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W. O. Cepurna, Y. Guo, T. A. Doser, J. A. Dyck, E. C. Johnson, J. C. Morrison; An Interval of Controlled Intraocular Pressure Elevation Alters Optic Nerve Head Gene Expression Without Compromising Retinal Perfusion. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3695.
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Elevated intraocular pressure (IOP) is the principal risk factor for glaucoma. While the optic nerve head (ONH) is thought to be the site of initial injury, the crucial molecular connections between elevated IOP and axon injury are unknown. Chronic animal glaucoma models have identified many retinal and ONH responses to elevated IOP, but the lack of precise control of IOP level and duration in these models limits their utility in separating initial molecular events from downstream effects. Acute non-ischemic IOP studies have been limited to the examination of ONH ultrastructure and axonal transport obstruction. Recent use of microarray analysis has allowed us to identify genes that are selectively regulated in rat ONH by chronic IOP elevation in eyes with small focal optic nerve injuries. This marked sensitivity of the rat ONH to elevated IOP caused us to hypothesize that even a short well-defined period of elevated IOP could reproduce changes in these same genes. This study was designed to determine if this paradigm reproduces the cellular ONH changes known to occur in our established chronic IOP elevation glaucoma model.
Unilateral IOP elevation was produced in Brown Norway rats (N=9) under isoflurane anesthesia by cannulation of the anterior chambers and IOP was kept at 50 mm Hg for 4 hours by infusion of balanced salt solution from a suspended reservoir. Retinal perfusion was evaluated periodically by direct ophthalmoscopy. At 24 hours following IOP elevation, the anterior 0.4 mm of ONH was collected, and RNA was extracted and reverse transcribed for quantitative PCR measurement.
The retina remained perfused during the 4-hour exposure to elevated IOP. At 24 hours post-exposure, interleukin-6, topoisomerase 2A and fibulin were significantly upregulated by 29.4-, 1.8- and 1.9-fold, respectively. Other measured messages, protein regulator of cytokinesis 1, neurofilament light (NEFL), and growth associated protein 43 (GAP43), remained at control levels.
A short period of controlled IOP elevation produces several alterations in ONH gene expression similar to those associated with focal optic nerve injury following chronic IOP elevation in the rat. These alterations occurred prior to reduction of axonal mRNA levels for NEFL and GAP43 that correlate with axon loss, suggesting that these cellular responses are initial injury events. These observations demonstrate the relevance and potential usefulness of controlled IOP elevation for short periods as a model of early glaucomatous injury in the rat.
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