Muller cell reactivity and photoreceptor cell death are reduced after experimental retinal detachment using an inhibitor of the Akt/mTOR pathway.
OBJECTIVE
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
Palomid 529 (600 microg) in balanced salt solution or balanced salt solution alone was injected intravitreally immediately after RD into the right eyes of 12 rabbits. Ten micrograms of BrdU was injected intravitreally on day 3. Animals were killed on day 3 or 7, at which time retinal sections were labeled with anti-BrdU to detect dividing cells, with anti-vimentin to identify Müller cells, and with the isolectin B4 to identify microglia and macrophages. Outer nuclear layer (ONL) thickness was measured from fluorescence-labeled nuclear-stained sections. Labeling was imaged using confocal microscopy. Six additional animals received either drug or balanced salt solution injections into normal eyes, and paraffin sections were stained with hematoxylin and eosin.


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 subretinal 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 proliferative vitreoretinopathy.
Neuroscience Research Institute, University of California, Santa Barbara, California 93106-5060, USA. g_lewis@lifesci.ucsb.edu
Geoffrey P
GP
Lewis
Ethan A
EA
Chapin
Jiyun
J
Byun
Gabriel
G
Luna
David
D
Sherris
Steven K
SK
Fisher
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001578:Benzopyrans / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D007267:Injections; D008264:Macrophages / Q000502:physiology; D018613:Microscopy, Confocal; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology*; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D011817:Rabbits; D012163:Retinal Detachment / Q000378:metabolism / Q000473:pathology*; D055351:Retinal Neurons / Q000473:pathology; D058570:TOR Serine-Threonine Kinases; D014822:Vitreous Body
D001578:Benzopyrans; D015415:Biomarkers; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C533469:palomid 529