Retinal damage after 3 to 4 months of elevated intraocular pressure in a rat glaucoma model

PURPOSE. TO characterize a long-term elevated intraocular pressure (IOP) gl aucoma model in the rat with respect to electroretinographic (ERG) changes and the pattern and mechanism of retinal ganglion cell (RGC) death. METHODS. An approximate doubling of IOP was induced in one eye (G) of femal e Wistar mts (150-180 g) by cautery of 3 episcleral/limbal veins. At interv als over 3 to 4 months, measurements of IOP and ERG changes (contact-lens e lectrode) were made in both the G and contralateral normal (N) eyes. At the end of 3 to 4 months of elevated IOP, RGCs were fluorescently labeled with Fluorogold (retrogradely from the superior colliculus), or retinas were la beled by intravitreal injection of a mitochondrial potential indicator dye and stained for apoptotic nuclei with a DNA dye. Flatmounts of fixed, dye-l abeled retinas were examined by epifluorescence, confocal, or interference contrast microscopy. RESULTS. Elevated IOP was consistently maintained for up to 4 months in G e yes, but ERG a- and b-waves showed a statistically significant decline, of 30% to 40% in amplitude, after 3 months. Loss of RGCs in G retinas was prim arily focal with no statistically significant loss demonstrable outside of the focal areas when assessed by an area sampling method for counting RGCs, which totaled 2% to 3% of the entire retinal area. Mitochondrial membrane potential of cells in the RGC layer was reduced by 17.5% (P < 0.05) in regi ons surrounding areas of focal loss compared with comparable locations in c ontrol N eyes. After 3.5 months' elevated IOP the G retinas showed cell nuc lei at various stages of apoptosis, from initial DNA condensation to fragme ntation. CONCLUSIONS. The three-vein episcleral/limbal vein occlusion model for indu cing glaucomatous pathology in the rat eye gives a consistent long-term ele vation of IOP. After 3 to 4 months of similar to 100% increased IOP, the ER G responses begin to decline, there is a variable focal loss of RGCs, and s ome of the remaining RGCs show characteristics of stress and apoptosis. The se changes seem consistent with retinal damage in human glaucoma (focal fie ld defects), and this rat model appears to mimic some features of primary o pen-angle glaucoma.