Fig. 4. Longitudinal section of the rat eye ONH with elevated IOP and early injury. Note that majority of degeneration (*) is located superiorly at the level of the sclera (S). Central retinal artery (A) and vein (V) mark the inferior aspect of the nerve and separate it from the sclera ( 400).

Additional evidence for a difference in mechanism among these models can be found in the extent of nerve and RGC damages. An assessment of the percentage of nerve damage or RGC loss as a function of the duration of IOP elevation has shown that the hypertonic saline and limbal laser models were each capable of producing injury as high as 80% over time periods of up to 11 weeks (Morrison et al., 2005). By contrast, maximum injury with the vein cautery model was no greater than 40% and frequently less, even in eyes with pressure elevations as long as 6 months (Sawada and Neufeld, 1999; Danias et al., 2006). In two studies, elevated IOP from vein cautery failed to produce any damage at all (Mittag et al., 2000; Grozdanic et al., 2003b).

Choroidal congestion may be directly responsible for this apparent reduction in optic nerve susceptibility following vein cautery (Goldblum

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and Mittag, 2002; Grozdanic et al., 2003b). Careful anatomic study of the rat optic nerve vasculature has shown that the choroidal veins are intimately connected to the veins surrounding the ONH and the optic nerve (Morrison et al., 1999). Thus, congestion of the choroidal vasculature is likely to increase pressure within these veins, which in turn may protect nerve fibers from the effects of elevated IOP, possibly by a splinting effect. Alternatively, since direct obstruction to aqueous humor outflow does not occur in this model, stress forces on the wall of the eye, including the peripapillary sclera, are likely to be different than with the other models. If, as suggested by Burgoyne, optic nerve damage depends on these stresses (Burgoyne et al., 2005), one would expect that damage would be different, and possibly less, following vein cautery.

Finally, while the cautery model has been used to demonstrate successful neuroprotection with the nitric oxide synthase inhibitor aminoguanidine (Neufeld et al., 1999, 2002), similar studies with the hypertonic saline model and in the DBA-2J mouse model have failed to corroborate this finding (Pang et al., 2005a; Libby et al., 2007). This further suggests that the mechanisms of optic nerve injury following cautery are different from those that occur in models that specifically rely on aqueous humor outflow obstruction.

Conclusions

The past 15 years have witnessed a remarkable expansion in our knowledge of the cellular events of optic nerve and retina injury due to elevated IOP. Much of this is due to the wide use of models based on experimentally elevated IOP in rats. As expected, these models have made it possible to study both optic nerve and retinal responses using state-of-the-art molecular biology techniques (Johnson et al., 2007; Yang et al., 2007), and they have provided opportunities for testing potentially useful compounds designed to protect optic nerves and RGCs from elevated IOP (Martin et al., 2003; Pang et al., 2005a; Zhou et al., 2005).

The advent of models in rats has quickly paved the way for the study of pressure-induced nerve damage in mice. These models, the most

commonly used of which are spontaneous and bilateral, allow genetic manipulation of potentially key pathways to help define their roles in glaucomatous damage (John et al., 1999; Libby et al., 2005; Howell et al., 2007) and are now beginning to see action for testing neuroprotective therapies (Libby et al., 2007). Regardless of these advantages, rat models will continue to be useful, as they are well suited for experimental elevation of IOP and allow specific study of this factor alone.

In spite of our enthusiasm for these models, we would like to emphasize several aspects of their application to POAG.

As mentioned above, the rat ONH lacks a collagenous lamina cribrosa that would appear substantial enough to provide either significant protection for optic nerve fibers or actively contribute to axonal damage. Yet, we, and others, have found that experimental IOP elevation can cause optic nerve damage and RGC loss in rats and, for that matter, in mice, which may have an even less robust lamina. This tells us that a

collagenous lamina cribrosa is not required to produce optic nerve damage in rodents with elevated IOP. This finding also suggests that glial cells, and astrocytes in particular, may contribute to this process—thanks to their intimate relationship to axons within the ONH. ONH gene array studies now indicate that elevated IOP in rats can produce upand down-regulation of a large number of genes (Johnson et al., 2007). Although it is unknown which exact cells are responsible for these changes, the predominance of astrocytes within the rat ONH suggests that they are worthy of specific studies, particularly for responses that might contribute directly to axonal injury.

An additional feature of rat glaucoma models produced by aqueous humor outflow obstruction is the fact that they exhibit a pattern of injury that begins regionally and then gradually spreads to the entire nerve. This is interesting since regional injury and a specific pattern of visual field loss are hallmark of human POAG. Although the pattern of injury differs between the two species, in both cases, it appears to result in unique anatomic

features at the level of the ONH. We believe that a careful study of the rat ONH anatomy and how this relates to the pattern of nerve injury will provide powerful insights into the mechanisms by which elevation of IOP results in axonal injury, RGC death, and blindness.

Finally, it must be remembered that pressure elevation in POAG is only moderate in most cases, and the resulting injury occurs over many years. In this regard, animal models relevant to POAG must avoid pressures that are excessively high. With rodent models, we believe that this is particularly important. Over the years, we have found evidence that even IOPs that are only mildly above normal are capable of producing focal injury within the ONH (Morrison et al., 2002; Johnson et al., 2007) (Fig. 6). Restricting pressures to this range and developing reliable, sensitive, and noninvasive methods for measuring these pressures will thus be critical. This will not only avoid the possibility of studying eyes with pressure elevations high enough to produce optic nerve injury through mechanisms not normally present in POAG, but it will avoid catastrophic global damage and restrict injury to the slow, progressive nature more typical of POAG.

Fig. 6. TEM of the superior ONH at the level of the sclera following hypertonic saline injection showing degenerating axons (*) with swelling and loss of normal axoplasm. Mean IOP elevation in this eye was only 18% above fellow eye for 5 weeks ( 600).

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Mild IOP elevations are also needed for animal models used to test neuroprotective compounds. Again, reliable methods for measuring IOP in these lower ranges help ensure identical IOP exposure for experimental (those receiving neuroprotective agent) and control (those receiving placebo or vehicle drug) groups. This will not only allow researchers to test compounds and mechanisms relevant to POAG but also reduce the chance of overlooking potentially therapeutic effective drugs by avoiding pressures that are so high enough that no neuroprotective compound could be useful.

Acknowledgements

This study was supported by NIH grant EY016866, EY010145 and unrestricted funds from Research to Prevent Blindness.

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