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Editors Selection IGR 9-4

Comments

Comment by Ivan Goldberg on:

22579 Effect of brimonidine on retinal ganglion cell survival in an optic nerve crush model, Ma K; Xu L; Zhang H et al., American Journal of Ophthalmology, 2009; 147: 326-331

See also comment(s) by Makoto Aihara • David Calkins • Robert Casson • Keith Martin • Neville Osborne • Jost Jonas •

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Treatment options for glaucoma are currently limited to reducing intraocular pressure (IOP), and too often fail from biological inefficacy, patient non-compliance, and adverse effects. What about neuroprotection � can we save retinal ganglion cells (RGCs) directly, independent of modulating IOP?
Ma and colleagues ask whether brimonidine, an α₂-agonist currently used to reduce IOP, protects RGCs after optic nerve crush injury.

The retrograde transport of fluorogold at 23-28 days after nerve crush is used to measure the subset of RGCs that are still connected to the superior colliculus

The nerve crush model is a reasonable animal model for glaucoma, as any injury to RGC axons in the optic nerve is likely to activate similar RGC death mechanisms, although it is not known whether there is an IOP-dependent component to cell death in this model. The authors admit that the application of brimonidine as a daily intraperitoneal injection probably doesn�t model the drugs� bioavailability in human eyes, but the paper does not directly address drug levels at the retina or optic nerve, or study topical application, or even provide IOP measurements. Nevertheless, they demonstrate a statistically significant, albeit very modest effect (61% brimonidine �survival� vs 53.5% in saline control). Disturbingly, in Figures 2 and 3 the y-axes do not start at 0, visually misleading the inattentive reader to a 100% increase in survival where the effect is actually less than 20%.
It must be noted that the authors do not actually measure survival as stated in the title and throughout the paper. Rather, they use retrograde transport of fluorogold at 23-28 days after nerve crush to measure the subset of RGCs that are still connected to the superior colliculus. Of course, RGCs may survive, even though their axons are severed and thus don�t carry the retrograde label back to the cell bodies in the retina. Indeed, the application of brimonidine one hour before optic nerve crush may lead to axon sparing at the time of the crush, rather than RGC survival over the ensuing weeks.

Human trials of optic neuropathies, separating the neuroprotective effects seen in animals from IOPreduction effects, will continue to challenge the study of brimonidine

As a candidate neuroprotective agent, brimonidine has suffered from inconsistency in the published animal and human studies, amplified by perceptions of Allergan�s association (the last author Jost is an Allergan advisor). In human trials of optic neuropathies, separating the neuroprotective effects seen in animals from IOP-reduction effects will continue to challenge the study of this drug. Ma and colleagues are to be commended for taking on such a tricky subject, and I look forward to their and others� ongoing work on RGC neuroprotection as the critical steps into the future of glaucoma therapy.

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