Abstract
Abstract: :
Purpose:Control of intraocular pressure (IOP) is the principal goal of current glaucoma therapy, but some patients experience progressive vision loss despite successful pressure normalization. The purpose of this study is to compare levels of retinal mRNAs altered by a short duration of elevated IOP to levels achieved following successful surgical IOP control in a rat model of neuropathy due to aqueous outflow obstruction. Methods: Brown Norway rats received unilateral episcleral vein injections of hypertonic saline to elevate IOP and cummulative IOP history was determined as mm Hg–days above untreated, fellow eyes. Following sustained IOP elevation, surgical cyclodialysis was used in one group of animals to lower and maintain IOP at normal eye levels. Retinas were collected for mRNA analysis from: Fellow eyes(n=12); eyes with a short term, untreated IOP elevation (101 ± 7 mm Hg–days, N=6); and eyes three weeks after a successful cyclodialysis (149 ± 12 mm Hg–days, N=9). Quantitative real–time PCR was used to measure retinal levels of Brn3b (retinal ganglion cell soma), Thy1 and neurofilament H (NFH, retinal ganglion cell axons), iba1 (activated microglia), GFAP (astrocytes), neurotrophin receptors TrkB, TrkC and p75NTR and transcription factors cJUN and JunB. Optic nerve injury was determined by masked grading of optic nerve cross–sections and ANOVA was used for statistical analysis. Results:Short term IOP elevation resulted in significant changes in mRNA levels (% of fellow eye mean±SEM) for NFH (54±13), TrkC (45±8), p75NTR (273±54), cJUN (171±10), JunB (366±74), GFAP (298±66) and Iba1(225±20). Cyclodialysis following short term IOP elevation resulted in the return of mRNA to levels that were no longer significantly different from fellow eye values for TrkC (89±13), cJun (126±9), JunB (185±29), p75NTR (157±29) and GFAP (227±67). In contrast, NFH (53±12) and iba1 (300±46) levels remained significantly altered following cyclodialysis. There was no significant change in the level of Brn3b, TrkB or Thy–1 in any treatment group. Conclusions:Using a rat glaucoma model, we demonstrate that IOP elevation followed by surgical IOP control results in normalization of some retinal mRNA levels initially altered by pressure. However, the expression of other retinal messages remains significantly altered, suggesting processes that may contribute to progressive vision loss or increased vulnerability over time. Persistent changes may suggest potential targets for future neuroprotection strategies.
Keywords: intraocular pressure • gene/expression • retina: neurochemistry