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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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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.
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.
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.
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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