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W. O. Cepurna, E. C. Johnson, T. A. Doser, Y. Guo, J. C. Morrison; An Interval of Controlled Elevation of IOP (CEI) Significantly Alters Optic Nerve Head (ONH) Axonal mRNA Levels Prior to the Appearance of Focal Optic Nerve (ON) Lesions. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2102.
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As a proof of principle, this study was designed to determine if a short interval of CEI can produce an unequivocal ON injury. In addition, ONH cell type marker mRNA levels were examined following the CEI exposure to determine when significant changes were detectable.
Intraocular pressure (IOP) was elevated to 60 mm Hg for 8 hours (CEI 60/8) in isoflurane anesthetized Brown Norway rats by anterior chamber cannulation and infusion of balanced salt solution from a suspended reservoir. Retinal perfusion was evaluated by direct ophthalmoscopy. At 10 days after exposure, rats (N=8) were perfusion fixed with glutaraldehyde to optimize morphological assessment. ON cross sections were graded for injury by masked observers. In our grading scale, approximately 12-15% of axons are degenerating in a grade 2 lesion. Message levels were measured by qPCR in control and comparable CEI 60/8 ONH at 0 hr, 12hr, 3 days and 10 days after exposure (8 eyes/group). ON were post-fixed and graded. Significance was tested by ANOVA.
At 10 days following CEI 60/8, ON injury grade (2.02±0.26) was significantly greater than control eye ON values (1.03±0.01, p<0.002) in perfusion fixed eyes. The observed lesions were focal and, in more than 80% of nerves, located in the superior portion of the ON cross section. In the set of post-fixed ON, injury grades were significantly increased only in the 10 day group (2.35±0.25 versus 1.1±0.03 in controls). ONH cell type marker mRNA expression analysis showed that initial increases in axonal mRNAs at 0 hr were followed by significant decreases to less than 50% of control values at 3 days (ON injury grade 1.38±0.27).
An 8 hr period of CEI produces a focal ON lesion apparent at 10 days following exposure. This is the same location as initial lesions observed in our chronic glaucoma model. Significant reductions in ONH axonal mRNA, as well as responses of other ONH cell type markers, appear prior to evident ON injury. CEI is a potentially powerful tool for studying the sequence and magnitude of ONH responses to elevated IOP and understanding their role in ON damage.
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