apoptotic stimuli (Martin et al., 1999). The activation of Mu¨ller glia and the activation of heat shock proteins are suggested to be part of an initial protective mechanism in response to elevated IOP, one that ultimately fails in glaucoma. Understanding intrinsic protective mechanism(s) that may be occurring prior to RGC death in glaucoma models could be an important step toward developing neuroprotective strategies for human glaucomas.

Using mouse models to develop neuroprotective strategies

As described above, it is becoming evident that multiple processes are involved in the degeneration of RGCs in glaucoma. This is important when considering neuroprotective strategies. It is unlikely that targeting a single process will prevent glaucoma in either mice or humans. Combinatorial therapeutic approaches that target multiple pathogenic processes are most likely to prove the most beneficial to human patients. It is important to note that treatment regimens that are protective in one setting may be harmful in another. Various cell types have been suggested to be protective in one setting but harmful in others (Tezel and Wax, 2004).

Somal protection

The profound protective effect of BAX deficiency (saves all RGC soma) in DBA/2J mice (Libby et al., 2005b) raises the possibility that BAX inhibitors may have a similar protective effect in humans. One can imagine that such treatments might block or delay RGC soma death until regenerative treatments can be developed to regrow axons. Alternatively, combination therapies may be developed involving both BAX inhibitors and drugs that target axon degeneration. These ideas can be readily tested using mice.

Axonal protection

We recently showed that the slow Wallerian degeneration allele (Wlds) (Lunn et al., 1989; Mack et al., 2001) protects from axon degeneration in

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DBA/2J mice (Howell et al., 2007). Wlds more than doubled the number of eyes with no detectable glaucoma compared to standard DBA/2J mice and preserved PERG. Combining Wlds with BAX deficiency tended to be more protective than Wlds alone, but the difference was not statistically significant. Wlds encodes a fusion protein containing 70 N-terminal amino acids of ubiquitination factor Ube4b linked to full-length nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1) (Mack et al., 2001). The mechanisms by which Wlds protects neurons are not fully understood (Araki et al., 2004; Laser et al., 2006). It will be important to understand these process(es) and to develop neuroprotective strategies that mimic the Wlds protection.

Erythropoietin administration

Erythropoietin (EPO) has neuroprotective properties in animal models of stroke, excitotoxic injury, and neuroinflammation (reviewed in Ehrenreich et al., 2004). EPO is thought to inhibit apoptosis because antiapoptotic genes such as Bcl2 have been shown to be upregulated upon EPO application (Sattler et al., 2004). EPO has a direct protective effect on RGCs in culture (Becerra and Amaral, 2002; Bocker-Meffert et al., 2002; Weishaupt et al., 2004; Yamasaki et al., 2005). Systemic EPO administration to DBA/2J mice from 4 months of age appears to prevent significant RGC death and axon degeneration by 12 months of age (Zhong et al., 2007) (Fig. 5). Based on the Zhong study, the protective effect of EPO against glaucoma is very promising and further studies evaluating its therapeutic potential are eagerly awaited. Interestingly, EPO appeared to reduce axon degeneration as well as RGC apoptosis (Zhong et al., 2007), whereas BAX deficiency prevented RGC apoptosis but axon degeneration still occurs (Libby et al., 2005b).

Radiation-based treatment

A radiation-based treatment completely prevents glaucomatous damage in DBA/2J mice. This treatment, discovered serendipitously, involves administering 1000 rads of radiation to mice in