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X. Wang, W. H. Baldridge, B. C. Chauhan; Acute Endothelin (ET)-1 Application Induces Reversible Fast Axonal Transport Blockade in Adult Rat Optic Nerve. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3288.
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Endothelin (ET)-1 is a peptide produced mainly by the vascular endothelium. Our previous work found that chronic administration of ET-1 to the rat optic nerve induced loss of RGCs and their axons. However, the mechanisms that lead to neuronal loss and alterations in the optic nerve are not fully understood. The aim of this work was to establish a model of acute ET-1 delivery in the rat optic nerve, and to investigate the effects of ET-1 on fast axonal transport in optic nerve.
Gelfoam soaked in 1 nM ET-1 was applied onto the surface of exposed right optic nerve of adult Brown Norway rats (at 0-1.5 mm behind the globe). After 1 hr, the gelfoam was removed and the nerve was rinsed with saline. Then gelfoam soaked in 20% horseradish peroxidase (HRP) was placed over both superior colliculi. Rats were sacrificed after 2, 4, 6 and 24 hrs (n=5, for each group) and the retinae and the entire length of both optic nerves were removed and fixed. The optic nerves were sectioned longitudinally. HRP was visualized using tetramethylbenzidine (TMB) methods and examined by light microscopy. Control rats underwent the same procedures but with saline application.
In normal rats, HRP labeling was observed over the entire length of the optic nerve at 2 hrs after application to the SC and remained evenly labeled up to 6 hrs. At 24 hrs, the density of labeling decreased and only a few HRP positive axons could be found. HRP positive retinal ganglion cells (RGCs) were first observed mainly in the temporal and superior quadrants of the retina at 6 hrs. At 24 hrs, RGCs were labeled almost evenly throughout the retina. In ET-1 treated optic nerves, at 2 hrs, the progression of HRP in all rats was arrested. The blockade started at the point of ET-1 application and extended to 1/4 - 2/3 of the distal portion of the nerve. Only the portion of the nerve near the chiasm remained HRP positive. At 4 hrs, 60% of the rats still showed evidence of axonal transport blockade and 40% showed partial recovery. At 6 and 24 hrs all rats showed recovery with HRP positive RGCs, although the number of labeled cells was less compared to the control. The density of HRP labeling in the nerves was lighter than that of normal rats at 6 hrs, but by 24 hrs there was no obvious difference.
Our results indicate that local acute application of ET-1 produces a reversible blockade of rapid axonal transport in optic nerve.
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