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Systemic Treatment with Nicotinamide Riboside is Protective in Three Mouse Models of Retinal Degeneration

By Xian Zhang, Nathaniel F Henneman, Preston E Girardot, Jana T Sellers, Micah A Chrenek, Ying Li, Jiaxing Wang, Charles Brenner, John M Nickerson, Jeffrey H. Boatright

Posted 06 Dec 2019
bioRxiv DOI: 10.1101/866798

Purpose: The retina is highly metabolically active, suggesting that metabolic dysfunction could underlie many retinal degenerative diseases. Nicotinamide adenine dinucleotide (NAD+) is a cofactor and a co-substrate in several cellular energetic metabolic pathways. Maintaining NAD+ levels may be therapeutic in retinal disease since retinal NAD+ levels decline with age and during retinal damage or degeneration. The purpose of this study was to investigate whether systemic treatment with nicotinamide riboside (NR), a NAD+ precursor, is protective in disparate models of retinal damage or degeneration. Methods: Three mouse models of retinal degeneration were tested: an albino mouse model of light-induced retinal degeneration (LIRD) and two models of retinitis pigmentosa (RP), including a mouse line deficient in interphotoreceptor binding protein (IRBP) gene expression (IRBP KO), and a naturally-occuring cGMP phosphodiesterase 6b mutant mouse model of RP (the Pde6brd10 mouse). Mice were intraperitoneally (IP) injected with PBS or NR at various times relative to damage or degeneration onset. One to two weeks later, retinal function was assessed by electroretinograms (ERGs) and retinal morphology was assessed by optical coherence tomography (OCT). Afterwards, retina sections were H&E stained for morphological analysis or by terminal deoxynucleiotidyl transferase dUTP nick and labeling (TUNEL). Retinal NAD+/NADH levels were enzymatically assayed. Results: The retinal degeneration models exhibited significantly suppressed retinal function, and where examined, severely disrupted photoreceptor cell layer and significantly decreased numbers of nuclei and increased accumulation of DNA breaks as measured by TUNEL-labeled cells in the outer nuclear layer (ONL). These effects were prevented by various NR treatment regimens. IP treatment with NR also resulted in increased levels of NAD+ in retina. Conclusions: This is the first study to report protective effects of NR treatment in mouse models of retinal degeneration. The positive outcomes in several models, coupled with human tolerance to NR dosing, suggest that maintaining retinal NAD+ via systemic NR treatment should be further explored for clinical relevance.

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