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

Abstract

24Purpose: The retina is highly metabolically active, suggesting that metabolic 25 dysfunction could underlie many retinal degenerative diseases. Nicotinamide 26 adenine dinucleotide (NAD + ) is a cofactor and a co-substrate in several cellular 27 energetic metabolic pathways. Maintaining NAD + levels may be therapeutic in 28 retinal disease since retinal NAD + levels decline with age and during retinal 29 damage or degeneration. The purpose of this study was to investigate whether 30 systemic treatment with nicotinamide riboside (NR), a NAD + precursor, is 31 protective in disparate models of retinal damage or degeneration. 32 33 Methods: Three mouse models of retinal degeneration were tested: an albino 34 mouse model of light-induced retinal degeneration (LIRD) and two models of 35 retinitis pigmentosa (RP), including a mouse line deficient in interphotoreceptor 36 binding protein (IRBP) gene expression (IRBP KO), and a naturally-occuring 37 cGMP phosphodiesterase 6b mutant mouse model of RP (the Pde6b rd10 mouse). 38 Mice were intraperitoneally (IP) injected with PBS or NR at various times relative 39 to damage or degeneration onset. One to two weeks later, retinal function was 40 assessed by electroretinograms (ERGs) and retinal morphology was assessed 41 by optical coherence tomography (OCT). Afterwards, retina sections were H&E 42 stained for morphological analysis or by terminal deoxynucleiotidyl transferase 43 dUTP nick and labeling (TUNEL). Retinal NAD + /NADH levels were enzymatically 44 assayed. 45 46 3 Results: The retinal degeneration models exhibited significantly suppressed 47 retinal function, and where examined, severely disrupted photoreceptor cell layer 48 and significantly decreased numbers of nuclei and increased accumulation of 49 DNA breaks as measured by TUNEL-labeled cells in the outer nuclear layer 50 (ONL). These effects were prevented by various NR treatment regimens. IP 51 treatment with NR also resulted in increased levels of NAD + in retina. 52 53 Conclusions: This is the first study to report protective effects of NR treatment in 54 mouse models of retinal degeneration. The positive outcomes in several models, 55 coupled with human tolerance to NR dosing, suggest that maintaining retinal 56 NAD + via systemic NR treatment should be further explored for clinical relevance. 57 58 59 60 61 62 63 64 65 66 67 68 0.00039 0.00374 0.058 0.961 25.3 Flash intensity (cd s/m 2 ) Flash intensity (cd s/m 2 ) Flash intensity (cd*s/m 2 ) * * * * 0.00039 0.00374 0.058 0.961 25.3 Flash intensity (cd s/m 2 ) Flash intensity (cd s/m 2 )

Systemic Treatment with Nicotinamide Riboside Is Protective in Two Mouse Models of Retinal Ganglion Cell Damage

“…Prophylactic systemic treatment with NR, a NAD + precursor, is protective in several mouse models of neurodegenerative disease, including Alzheimer disease [ 56 ], Parkinson disease [ 57 ], and retinal degenerations [ 34 , 35 ]. We report here that systemic delivery of NR significantly increased NAD + levels in retinas of C57BL/6J and DBA/2J mice ( Figure 1 ), similar to findings we reported in BALB/c mice [ 34 , 35 ]. The difference between same-strain cohorts of levels of retinal NAD + is considerably different in the two strains, with an increase of ~17% for DBA/2J and an increase of ~205% for C57BL/6J mice.…”

“…Also, intravitreal injections of NR protected against RGC axon loss induced by TNF, possibly by upregulating kinases specific to NR biosynthesis and SIRT1-mediated autophagic flux [ 33 ]. In our previous work, prophylactic systemic treatment with NR provided significant protection in mouse models of retinal degeneration, including light-induced retinal degeneration [ 34 ] and several retinitis pigmentosa models [ 35 ]. However, the protective effects of NR treatment in glaucoma or RGC damage models have not been explored.…”

Integration of human stem cell-derived in vitro systems and mouse preclinical models identifies complex pathophysiologic mechanisms in retinal dystrophy

“…Since Dram2 loss causes a slow-progressing and mild retinal dystrophy in mice, we tested if the phenotype could be exacerbated by additional environmental stress. We selected three pre-clinical models commonly used to model AMD: 1) the laser-induced choroidal neovascularization (CNV) model (Lambert et al, 2013), 2) the sodium iodate model (NaIO 3 ), in which photoreceptor degeneration happens secondarily to RPE-specific toxicityinduced cell death (Balmer et al, 2015;Zhang et al, 2021) and 3) the constant light exposure model (CLE), in which phototoxicity directly causes photoreceptor death (Natoli et al, 2016), (Figure 5).…”

Systemic Treatment With Nicotinamide Riboside Is Protective in a Mouse Model of Light-Induced Retinal Degeneration

“…Some data presented here were presented in abstract form at the annual meeting of the Association for Research in Vision and Ophthalmology. 78 …”