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Glaucoma
Progression Under the Microscope – Can Basic Science Provide the Link
Between Structural and Functional Deterioration?
Keith R Martin
Centre for Brain Repair and Department of Ophthalmology, University of Cambridge
Abstract
The mechanisms of progression in glaucoma remain incompletely understood, but basic science research is gradually elucidating the processes
involved. Axonal injury is a major event in glaucoma and the cellular mechanisms involved in axonal degeneration are different from those that
lead to retinal ganglion cell body death. Thus, preventing cell body death is necessary but not sufficient to prevent progressive loss of function
in glaucoma, and axonal protection is an important therapeutic goal. Basic science approaches are also suggesting new ways to detect and
monitor progression. Techniques to image individual retinal ganglion cells and their axons in the living eye are improving rapidly. Cells
undergoing apoptosis can be labelled and identified, and it may be possible in the future to use retinal ganglion cell apoptosis rates as a
biomarker of glaucoma progression. However, slow progression may be difficult to detect using such techniques; therefore, biomarkers that
identify ganglion cells that are sick but not yet committed to die are an important research goal.
Keywords
Glaucoma, neuroprotection, apoptosis, high-resolution imaging, Wallerian degeneration, axoprotection
Disclosure: Keith R Martin is supported by a GlaxoSmithKline (GSK) Clinician Scientist Fellowship, a Fight for Sight (UK) research grant and the Glaucoma Foundation.
Received: 1 September 2009 Accepted: 5 October 2009
Correspondence: Keith R Martin, Centre for Brain Repair, University of Cambridge, Forvie Site, Robinson Way, Cambridge, CB2 0PY, UK. E: krgm2@cam.ac.uk
Support: Supported by Pfizer. The views expressed are those of the authors and not necessarily those of Pfizer.
Mechanisms of Progression in Glaucoma failure of glutamate homeostasis
6
have all been implicated; other
Glaucoma is a neurodegenerative disease characterised by mechanisms are also likely to be involved.
progressive loss of retinal ganglion cells (RGCs) over time with
associated progressive visual field loss. Elevated intraocular pressure However, although there is strong evidence that the optic nerve
is the strongest risk factor for glaucoma,
1
but the mechanisms head is an important site of injury in glaucoma, this does not preclude
by which damage occurs in the disease remain incompletely the possibility that glaucomatous neurodegeneration may be
understood; however, a number of important principles have been compounded by factors affecting other RGC compartments. Numerous
established. First, there is strong evidence that the optic nerve head other mechanisms can potentially affect RGC survival, including toxic
is an important site of injury. Characteristic optic nerve changes are and ischaemic injuries at the level of the retina and secondary
observed in glaucoma and correlate with the pattern of visual field degeneration, where RGCs not directly injured degenerate later as a
loss. Glaucomatous visual field defects often pertain to the horizontal consequence of neighbouring cell death.
7
Thus, progression in
mid-line and such a pattern would be difficult to explain if the site glaucoma is likely to involve a complex interaction between RGC injury
of injury were predominantly to the RGC bodies in the retina. The at multiple locations, with the optic nerve head probably most
arcuate nature of many field defects observed in glaucoma also significant; the individual’s susceptibility and compensatory responses
suggests the optic nerve head as the site of injury. In addition to such to glaucomatous stress are also important.
clinical evidence, recent basic science studies have pointed to the
lamina cribrosa region of the optic nerve as a major site of injury in Protecting All Compartments of
the disease. Retinal Ganglion Cells Is Essential to
Prevent Progression
Groundbreaking work by Howell et al. using mice with hereditary In order to preserve function in glaucoma, it is necessary – but not
chronic glaucoma (the DBA/2J strain) provided experimental sufficient – to keep RGC bodies alive in the retina. Maintenance of
evidence for a focal insult to optic nerve axons at the glial lamina, the visual function requires preservation of all compartments of the RGC
rodent analogue of the lamina cribrosa.
2
Damaged axons at the glial including the axon, dendrites and distal synapses.
8
Only if all
lamina appeared dystrophic compared with other portions of the components of the cell survive and continue to function can vision be
optic nerve in the early stages of DBA/2J glaucoma. The exact nature preserved. However, it is becoming clear that the therapeutic
of the insult experienced by RGC axons at the optic nerve head strategies required to protect different compartments may differ. As
is unclear, but oxidative stress,
3
mitochondrial dysfunction
4,5
and an example, RGC bodies in the retina are known to die by apoptosis,
9
© TOUCH BRIEFINGS 2009 27
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