Inhibition of retinal detachment-induced apoptosis in photoreceptors by a small peptide inhibitor of the fas receptor

Invest Ophthalmol Vis Sci. 2010 Apr;51(4):2177-84. doi: 10.1167/iovs.09-4439. Epub 2009 Oct 22.


Purpose. To test the effect of a small peptide inhibitor (Met12) of the Fas receptor on the activation of extrinsic and intrinsic apoptosis pathways after retinal detachment. Methods. Retinal-RPE separation was created in Brown Norway rats by subretinal injection of 1% hyaluronic acid. Met12, derived from the Fas-binding extracellular domain of the oncoprotein Met, was injected into the subretinal space at the time of separation. A mutant peptide and vehicle administered in a similar fashion acted as inactive controls. The extrinsic apoptotic pathway was induced in 661W cells using a Fas-activating antibody in the presence or absence of Met12. Caspase 3, caspase 8, and caspase 9 activities were measured with calorimetric and luminescent assays in retinal extracts and cell lysates. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) was performed in retinal sections 3 days after separation. Histology was performed in retinal sections 2 months after retinal detachment. Results. Met12 inhibited Fas-induced caspase 8 activation in 661W cells. Similarly, administration of Met12 into the subretinal space inhibited the activation of caspase 3, caspase 8, and caspase 9 after retinal detachment. This corresponded to a decreased level of TUNEL-positive staining of photoreceptors after retinal-RPE separation in animals that received Met12, but not inactive mutant, peptide treatment. After 2 months, the outer nuclear layer was significantly thicker, and the photoreceptor count was higher in animals treated with subretinal Met12. Conclusions. The small peptide Met12 may serve as a photoreceptor-protective agent in the setting of retinal-RPE separation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Blotting, Western
  • Caspase 3 / metabolism
  • Caspase 8 / metabolism
  • Caspase 9 / metabolism
  • Cell Count
  • Cell Culture Techniques
  • Cell Survival
  • In Situ Nick-End Labeling
  • Male
  • Oligopeptides / pharmacology*
  • Photoreceptor Cells, Vertebrate / drug effects
  • Photoreceptor Cells, Vertebrate / pathology*
  • Rats
  • Rats, Inbred BN
  • Retinal Detachment / prevention & control*
  • fas Receptor / antagonists & inhibitors*
  • fas Receptor / metabolism


  • Oligopeptides
  • fas Receptor
  • Casp8 protein, rat
  • Caspase 3
  • Caspase 8
  • Caspase 9