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G. P. Lewis, G. Luna, J. Byun, E. A. Chapin, D. Sherris, S. K. Fisher; Palomid 529, An Inhibitor of the Akt/mTOR Pathway Reduces Photoreceptor Cell Death Following Experimental Retinal Detachment. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3883.
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To test the effects of the small molecule Palomid 529, an inhibitor of the Akt/mTor signal transduction pathway, on photoreceptor cell death resulting from retinal detachment (RD).
Experimental RDs were made in the right eyes of pigmented rabbits (n=6). 600 µg of Palomid 529 in 50 µl of PBS, or PBS alone was injected intravitreally on day 0, immediately after RD. Each rabbit received 10 µg of BrdU intravitreally on day 3. Animals were sacrificed on day 7, at which time the tissue was fixed, embedded in agarose and sectioned. Six additional animals received either vehicle or drug injections into normal eyes and paraffin sections of the retina were stained with H & E. To determine the level of photoreceptor cell survival following RD, agarose sections were labeled with a nuclear stain and the width of the outer nuclear layer (ONL) was measured. Potential side effects of the drug were examined by 1) confocal imaging of anti-BrdU, anti-vimentin, and isolectin B4 labeling and 2) light microscopy (LM) of H & E stained sections.
Seven days after RD the ONL was significantly thicker in drug treated detached retinas (27.71 µm) compared to vehicle treated detached retinas (19.40 µm; p< 8.81 E-06). The ONL from the normal retina was, however, thicker (34.45 µm) than both the drug (p<0.001) and vehicle (p<1.27 E-11) treated detached retinas. There was no difference in anti-BrdU, -vimentin and isolectin B4 labeling in attached retinal regions from within drug injected eyes compared to the vehicle injected eyes, indicating that the drug did not induce proliferation, glial, or immune cell reactivity. In addition the LM did not show any deleterious effects on overall retinal organization.
These data indicate that Palomid 529 slows photoreceptor cell death following RD without obvious side effects to the retina. This suggests that inhibiting the Akt/mTor signal transduction pathway may be neuroprotective to photoreceptors and perhaps represents a novel therapy for other photoreceptor degenerations.
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