Glaucoma neuroprotection

Jonathan Crowston

In glaucoma, the mechanisms of cell death differ for the retinal ganglion cell body vs. the axon.

Cell body death

For the cell body, the two major death mechanisms are apoptosis and necrosis (see Fig. 1). Both are known to occur in acute and chronic neurodegenerative diseases.
Apoptosis is an active process, directed by genes, in which a cell undergoes a very organized series of events. These events are mediated by caspases, which digest proteins and can disassemble the cell without inciting inflammation. The cell undergoes cell death and flags itself for phagocytosis by surrounding macrophage populations. The mitochondrion is a key regulator of the apoptosis process.

Fig. 1. The retinal ganglion cell body may die via apoptosis, necrosis or autophagy.

Apoptosis has been show to occur in both experimental models of glaucoma¹ and in human glaucoma.² A 1997 study by Kerrigan et al. examined a number of cadaver specimens of glaucoma eyes and controls, using a TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (UTP)-biotin nick end-labeling) assay, which detects DNA fragmentation characteristic of apoptosis.² Apoptosis occurred in 10 of 18 cases with glaucoma, and only 1 of 11 control cases. Although there was a 15-fold increase in apoptosis in glaucoma eyes vs. controls, the rates of apoptosis were actually very low – only about 1-2 occurrences in every 10,000 cells – and therefore difficult to detect.
Necrosis is another mechanism of cell body death. Unlike apoptosis, necrosis is a passive process in which the cell membrane is rapidly destroyed and toxic cellular contents spill into the extracellular environment.
Autophagy is another cell death mechanism that is generating increased interest. In this mode, the cell compartmentalizes part of its cytoplasm by enclosing it in membrane-bound vesicles, which are then fused with lysosomes. The proteases and the digestive enzymes in the lysosome digest the cytoplasmic contents. The degradation products are, in fact, often used as source of energy for the cell to survive. But in some cases, if autophagy is abnormal or if it becomes overwhelming, it can induce the cells to undergo programmed cell death.

Axon death

The axon can die by a process known as ‘Wallerian degeneration’, which results from an injury to the long axon that spreads from the ganglion cell to the lateral geniculate nucleus (see Fig. 2). If the axon is cut, the distal part of the axon initially undergoes a very well orchestrated degenerative process, and is phagocytized. The cell body can then live for a number of days, but ultimately undergoes apoptosis. Wallerian degeneration occurs both in the peripheral as well as the central nervous system. A more recently described phenomenon is ‘die back’ or accidental death. In this process, the injury actually occurs to the cell body, but the first manifestations of injury are in the distal axon, which then shrinks back from the synapse. The process of dieback death can occur over a matter of months and may be more important in chronic neurodegenerative processes.

Fig. 2. ‘Wallerian degeneration’ and ‘die back’ are two mechanisms described for axonal death.

Mechanisms that may modulate the vulnerability of cells in glaucoma

A number of mechanisms play a role in modulating the cells vulnerability to death.
Intraocular pressure. One of the key mechanisms to ganglion cell death in glaucoma is compression of the axon at the level of the lamina cribosa due, in many instances, to elevated intraocular pressure. Elevated pressure distorts the lamina cribrosa, which pinches the axons, disrupts axoplasmic flow, and prevents neurotrophic factors from reaching the cell body. The cell undergoes apoptotic death.
Ischemia. An impaired blood supply to the optic nerve head can certainly induce neuronal cell death. However, it is difficult to accurately measure blood supply to the optic nerve head.
Glial cells. In a healthy nerve, glial cells probably play more of a supportive role. However, in disease states, the glial cells can become activated and migrate to the lamina cribrosa, the site of major damage in glaucoma. These activated microglial and astrocytes can induce retinal ganglion cell death.
Glutamate. Low levels of glutamate, a major neu-rotransmitter in the brain, are needed for normal brain functioning. However, when glutamate levels are elevated or when neurons become more susceptible to glutamate, neuronal death can occur by apoptosis or necrosis.
Free radicals. Free radicals are also thought to play a major role in neuronal degeneration by damaging cell membranes, enzymes, proteins and DNA. The result-ing oxidative damage is thought to be a major player in both the aging process, as well as in age-related neurodegenerative diseases. Mitochondria, which are important in regulating apoptic cell death, are a key site for free radical degeneration and probably play a very important role in neuronal loss in glaucoma. Measurable oxidative damage in both the retina and the optic nerve has been found to occur even after one or two hours of pressure elevation.
The immune system. Antibodies generated by B-cells may react to antigens present on the optic nerve head. Also, the immune system may play a protective role in normal situations. Schwartz et al. has shown that the immune system can protect retinal ganglion cells from secondary degeneration through a response mediated by T-cells.³ However, loss of this protective function may augment retinal ganglion cell death in glaucoma. Many of these different mechanisms that induce damage in retinal ganglion cells are present in the everyday lives in normal nerves. Cell death ultimately depends on the response of the neuron to the dam-age and the balance between the survival and death factors.

References

1. Quigley HA, Nickells RW, Kerrigan LA, Pease ME, Thibault DJ, Zack DJ. Retinal ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis. Invest Ophthalmol Vis Sci 1995; 36:774-786.
2. Kerrigan LA, Zack DJ, Quigley HA, Smith SD, Pease ME. TUNEL-positive ganglion cells in human primary open-angle glaucoma. Arch Ophthalmol 1997; 115: 1031-1035.
3. Schwartz M. Harnessing the immune system for neuroprotection: therapeutic vaccines for acute and chronic neurodegenerative disorders. Cell Mol Neurobiol 2001; 21: 617-627.