Oxidative stress in glaucomatous neurodegeneration: Mechanisms and consequences
Section snippets
Brief introduction to oxidative stress
Partially reduced metabolites of molecular oxygen (O2) are referred to as “reactive oxygen species” (ROS) due to their higher reactivities relative to molecular O2. ROS are generated intracellularly through a variety of processes, for example, as by-products of normal aerobic metabolism and as second messengers in various signal transduction pathways. ROS can also be derived from exogenous sources, either being taken up directly by cells from the extracellular milieu, or produced as a
Tissue stress in the glaucomatous optic nerve head and retina
Progressive loss of optic nerve axons and retinal ganglion cells (RGCs) result in characteristic optic nerve atrophy and visual field defects in glaucoma patients. In many patients with glaucoma, intraocular pressure (IOP) is higher than the statistically normal limits; and extensive evidence supports that elevated IOP-initiated factors are important for the initiation and progression of neuronal damage in these patients. Current therapeutic management of glaucoma therefore aims to halt disease
Caspase-dependent and caspase-independent components of RGC death
Simulation of the noxious conditions of human glaucoma in experimental models results in the apoptotic death of RGCs in a caspase-dependent manner. For example, in vitro studies provide compelling evidence that the apoptosis of retinal neurons induced by different stimuli share a common caspase cascade (Tezel and Wax, 2000a, Tezel and Wax, 2000b), which can be inhibited using specific inhibitors of caspases (Tezel and Wax, 1999). In addition, RGC death induced by IOP elevation, in vivo, has
Secondary degeneration of RGCs
Although the loss of optic nerve axons in glaucomatous eyes is accompanied by the apoptosis of RGCs, the exact nature and the primary site of injury remain unclear. However, it is widely accepted that primarily undamaged neurons in a neurodegenerative insult to the optic nerve can eventually undergo a secondary degeneration due to toxic substances released by injured neurons or stressed glia (Levkovitch-Verbin et al., 2001; Tezel et al., 2004b; Yoles and Schwartz, 1998). The likelihood of a
Proteomic identification of oxidatively modified proteins in ocular hypertensive retinas
Recent evidence supports that besides direct cytotoxic consequences, ROS can also modulate protein function through oxidative modifications during glaucomatous neurodegeneration. Oxidant attack to proteins results in site-specific amino acid modifications, fragmentation of the peptide chain, aggregation of cross-linked reaction products, altered electrical charge, increased susceptibility to proteolysis, and function loss. Protein carbonyl formation is a widely utilized marker for protein
Association of ROS with generation of AGEs
Oxidative stress increases with age in the brain; and the ability of neurons to respond to oxidative stress declines with age mostly due to an imbalance between increasing oxidant production and decreasing antioxidant capacity. Similar to many other age-dependent neurodegenerative diseases of the brain, age-dependent pathogenic processes associated with oxidative stress are not unexpected in glaucoma, since this disease is also more common in the elderly (Quigley and Vitale, 1997).
Extended
Association of oxidative stress with tissue remodeling in glaucoma
In addition to tissue alterations secondary to extracellular AGE accumulation, oxidative stress in the glaucomatous optic nerve head and retina may also be associated with other cellular events involved in tissue remodeling. The characteristic clinical appearance of neurodegenerative alterations in the glaucomatous optic nerve head is called optic disc cupping and corresponds to backward bowing and disorganization of lamina cribrosa along with neuronal loss (Tezel et al., 2004a). Glaucomatous
Diverse cellular responses to tissue stress in glaucomatous eyes
As supported by glial activation, tissue stress in glaucomatous eyes does not only affect RGCs. In fact, widespread stress response, including stress protein upregulation and hypoxic and oxidative stress, is also evident in glial cells in the glaucomatous optic nerve head and retina. Based on double immunolabeling studies, increased expression of different heat shock proteins (Tezel et al., 2000b) or HIF-1α (Tezel and Wax, 2004a) in glaucomatous human eyes has been localized to both RGCs and
The role of ROS in the activation of immune response in glaucoma patients
Increasing evidence from clinical and experimental studies over the past decade strongly supports the involvement of the immune system in the neurodegenerative process of glaucoma (Tezel and Wax, 2004b). In addition to serum and tissue findings supporting aberrant immune system activity in glaucoma patients (Tezel et al., 1999, Tezel et al., 1998; Wax et al., 1998a, Wax et al., 1998b, Wax et al., 2001), glial cells in glaucomatous human eyes also exhibit an activation in their antigen
Conclusions
Growing evidence supports that RGCs in glaucomatous eyes are under oxidative stress, which is associated with pathogenic mechanisms leading to glaucomatous neurodegeneration. Increased ROS generation leads to RGC degeneration, glial dysfunction, and activation of immune response in glaucoma. However, many aspects of the relationship between oxidative stress and the neurodegenerative process are not entirely clear. During glaucomatous neurodegeneration, ROS may be directly neurotoxic to RGCs,
Acknowledgments
Dr. Tezel is supported by National Eye Institute (R01 EY013813, R24 EY015636), Bethesda, MD; and an unrestricted grant to University of Louisville Department of Ophthalmology & Visual Sciences from Research to Prevent Blindness Inc., New York, NY. Dr. Tezel is also a recipient of the Research to Prevent Blindness Sybil B. Harrington Special Scholar Award.
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