June 2020
Volume 61, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2020
Systemic Treatment with Nicotinamide Riboside is Protective in Four Mouse Models of Retinal Degeneration
Author Affiliations & Notes
  • xian zhang
    Ophthalmology, Emory University, Atlanta, Georgia, United States
    Second Xiangya Hospital of Central South University, China
  • Nathaniel Henneman
    Institut Necker-Enfants Malades, France
  • Preston E Girardot
    Ophthalmology, Emory University, Atlanta, Georgia, United States
  • Ying Li
    Ophthalmology, Emory University, Atlanta, Georgia, United States
  • Nan Zhang
    Ophthalmology, Emory University, Atlanta, Georgia, United States
    Second Xiangya Hospital of Central South University, China
  • Jana T Sellers
    Ophthalmology, Emory University, Atlanta, Georgia, United States
  • Micah A Chrenek
    Ophthalmology, Emory University, Atlanta, Georgia, United States
  • Jiaxing Wang
    Ophthalmology, Emory University, Atlanta, Georgia, United States
  • Eldon E Geisert
    Ophthalmology, Emory University, Atlanta, Georgia, United States
  • Charles Brenner
    Carver College of Medicine, University of Iowa, Iowa, United States
  • John M Nickerson
    Ophthalmology, Emory University, Atlanta, Georgia, United States
  • Jeffrey H Boatright
    Ophthalmology, Emory University, Atlanta, Georgia, United States
    Atlanta Veterans Administration Medical Center, Georgia, United States
  • Footnotes
    Commercial Relationships   xian zhang, None; Nathaniel Henneman, None; Preston Girardot, None; Ying Li, None; Nan Zhang, None; Jana Sellers, None; Micah Chrenek, None; Jiaxing Wang, None; Eldon Geisert, None; Charles Brenner, ChromaDex (P); John Nickerson, None; Jeffrey Boatright, None
  • Footnotes
    Support  The Abraham J. and Phyllis Katz Foundation (JHB); Emory Eye Center annual grant (XZ); The joint training program between Emory University School of Medicine and Xiangya School of Medicine, Central South University. China Scholarship Council (201806370277 XZ); NIH R01EY028859 (JHB); NIH R01EY021592 (JMN); NIH R01EY028450 (JMN); VA I01RX002806 (JHB); VA I21RX001924 (JHB); VARR&D C9246C (Atlanta VAMC); NIH P30EY06360 (Emory); and an unrestricted departmental award from Research to Prevent Blindness. Inc. to the Ophthalmology Department at Emory University.
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 2753. doi:
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      xian zhang, Nathaniel Henneman, Preston E Girardot, Ying Li, Nan Zhang, Jana T Sellers, Micah A Chrenek, Jiaxing Wang, Eldon E Geisert, Charles Brenner, John M Nickerson, Jeffrey H Boatright; Systemic Treatment with Nicotinamide Riboside is Protective in Four Mouse Models of Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2020;61(7):2753.

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

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Abstract

Purpose : Nicotinamide adenine dinucleotide (NAD+) is a coenzyme and a co-substrate that declines with age and during retinal degeneration. Maintaining NAD+ levels may be therapeutic in retinal disease. The purpose of this study was to investigate whether systemic treatment with nicotinamide riboside (NR), a NAD+ precursor, maintains retinal NAD+ levels via unique biosynthetic pathways and is protective in disparate models of retinal damage or degeneration.

Methods : Four mouse models of retinal degeneration were tested, including light-induced retinal degeneration (LIRD) and 3 models of retinitis pigmentosa (RP): the I307N rhodopsin mouse, the IRBP knock-out mouse (IRBP KO), and the Pde6brd10 mouse (rd10). Following intraperitoneal (IP) injection with NR, retinal function was assessed by electroretinogram (ERG) and retinal morphology and inflammation were assessed by optical coherence tomography (OCT) and post-mortem staining of retinal sections. Retinal NAD+ and NADH levels were enzymatically assayed. Ultrastructure was observed by transmission electron microscopy (TEM). AAV8_shRNA vectors were subretinally injected to suppress expression of NMRK1 and NMRK2, kinases unique to the NR-NAD+ pathway.

Results : Each retinal degeneration model exhibited significantly suppressed retinal function, disrupted photoreceptor and RPE layers, significantly increased accumulation of TUNEL-labeled cells in the outer nuclear layer, and mitochondrial dysmorphology. These outcomes were prevented by various NR treatment regimens (examples for LIRD in Figs. 1 & 2). Knocking down NMRK1 and NMRK2 expression partially blocked NR-induced protection. Treatment with NR also resulted in increased levels of NAD+ (38.69±5.80 vs 87.76±10.36 ; p<0.01, with unpaired t-test) in retina.

Conclusions : This is the first study to report protective effects of NR treatment in models of retinal degeneration. NR treatment almost completely protected against functional and morphological losses in the LIRD and I307N models. Degeneration was significantly delayed in the IRBP KO and rd10 models. This protection may be due to preservation of retinal NAD+ following conversion of NR to NAD+ via NMRK1/NMRK2 activity. Maintaining or increasing retinal NAD+ via systemic NR treatment or overexpressing the kinases should be further explored for clinical relevance.

This is a 2020 ARVO Annual Meeting abstract.

 

 

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