April 2010
Volume 51, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2010
Receptor Interacting Protein 1 Kinase is an Essential Mediator of Programmed Photoreceptor Necrosis After Retinal Detachment
Author Affiliations & Notes
  • Y. Murakami
    Department of Ophthalmology, Massachusettes Eye and Ear Infirmary, Boston, Massachusetts
  • G. Trichonas
    Department of Ophthalmology, Massachusettes Eye and Ear Infirmary, Boston, Massachusetts
  • A. Thanos
    Department of Ophthalmology, Massachusettes Eye and Ear Infirmary, Boston, Massachusetts
  • Y. Morizane
    Department of Ophthalmology, Massachusettes Eye and Ear Infirmary, Boston, Massachusetts
  • S. Jardeleza
    Department of Ophthalmology, Massachusettes Eye and Ear Infirmary, Boston, Massachusetts
  • T. Hisatomi
    Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
  • E. S. Gragoudas
    Department of Ophthalmology, Massachusettes Eye and Ear Infirmary, Boston, Massachusetts
  • J. W. Miller
    Department of Ophthalmology, Massachusettes Eye and Ear Infirmary, Boston, Massachusetts
  • D. Vavvas
    Department of Ophthalmology, Massachusettes Eye and Ear Infirmary, Boston, Massachusetts
  • Footnotes
    Commercial Relationships  Y. Murakami, None; G. Trichonas, None; A. Thanos, None; Y. Morizane, None; S. Jardeleza, None; T. Hisatomi, None; E.S. Gragoudas, None; J.W. Miller, None; D. Vavvas, None.
  • Footnotes
    Support  Bacardi, Research to Prevent Blindness, Lions, Onassis, Fight For Sight, Harvard Ophthalmology Department Support, NIH Core Grant for Vision Research to MEEI
Investigative Ophthalmology & Visual Science April 2010, Vol.51, 4034. doi:https://doi.org/
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      Y. Murakami, G. Trichonas, A. Thanos, Y. Morizane, S. Jardeleza, T. Hisatomi, E. S. Gragoudas, J. W. Miller, D. Vavvas; Receptor Interacting Protein 1 Kinase is an Essential Mediator of Programmed Photoreceptor Necrosis After Retinal Detachment. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4034. doi: https://doi.org/.

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

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Abstract

Purpose: : To investigate the role of receptor interacting protein 1 (RIP1) kinase during photoreceptor death after retinal detachment (RD).

Methods: : RD was created in the eyes of Brown Norway rats by subretinal injection of viscoelastic (Provisc). The eyes without RD were used as a control. Expression levels of RIP family members were assessed by quantitative real-time PCR. Treated eyes received Z-VAD (pan-caspase inhibitor) and/or necrostatin-1 (RIP1 kinase 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. Oxidative stress in the retina was assessed by ELISA for carbonyl adducts on proteins. Cellular localization of apoptosis-inducing factor (AIF) was assessed by immunostaining.

Results: : RIP3 expression, a key activator of RIP1 kinase, increased over 10-fold in the retina 3 days after RD. Caspase inhibition by Z-VAD failed to prevent photoreceptor loss after RD; however, ultrastructural analysis revealed that the form of photoreceptor death changed from apoptosis to necrosis. These necrotic changes observed in Z-VAD-treated retina were substantially prevented by combined treatment with necrostatin-1 and Z-VAD, along with a reduction in oxidative stress and the nuclear translocation of AIF.

Conclusions: : These findings indicate that RIP1 kinase plays an essential role after RD to induce programmed necrosis and that simultaneous inhibition of RIP1 kinase and caspases may be a novel therapeutic strategy to prevent photoreceptor death after RD.

Keywords: retinal detachment • apoptosis/cell death • neuroprotection 
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