April 2011
Volume 52, Issue 14
Free
ARVO Annual Meeting Abstract  |   April 2011
The Role of RIP-mediated Necrosis and Autophagy in Photoreceptor Death after Retinal Detachment
Author Affiliations & Notes
  • Yusuke Murakami
    Department of Ophthalmology, Massachusettes Eye and Ear Infirmary, Boston, Massachusetts
  • George Trichonas
    Department of Ophthalmology, Massachusettes Eye and Ear Infirmary, Boston, Massachusetts
  • Aristomenis Thanos
    Department of Ophthalmology, Massachusettes Eye and Ear Infirmary, Boston, Massachusetts
  • Dimosthenis Mantopulos
    Department of Ophthalmology, Massachusettes Eye and Ear Infirmary, Boston, Massachusetts
  • Yuki Morizane
    Department of Ophthalmology, Massachusettes Eye and Ear Infirmary, Boston, Massachusetts
  • Maki Kayama
    Department of Ophthalmology, Massachusettes Eye and Ear Infirmary, Boston, Massachusetts
  • Toshio Hisatomi
    Ophthalmology, Kyushu University, Fukuoka, Japan
  • Joan Miller
    Department of Ophthalmology, Massachusettes Eye and Ear Infirmary, Boston, Massachusetts
  • Demetrios Vavvas
    Department of Ophthalmology, Massachusettes Eye and Ear Infirmary, Boston, Massachusetts
  • Footnotes
    Commercial Relationships  Yusuke Murakami, None; George Trichonas, None; Aristomenis Thanos, None; Dimosthenis Mantopulos, None; Yuki Morizane, None; Maki Kayama, None; Toshio Hisatomi, None; Joan Miller, None; Demetrios Vavvas, None
  • Footnotes
    Support  Research to Prevent Blindness Foundation (DV), Lions Eye Research Fund (DV), Onassis Foundation (DV), NEI grant EY014104 (MEEI Core Grant)
Investigative Ophthalmology & Visual Science April 2011, Vol.52, 6588. doi:
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      Yusuke Murakami, George Trichonas, Aristomenis Thanos, Dimosthenis Mantopulos, Yuki Morizane, Maki Kayama, Toshio Hisatomi, Joan Miller, Demetrios Vavvas; The Role of RIP-mediated Necrosis and Autophagy in Photoreceptor Death after Retinal Detachment. Invest. Ophthalmol. Vis. Sci. 2011;52(14):6588.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : Detachment of photoreceptors from the retinal pigment epithelium, as seen in various retinal disorders, causes photoreceptor loss and subsequent vision decline. Although caspase-dependent apoptotic pathways are activated after retinal detachment (RD), caspase inhibition by the pan-caspase inhibitor Z-VAD fails to prevent photoreceptor death. In other experimental models, when caspases are inhibited, receptor interacting protein (RIP)-mediated necrosis and/or autophagy becomes the predominant cell death pathway. In this study, we investigated whether these pathways are important in RD, and establish novel therapeutic interventions.

Methods: : RD was created in the eyes of Brown Norway rats by subretinal injection of viscoelastic. Expression levels of RIP family members were measured by quantitative real-time PCR and Western blotting. Lipidated form of light chain 3 (LC3-II), a marker of autophagy, was evaluated by Western blotting. Treated eyes received Z-VAD (pan-caspase inhibitor), necrostatin-1 (RIP1 kinase inhibitor), and/or 3-methyladenine (3-MA; autophagy inhibitor) injected subretinally at the time of RD induction. Photoreceptor death was evaluated by transmission electron microscopy and changes of outer nuclear layer thickness at 3 days after RD.

Results: : After RD, expression of RIP1 was elevated 2 fold and RIP3 expression, a key activator of RIP1 kinase, increased over 10 fold. On the other hand, LC3-II expression did not show any significant difference after RD. Morphological assessment of detached retina treated with Z-VAD showed decreased apoptosis but significantly increased necrotic photoreceptor death. Treatment with Z-VAD+Nec-1 substantially prevented those necrotic changes and protects photoreceptors from RD-induced cell death; while 3-MA demonstrated no significant protective effect.

Conclusions: : RIP-mediated necrosis becomes the predominant form of cell death when apoptosis is blocked, and simultaneous inhibition of caspases and RIP kinase provides effective neuroprotection after RD.Defining the role of autophagy in RD will require further studies using knockout animals or other specific inhibitors of the autophagic pathways.

Keywords: retinal detachment • neuroprotection • photoreceptors 
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