Glaucoma Watch prev next

Feb 29 2008

Oxidative Stress in Glaucoma: A Burden of Evidence

posted by: Suraj Afshar, OD

This comprehensive article is a synthesis of many studies that provide current evidence of the role of oxidative stress in glaucoma. The authors addressed three modes of experimentation: human, animal and in vitro. Evidence suggests that oxidative free radicals, whether induced by ischemia or elevation of IOP, result in apoptosis and death of retinal ganglion cells and progressive vision loss in glaucoma. Taken together, the studies found that neuroprotection can be achieved through antioxidants, flavonoids and astrocyte cocultures. The synthesis included 121 references and was conducted by DO/PhD candidate Domalapalli Maneesh Kumar and Neeraj Agarwal, PhD, and can be found in the May 2007 edition of Journal of Glaucoma.

The human trials section included the work of Gherghel et al, Yildrim et al, and Ferreira et al which demonstrated that enzymatic and nonenzymatic indicators in serum may assess oxidative burden. They found that mechanisms that are designed to combat oxidative stress such as Glutathione peroxidase to be nearly three times greater in glaucoma patients, indicating the high levels of oxidative burden. The higher levels of oxidative stress in serum indicate that retinal damage can be an ocular manifestation of underlying systemic conditions. The work of Izzotti et al and Sacca et al revealed that if the oxidative stress in the anterior chamber of the eye is great enough, it can directly damage the DNA of the trabecular meshwork and upset the regulation of IOP, potentially contributing to the mechanisms of glaucoma.

The animal studies segment included the work of Moreno et al, where induced chronic elevation of IOP in rats led to a dramatic decrease in antioxidant defense systems and increased retinal ganglion cell death. Tezal et al studied the oxidative effect on retinal proteins, demonstrating that continued oxidative stress modifies active binding sites of GAPDH leading to nuclear accumulation of GAPDH bound DNA. It has been shown that accumulation of GAPDH bound DNA is actually a propagator of neuronal apoptosis in Alzheimer, Huntington and Parkinson degenerative diseases. In hypertensive eyes there was a higher sensitivity to oxidative damage, disrupting the conversion of glutamate to glutamine primarily located in the Muller cell layer of the retina. Dreyer et al found that elevated intravitreal glutamate, a neurotoxin at high levels, directly correlates with the apoptosis of retinal ganglion cells in glaucoma. Nucci et al went further and demonstrated that acute elevation of IOP increases glutamate levels in rats with subsequent nerve loss. Cummings et al used mass spectroscopy to further identify specific proteins responsible for oxidative damage in glaucoma, opening the doorway for specific therapies to be developed.

The in-vitro studies were consistent with results from the animal and human trials, and yielded additional information as well. Maher et al, in his RGC-5 study, found that in vitro treatment of retinal ganglion cells with flavonoids could be used to prevent the effects of oxidative stress and that these flavonoids induced the synthesis of proteins which have antioxidative effects and thus were neuroprotectant. In addition, in vitro retinal ganglion cells that were subjected to high levels of pressure, up to 70mm Hg, resulted in apoptosis but could be reversed by interleukin-6. A study by Lucius and Sievers examined postnatal primary retinal ganglion cells that experienced axonal degeneration by exposure to oxidative radicals. These ganglion cells were then treated with vitamins E and C and astrocyte cocluture, resulting in stoppage of axonal loss; further treatment actually improved the number and length of neurites from the explanted retina. The study concluded that endogenous astrocytes can protect retinal ganglion cell destruction by its neurotrophic factors.

The studies noted above, along with many others cited in the article, provide compelling and evidence of the role that oxidative stresses play in glaucoma. However, the actual cause of glaucomatous ganglion cell loss is still mysterious. There are many studies cited in the review that show that glutamate levels in glaucoma patients remain unchanged and that oxidative stresses are not the primary insult inducing retinal ganglion cell death. Thus, the actual mechanism of retinal ganglion cell death remains unproven. Despite this, the data regarding oxidative stresses must be considered. And in light of these studies, the article suggests that a proposed solution to nerve loss in glaucoma and visual field defects is neuroprotection through antioxidant treatment, flavonoids or endogenous astrocyte cocultures.

Syed Hasnain MD - on Apr 03, 2008

This article manifests some interesting insight. So far, we have failed to address the fundamental question: Why (among the one million densely packed nerve fibers in a 1.5 mm sized optic disc) only the peripheral fibers are selectively destroyed first and the central fibers the last? Is it possible that apoptosis or any other biological process can result in selective destuction of arcuate fibers in the initial stages of glaucoma?

More interestingly, the destruction of the arcuate fibers is so neat and precise as though the arcuate fibers have been cut with a scissor among the million or so densely packed disc or among the spread out nerve fibers in the retina. I do not believe there is any biological mechanism (including apoptosis), which could selectively destroy the arcuate fibers and leave the remaining nerve fibers unscathed.

If apoptosis of the retinal ganglion cells was indeed occurring then there would have been haphazard and random destruction of the
ganglion cells resulting in erratic visual field defects. There is no disease in which apoptosis is occurring selectively and not randomly. Apoptosis simply could not cause the selective destruction of the ganglion cells, which supply the arcuate fibers in
initial stages. It is not possible, biologically or mechanically, that raised IOP or any other mechanism could selectively destroy the
peripheral fibers first and the central ones the last.

We have to look for a mechanism that separates the peripheral fibers from the central ones. I believe the shifting of the optic disc is prerequisite for the separation of these nerve fibers. I hypothesize that the optic disc is not cupping as it was first suggested 150 years ago. I believe the optic disc is ‘sinking’ in its entirety -- this is what the pictures of the glaucomatous optic disc are revealing. The sinking is evidenced by the sloping and kinking of the blood vessels at the scleral edge. As the optic disc sinks
the blood vessels kink to follow the sinking disc. An analogy to this phenomenon would be that of a sinking (or dipped) manhole cover in the road.

Due to sinking of the disc, the nerve fibers would separate at the edge (junction of retina and the disc). As the optic disc starts sinking the peripheral fibers because of their deeper location are stretched and cut first at the scleral edge. As glaucoma
progresses and the peripheral fibers are being depleted the central fibers move closer to the scleral edge and are thus also destroyed.

This cascade of reactions would continue until all the nerve fibers
are severed and the optic disc is perished. At the end stage of glaucoma the optic disc area is replaced with an empty crater where none of the nerve fiber remains.

This is what end stage glaucoma disc histology is revealing. In glaucoma the nerve fibers are being severed at the edge and thus depleted. This severing of the nerve fibers is resulting in the retrograde death of the ganglion cells. In sinking of the optic disc, the peripheral fibers would be destroyed first and the central fibers at the end. This is what the visual fields are revealing. If the cupping was taking place then the central fibers would be destroyed first, resulting in immediate blindness due to loss of central vision. I have presented my arguments in favor of 'sinking optic disc' in a power point presentation on my website: I would be interested in any feedback. I commend the NGS for posting such provoking articles.

Syed S. Hasnain M.D.