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W. O. Cepurna, E. C. Johnson, L. Jia, J. C. Morrison; Retinal Ganglion Cell Loss in a Glaucoma Model: Does Neurotrophin Deprivation Play a Critical Role?. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3276. doi: https://doi.org/.
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Reduced retrograde transport of BDNF and its full-length receptor, TrkB, is hypothesized to contribute directly to retinal ganglion cell (RGC) loss in glaucoma. This hypothesis has produced many strategies to increase RGC survival in experimental glaucoma by supplementing retinal BDNF and TrkB levels. While short term survival may be enhanced, none of these strategies alters ultimate RGC loss. This study examines the assumption that elevated IOP depletes endogenous retinal BDNF and TrkB receptor protein levels in a rat glaucoma model.
Chronic unilateral IOP elevation was produced in Brown Norway rats by injection of hypertonic saline into episcleral veins (N=70). IOP histories were collected and, at 10 and 35 days post-injection, retinas were collected for analysis. Additional intact retinas were prepared for immunohistochemistry. Retinal TrkB and BDNF protein levels were quantified by western analysis. The mRNA levels of BDNF and TrkB were determined using qRT-PCR.
No change was detected in retinal BDNF protein levels by either immunohistochemistry or western analysis. Moreover, western analysis also demonstrated that full-length TrkB protein increased 3-fold in the most severely injured retinas (p<0.05), while the activated (phosphorylated) receptor level was unchanged. At 35 days elevated IOP, both BDNF and full-length catalytic TrkB mRNA levels declined to 75±7% and 62±7% of control values (R2=0.12 and 0.25 respectively, p<0.03), making it unlikely that the observed protein levels resulted from endogenous upregulation.
We found no evidence that BDNF protein levels are reduced in the retina following chronic IOP elevation. On the other hand, the increased full-length TrkB available for activation may explain the short term survival enhancement provided by exogenously supplied BDNF following injury observed by others. Additionally, alterations in neurotrophic signaling may still contribute to ultimate RGC fate, as suggested by our previous reports of early and persistent upregulation of p75NTR, which can potentially activate multiple pro- and anti-apoptotic pathways. Elucidation of these complex events is likely to suggest new strategies for neuroprotection in glaucoma.
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