Oral supplementary nicotinamide riboside treats several components of the DBA/2J murine model of pigment dispersion glaucoma

Abstract

Purpose : To test whether oral administration of nicotinamide riboside (NR), a nicotinamide adenine dinucleotide ( NAD⁺) precursor, protects retina ganglion cells (RGCs) against neurodegeneration in the DBA/2J (D2) mouse model of age-related inherited pigment dispersion glaucoma.

Methods : NR administration in drinking water and food (4000mg/kg of body weight per day) started when DBA/2J mice were 4 months old and continued until 12 months old. Control cohort identically received vehicle water and food with no added NR. Intraocular pressure (IOP) was measured every month until experiment completion. Pattern electroretinography (PERG) was recorded at 4, 6, 9 and 12 months old using a Celeris system (Diagnosys LLC, MA). Retinas were harvested for whole mount immunofluorescence staining with RGC marker Brn3a and imaged by fluorescent confocal microscopy. Retinal NAD⁺ levels were enzymatically assayed (Abcam, CA). Iris depigmentation degree was assessed by transillumination pattern assay.

Results : The retina NAD⁺ level of NR-treated aged D2 mice was significantly higher than untreated aged mice (220±21.5% vs 108±5.9% of young naïve D2 retina NAD⁺ level, N=6-8, p<0.05). Brn3a-positive immunofluorescent cell counts were significantly higher in NR-treated aged D2 mice compared with untreated ones (1412±248 cells per field vs 475±378 cells per field, N=20, p<0.05). PERG P1 and N2 amplitudes were significantly higher from NR group than vehicle group (P1: 2.89±0.27uV vs 1.37±0.12uV, N=40, p<0.05; N2: (-5.85±0.5uV vs -3.11±0.24uV, N=40, p<0.05). The degree of iris atrophy in NR group was much less severe compared with vehicle group.(Fig.1)
The IOP in NR group was modestly but significantly lower than vehicle group when DBA/2J mice were 7, 8 and 9 months old; there was no significant difference at other time points.

Conclusions : NR oral supplementation significantly preserved RGC numbers and retina function in aging D2 mice. Interestingly, treatment also prevented iris atrophy, delayed IOP elevation associated with this glaucoma model, and elevated retinal NAD+ levels. NR oral supplementation thus treated several aspects of murine pigment dispersion glaucoma. Given parallels between this model and glaucoma in humans, our data indicate that NR is worth exploring as a therapeutic candidate in treatment of glaucoma.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.