June 2013
Volume 54, Issue 15
Free
ARVO Annual Meeting Abstract  |   June 2013
PARP1 Knock-Out Mice Prevents N-methyl-N-nitrosourea-induced Photoreceptor Degeneration
Author Affiliations & Notes
  • Xinrong Zhou
    Dept of Opthalmology, Johns Hopkins University School of Medicine, Baltimore, MD
    Dept of Opthalmology, Harbin Medical University, the 2nd Affiliated Hospital, Harbin, China
  • Tomohiro Masuda
    Dept of Opthalmology, Johns Hopkins University School of Medicine, Baltimore, MD
  • Zhiyong Yang
    Dept of Opthalmology, Johns Hopkins University School of Medicine, Baltimore, MD
  • Gillian Shaw
    Dept of Opthalmology, Johns Hopkins University School of Medicine, Baltimore, MD
  • Cynthia Berlinicke
    Dept of Opthalmology, Johns Hopkins University School of Medicine, Baltimore, MD
  • Shaida Andrabi
    Neuroregeneration Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD
    Dept of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD
  • Yingfei Wang
    Neuroregeneration Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD
  • Valina Dawson
    Neuroregeneration Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD
    Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD
  • Ted Dawson
    Neuroregeneration Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD
    Dept of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD
  • Donald Zack
    Dept of Opthalmology, Johns Hopkins University School of Medicine, Baltimore, MD
  • Footnotes
    Commercial Relationships Xinrong Zhou, None; Tomohiro Masuda, None; Zhiyong Yang, None; Gillian Shaw, None; Cynthia Berlinicke, None; Shaida Andrabi, None; Yingfei Wang, None; Valina Dawson, None; Ted Dawson, None; Donald Zack, Alcon (C), Merck (F), Allergan (C)
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2013, Vol.54, 1373. doi:
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      Xinrong Zhou, Tomohiro Masuda, Zhiyong Yang, Gillian Shaw, Cynthia Berlinicke, Shaida Andrabi, Yingfei Wang, Valina Dawson, Ted Dawson, Donald Zack; PARP1 Knock-Out Mice Prevents N-methyl-N-nitrosourea-induced Photoreceptor Degeneration. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1373.

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

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Abstract

Purpose: Poly-ADP-ribose polymerase -1 (PARP-1) knock-down/knock-out can be neuroprotective and has been reported to promote photoreceptor (PR) survival in models of retinal degeneration. To build upon these studies, we wanted to explore to effect of PARP-1 knockout on the PR degeneration induced by the alkylating agent N-methyl-N-nitrosourea (MNU).

Methods: Knock-out (KO) and Wild-type (WT) mice were injected intraperitoneally with MNU (60 mg/kg). Optical coherence tomography (OCT) images were recorded before euthanization. Photoreceptor loss was analyzed at 1, 3, 6 , 12, 18 , 24, 48 and 72 hours after MNU treatment. Retinal function was assessed by electroretinography (ERG) over the same time course. TUNEL staining was utilized to evaluate photoreceptor apoptosis. PARP1 activation was assessed by PAR Western blot. Finally, we tested retinal cell cultures from WT and PARP1 KO mice for their relative susceptibility to MNU toxicity.

Results: Significant PAR accumulation was identified in WT retinas 6 hours after MNU treatment, suggesting MNU can activate PARP signaling in the retina. MNU can lead to a rapid decrease in retinal function, as measured by ERG, at 6 hours post-injections. With the absence of any structural changes in WT MNU-treated group , all ERG components decreased progressively. Amplitude of a-waves and b-waves in both scotopic and photopic light stimulus showed significant reductions, nearly to flat when compared with those of normal a-waves and b-waves. Preceded by changes in retinal function, ONL was entirely absent on OCT images after 12 hours in WT mice. In contrast, the ONL was well preserved in PARP knockout mice, and ERG also revealed clear difference between wt and PARP knockouts. In dissociated retinal cultures, MNU induced significant cell death in wt retinal cells at 24 hours, with only 10% cells surviving the treatment. In contrast, PARP-1 knockout enhanced cell survival approximately 2-fold.

Conclusions: Our results demonstrate that PARP activation plays a pivotal role in MNU-induced photoreceptor death in vitro and in vivo, and genetic deletion of PARP1 can promote photoreceptor survival. We suggest PARP1 may be a target for developing novel therapeutics to treat some forms of retinal degenerative disease.

Keywords: 695 retinal degenerations: cell biology • 615 neuroprotection • 449 cell survival  
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