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E. A. Chapin, G. P. Lewis, S. K. Fisher, D. Sherris; Müller Cell Proliferation and Glial Scar Formation Is Reduced Following Experimental Retinal Detachment Using Palomid 529, an Inhibitor of the Akt/mTOR Pathway. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5183.
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To test the effect of a novel, small molecule, Palomid 529, an anti-angiogenic agent which has been shown to target and inhibit the Akt/mTor signal transduction pathway, on Müller cell proliferation and scar formation after experimental retinal detachment; two events that occur in the human disease, proliferative vitreoretinopathy (PVR).
Experimental retinal detachments were made in the right eyes of pigmented rabbits. Six hundred micrograms of Palomid 529 in 50 microliters of PBS, or PBS alone was injected intravitreally on day 0, immediately after retinal detachment. Each rabbit received 10 micrograms of BrdU intravitreally on day 3. Animals were sacrificed on day 3 or 7, at which time the tissue was fixed in paraformadehyde, embedded in agarose and sectioned at 100 microns. The sections were labeled with anti-BrdU, to detect dividing cells, and anti-vimentin, to identify Müller cells. Labeling was imaged on an Olympus Fluoview confocal microscope, and the resultant digital images were analyzed to determine the number of proliferating cells as well as the number and length of subretinal glial scars.
In control detachments, Müller cells make up the majority of BrdU labeled cells, and are the cells that form glial scars by growing into the subretinal space. Our data show a statistically significant decrease in the number of BrdU labeled Muller cells per millimeter at both the 3 and 7 day time points. No glial scars were observed at the 3 day time point in either control or drug treated animals, however, there was a significant decrease in the number and size of sub-retinal scars at day 7.
Our data indicate that Palomid 529 is an effective suppressor of Müller cell proliferation and glial scar growth in a rabbit model of retinal detachment. This suggests that inhibiting the Akt/mTor signal transduction pathway may be an effective strategy to decrease proliferation induced by detachment and perhaps represents a novel therapy for related human diseases such as PVR.
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