Muller Cell Reactivity and Photoreceptor Cell Death is Reduced Following Experimental Retinal Detachment using an Inhibitor of the Akt/mTOR Pathway
Geoffrey P. Lewis 1*,
Ethan A Chapin 1,
Jiyun Byun 2,
Gabriel Luna 1,
David Sherris 3,
and
Steven K. Fisher 1
1 Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, California, United States
2 Mayachitra, Inc, Santa Barbara, California, United States
3 Paloma Pharmaceuticals, Inc., Jamaica Plain, Massachusetts, United States
* To whom correspondence should be addressed. E-mail: g_lewis{at}lifesci.ucsb.edu.
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Abstract |
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Purpose: To test the effect of Palomid 529, an inhibitor of the Akt/mTOR pathway, on Müller cell proliferation, subretinal glial scar formation, and photoreceptor survival after experimental retinal detachment (RD).
Methods: 600 µg of Palomid 529 in balanced salt solution (BSS), or BSS alone was injected intravitreally immediately after RD in the right eyes of 12 rabbits. Ten µg of BrdU was injected intravitreally on day 3. Animals were sacrificed on day 3 or 7, at which time retinal sections were labeled with anti-BrdU, to detect dividing cells, anti-vimentin to identify Müller cells, and the isolectin B4 to identify microglia and macrophages. Outer nuclear layer (ONL) thickness was measured from fluorescently labeled nuclear stained sections. Labeling was imaged using confocal microscopy. Six additional animals received either drug or BSS injections into normal eyes and paraffin sections were stained with H&E.
Results: In the drug treated eyes there was a significant decrease in the number of anti-BrdU labeled Müller cells, the number and size of sub-retinal scars, and the number of isolectin B4 labeled cells. The ONL was also significantly thicker and there was no evidence of toxic effects.
Conclusions: Palomid 529 is an effective suppressor of Müller cell proliferation, glial scar formation, and photoreceptor cell death in a rabbit model of RD. This suggests that inhibiting the Akt/mTor signal transduction pathway may be an effective strategy to decrease proliferation and photoreceptor cell death induced by detachment and perhaps represents a novel therapy for related human diseases such as PVR.
Key Words:
retinal detachment, Mueller cell, antiproliferative effects, PVR, Gliosis, Akt/mTor
