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Glaucoma Dialogue IGR 11-1

Response

Comment by Jost Jonas 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

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The authors thank the reviewers Makoto Aihara, David Calkins, Robert Casson, Jeffrey Goldberg, Keith Martin, Barbara Lorber and Neville Osborne for their comments and completely agree with them in:

• that the findings of our study¹ are not novel, but that they confirm previous investigations as also cited in the manuscript;
• that the findings are not at all conclusive and that further studies are necessary;
• that the outcome measure of the study was not an indicator of retinal ganglion cell survival per se, but that it is rather a measure of active axonal transport, which is the basis for fluorogold movement from the colliculus to the retina.² The observed effect of systemic brimonidine treatment could have represented, therefore, a modest increase in the efficacy of axonal transport;
• that, in a similar manner, the study did not assess the survival of retinal ganglion cells, but that instead the number of axons was studied which were able to transport the fluorogold back from the superior colliculus to the retinal ganglion cells at 23-28 days after the optic nerve crush. It may not necessarily mean the number of surviving ganglion cells;
• that the magnitude of the difference between the study group and the control group was relatively quite small;
• that it has remained unclear whether the potential effect of brimonidine was due to an indirect effect or due to a direct effect of the intraperitoneal injections of brimonidine on α_2A-receptors which have been reported to be associated with retinal ganglion cells;
• that a potential mechanism through which brimonidine may have been protective against the optic nerve fiber loss may have involved anti-apoptotic effects related to α₂-adrenoreceptor activation, ³ upregulation of brain derived growth factor,⁴ or modulation of the NMDA receptor;⁵
• that it is uncertain if the protective effect of brimonidine may be sustained in a clinically useful way as only one time point was studied in the investigation; the question arises whether the study revealed just a delayed death of retinal ganglion cell (axons) or indeed a true protection;
• that the results from the Low-pressure Glaucoma Treatment Study may shed further light on the question whether indeed brimonidine has a neuroprotective effect;⁶ and
• that one of the authors (JBJ) is member of an advisory board of Allergan Co., that this board advises on Posurdex�, a device for the intraocular delivery of steroids, and that there is no connection at all with the topic of the study discussed.

Most importantly and as also pointed out by the reviewers, not only in primarily neurological diseases, but also in glaucoma, many candidate drugs have unfortunately not shown any definite evidence for neuroprotection in a clinical study despite clear results in numerous animal experimental investigations. The present study may, therefore, be taken only as a hint, but not all as an evidence, of a potentially neuroprotective effect of brimonidine.

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