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K.R. Martin, H.A. Quigley, D.F. Valenta, J. Kielczewski, M.E. Pease; Experimental Intraocular Pressure Elevation Alters the Distibution of Dynein Motor Protein Subunits in the Rat Optic Nerve . Invest. Ophthalmol. Vis. Sci. 2003;44(13):1095.
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Purpose: Acute intraocular pressure (IOP) elevation causes accumulation of retrogradely-transported brain derived neurotrophic factor and its receptor at the optic nerve head (ONH) in rats and monkeys. Obstruction of axonal transport may therefore be involved in glaucoma pathogenesis, but it is unknown if obstruction is specific to certain transported factors or represents a generalized failure of retrograde axonal transport. The dynein motor complex mediates retrograde axonal transport in retinal ganglion cells (RGC). Our hypothesis was that elevated IOP interferes with dynein function. We studied the distibution of dynein subunits in the retina and optic nerve after acute and chronic experimental IOP elevation in the rat. Methods: IOP was elevated unilaterally in 54 rats either acutely (by anterior chamber cannulation for 4 hours, n=12) or chronically (by translimbal trabecular laser treatment, n=42). Dynein subunit distribution was compared in treated and control eyes by immunohistochemistry and Western blotting at 1 day (n=12), 3 days (n=4), 1 week (n=15), 2 weeks (n=12) and 4 weeks (n=11). For immunohistochemistry, sections through the ONH were probed with an anti-dynein heavy chain (HC) antibody and graded semi-quantitatively by masked observers. Other freshly enucleated eyes were microdissected for separate Western blot quantification of dynein intermediate complex (IC) in myelinated and unmyelinated optic nerve, ONH and retina. Results: Immunohistochemistry showed accumulation of dynein HC at the ONH in IOP elevation eyes compared to controls (p<0.001, Wilcoxon paired sign-rank test, n=29). ONH dynein IC was elevated by 46.5% in chronic IOP elevation eyes compared to controls by Western blotting (p<0.001, 95% CI = 25.9% to 67.8%, n=17). The maximum increase in ONH dynein IC was 78.7% after 1 week (p<0.05, n=5), but significant increases were also detected after 4 hours and 4 weeks of IOP elevation (p<0.05, n=4 rats per group). Total retinal dynein IC was increased by 8.7% in chronic IOP elevation eyes compared to controls (p<0.03, 95% CI 1.4% to 16.1%, n=24). In the retina, IOP elevation particularly affected the 72kD subunit of dynein IC, which was 100.7% higher in chronic IOP elevation eyes compared to controls (p<0.00001, 95% CI 71.0% to 130.4%, n=21). Dynein IC changes in myelinated and unmyelinated optic nerve were not significant (p>0.05). Conclusions: Dynein acculmulates at the ONH with experimental IOP elevation in the rat, suggesting that elevated IOP interferes with the fundamental mechanisms of retrograde axonal transport in RGC.
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