Oxidative stress in glaucomatous neurodegeneration: Mechanisms and consequences

doi:10.1016/j.preteyeres.2006.07.003

Progress in Retinal and Eye Research

Volume 25, Issue 5, September 2006, Pages 490-513

https://doi.org/10.1016/j.preteyeres.2006.07.003 Get rights and content

Abstract

Reactive oxygen species (ROS) are generated as by-products of cellular metabolism, primarily in the mitochondria. Although ROS are essential participants in cell signaling and regulation, when their cellular production overwhelms the intrinsic antioxidant capacity, damage to cellular macromolecules such as DNA, proteins, and lipids ensues. Such a state of “oxidative stress” is thought to contribute to the pathogenesis of a number of neurodegenerative diseases. Growing evidence supports the involvement of oxidative stress as a common component of glaucomatous neurodegeneration in different subcellular compartments of retinal ganglion cells (RGCs). Besides the evidence of direct cytotoxic consequences leading to RGC death, it also seems highly possible that ROS are involved in signaling RGC death by acting as a second messenger and/or modulating protein function by redox modifications of downstream effectors through enzymatic oxidation of specific amino acid residues. Different studies provide cumulating evidence, which supports the association of ROS with different aspects of the neurodegenerative process. Oxidative protein modifications during glaucomatous neurodegeneration increase neuronal susceptibility to damage and also lead to glial dysfunction. Oxidative stress-induced dysfunction of glial cells may contribute to spreading neuronal damage by secondary degeneration. Oxidative stress also promotes the accumulation of advanced glycation end products in glaucomatous tissues. In addition, oxidative stress takes part in the activation of immune response during glaucomatous neurodegeneration, as ROS stimulate the antigen presenting ability of glial cells and also function as co-stimulatory molecules during antigen presentation. By discussing current evidence, this review provides a broad perspective on cellular mechanisms and potential consequences of oxidative stress in glaucoma.

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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Oxidative stress in glaucomatous neurodegeneration: Mechanisms and consequences

Abstract

Section snippets

Brief introduction to oxidative stress

Tissue stress in the glaucomatous optic nerve head and retina

Caspase-dependent and caspase-independent components of RGC death

Secondary degeneration of RGCs

Proteomic identification of oxidatively modified proteins in ocular hypertensive retinas

Association of ROS with generation of AGEs

Association of oxidative stress with tissue remodeling in glaucoma

Diverse cellular responses to tissue stress in glaucomatous eyes

The role of ROS in the activation of immune response in glaucoma patients

Conclusions

Acknowledgments

FEBS Lett.

Prog. Neurobiol.

J. Biol. Chem.

Gen. Pharmacol.

Atherosclerosis

FEBS Lett.

Prog. Retinal Eye Res.

Free Radic. Biol. Med.

J. Biol. Chem.

J. Neuroimmunol.

Am. J. Med.

J. Biol. Chem.

Surv. Ophthalmol.

J. Biol. Chem.

Trends Neurosci.

Biochimie

J. Biol. Chem.

Curr. Opin. Cell. Biol.

Surv. Ophthalmol.

Prog. Retinal Eye Res.

Exp. Eye Res.

Neuroscience

J. Biol. Chem.

Surv. Ophthalmol.

Cell

Prog. Retinal Eye Res.

Neuroscience

Am. J. Med.

Exp. Eye Res.

Ophthalmology

Cell Signal

Neurosci. Lett.

Exp. Neurol.

Exp. Eye Res.

Free Radic. Biol. Med.

Exp. Neurol.

Surv. Ophthalmol.

Cell

Cell

Brain Res.

Cell

Mitochondrial abnormalities in patients with primary open-angle glaucoma

Invest. Ophthalmol. Vis. Sci.

Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human optic nerve head astrocytes

Glia

Oxidative stress in neurodegeneration: cause or consequence?

Nat. Med.

Effect of intraocular pressure on rapid axoplasmic transport in monkey optic nerve

Invest. Ophthalmol.

Pattern of visual field defects in normal-tension and high-tension glaucoma

Curr. Opin. Ophthalmol.

Lipid peroxidation in open-angle glaucoma

Acta. Ophthalmol. (Copenhagen)

Astrocyte mitochondrial mechanisms of ischemic brain injury and neuroprotection

Neurochem. Res.