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Editors Selection IGR 14-3

Experimental Glaucoma: Neuroprotection

Comment by Horacio Uri Saragovi on:

50979 Etanercept, a widely used inhibitor of tumor necrosis factor-α (TNF-α), prevents retinal ganglion cell loss in a rat model of glaucoma, Roh M; Zhang Y; Murakami Y et al., PLoS ONE, 2012; 7: e40065

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Several previous studies established that TNF-α was upregulated and etiologically implicated in the pathology of glaucoma in rodents and in primates. Therefore the evaluation of an anti- TNF-α reagent was a long overdue and worthwhile experiment. Roh et al. use the episcleral vessel cautery model of glaucoma in rats. This is a very good model that can maintain high IOP for extended periods, with minimal failure rates. Here, a transient spike of very high IOP was reported after a few hours but it then dropped to a more acceptable elevated IOP level for 28 days or longer. This spike is sometimes reported and it seems to depend on the investigators' technique. High IOP causes a slow, chronic, and progressive death of RGCs making it useful to test anti-TNF-α reagents. Moreover, the model had been established to up-regulate TNF-α, and therapeutic efficacy had been shown using genetic models or after intravitreal injection of agents that down-regulate TNF-α activity.^1,2

The paper shows evidence that Etanercept delivered subcutaneously lowered TNF-α and RGC damage. However, in this work the authors use a prophylactic paradigm, starting Etanercept injections at day 1 of high IOP induction.

The paper also addresses the question of where TNF-α comes from. The authors show evidence that most or all of the TNF-α produced within three to five days after induction of high IOP (quantified to ~1 pg/mg retinal protein) stems from Iba-1+ activated microglia. They quantified Iba-1+ activated microglia to ~150 cells/mm² around the ON head.

Three comments come to mind with respect to therapy. (1) This is exciting because the result could have an immediate impact on translational medicine, given that the pharmacokinetics and relative safety of Etanercept and other anti-TNF-α reagents are well known; (2) It will be imperative to extend the research to therapeutic paradigms where elevated TNF-α and RGC damage pre-date treatment, since this will be the state of most patients; (3) It will be interesting to use Etanercept in combination with pressure lowering drugs.³ Four comments come to mind with respect to the retinal source of TNF-α. (1) Several authors have shown, in the same experimental model, that TNF-α mRNA and protein are present in retinal glia and in Müller cells; (2) A normal retina has detectable TNF-α in the absence of such Iba-1+ activated microglia, so there must be another source; (3) It is difficult to fathom how ~150 activated microglia in the central retina (around the rat ON head which is ~1 mm²) can produce all of the TNF-α that will impact on the health of all RGCs including the periphery; (4) It is intriguing that Etanercept prevented the appearance of the TNF-α producing Iba-1+ activated microglia around the ON head, and to me this suggests a feedback loop or regulatory mechanism that needs to be evaluated.

There are of course many hypotheses and possible explanations for these questions, and one hopes that they will be subject of additional experiments. Because the methodology is reported in a clear fashion, this should allow other investigators to reproduce it. Moreover, this could entice proof-of-concept trials aiming to reduce neurotoxicity in glaucoma and perhaps in other neurodegenerative conditions.

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