliative material on the surface of the anterior capsule of the lens. Exfoliative material may also be present in the corneal endothelium and the trabecular meshwork. Other clinical features include atrophy of the pupillary border and iris transillumination defects (Naumann et al., 1998). XFS may be associated with ocular problems such as high intraocular pressure (IOP), and glaucomatous optic neuropathy. It may be also associated with poor mydriasis, zonular instability, corneal endotheliopathy, central retinal vein occlusion and cataract (Ritch & Schlötzer-Schrehardt, 2001). Systemic associations found in XFS include angina pectoris, hypertension, myocardial infarction, and stroke. An active involvement of the trabecular meshwork in this abnormal matrix process that leads to a progressive accumulation of XFS material in the juxtacanalicular tissue is considered as the possible cause of chronic high pressure in XFS eyes (Schöltzer-Schrehardt et al., 1992; Koliakos et al., 2001). The principal ocular cells implicated in the production XFS material are those closely associated with the aqueous humor circulation and are influenced by the substances that are present in it. Increasing evidence suggests that ascorbic acid plays an important role in the defense mechanisms of the ocular tissues against free radical damage (Varma, 1987, 2001). A decrease in ascorbic acid and an increase of 8-isoprostaglandin F2a have been reported in the aqueous humor of patients with XFS (Koliakos et al., 2003). The principal ocular cells implicated in the production of exfoliative material are those closely associated with the aqueous humor circulation and are influenced by the substances present in it. Investigation of qualitative and quantitative alterations of the aqueous humor composition might, therefore, provide an important insight into the factors involved in this disorder. Recent studies reported differences in the concentration of matrix metalloproteinases (Schöltzer-Schrehardt et al., 2003) and growth factors (Koliakos et al., 2000, 2001) in the aqueous humor of XFS patients. It is well known that growth factors and proteases can be activated by free radicals, so the occurrence of oxidative stress and therefore the antioxidant status of the aqueous humor may play a role in the oxidative metabolism of the cells implicated in the production of exfoliative material. The antioxidant status was evaluated in order to assess the occurrence of oxidative stress in the aqueous humor of glaucoma patients. It was meassured through the determination of Total Reactive Antioxidant Potential (TRAP) levels and antioxidant enzymes activities. Antioxidant status of biological samples is regarded as an indicator of oxidative stress (Evelson et al., 2001). A decrease in the antioxidant capacity of tissues and body fluids may