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

Abstract

Glaucoma etiology often includes retinal ganglion cell (RGC) death associated with elevated intraocular pressure (IOP). However, even when IOP is managed well, disease can progress. It is thus important to develop therapeutic approaches that directly protect RGCs in an IOP-independent manner. Compromised nicotinamide adenine dinucleotide (NAD+) metabolism occurs in neurodegenerative diseases, including models of glaucoma. Here we report testing the protective effects of prophylactically systemically administered nicotinamide riboside (NR), a NAD+ precursor, in a mouse model of acute RGC damage (optic nerve crush (ONC)), and in a chronic model of RGC degeneration (ocular hypertension induced by intracameral injection of microbeads). For both models, treatment enhanced RGC survival, assessed by counting cells in retinal flatmounts immunostained for Brn3a+. In the ONC model, treatment preserved RGC function, as assessed by pattern electroretinogram, and suppressed retinal inflammation, as assessed by immunofluorescence staining of retinal fixed sections for glial fibrillary acidic protein (GFAP). This is the first study to demonstrate that systemic treatment with NR is protective in acute and chronic models of RGC damage. The protection is significant and, considering that NR is highly bioavailable in and well-tolerated by humans, may support the proposition of prospective human subject studies.

From bench to behaviour: The role of lifestyle factors on intraocular pressure, neuroprotection, and disease progression in glaucoma

“…Together, these factors resulted in a decreased loss of retinal ganglion cell number and function 48–51 . This finding was consistent across animal models including optic nerve crush and chronic ocular hypertension 52 . However, overexpression and direct introduction of nicotinamide are not the only ways to achieve neuroprotection; Chou and colleagues proved that simply a diet rich in Vitamin B3 led to increased pattern electoretinogram (PERG) adaptation (an amplitude‐based test of RGC function) and retinal ganglion cell number in glaucomatous mice 53 …”

“…[48][49][50][51] This finding was consistent across animal models including optic nerve crush and chronic ocular hypertension. 52 However, overexpression and direct introduction of nicotinamide are not the only ways to achieve neuroprotection; Chou and colleagues proved that simply a diet rich in Vitamin B3 led to increased pattern electoretinogram (PERG) adaptation (an amplitude-based test of RGC function) and retinal ganglion cell number in glaucomatous mice. 53 In human open-angle glaucoma populations, these findings were translated as a potential therapeutic in randomised clinical trials, where nicotinamide was found to improve short-term retinal function.…”

The use of Nicotinamide and Nicotinamide riboside as an adjunct therapy in the treatment of glaucoma

“…Additionally, NR presented better pharmacokinetic and pharmacological properties. 32,68,69 A study conducted in both healthy human volunteers and mice reported that an NR dose of 1000 mg twice daily (2000 mg in total) can significantly increase blood levels of NAD + (up to 2.7 fold after one dose) and that single doses of 100, 300 and 1,000 mg of NR produce dosedependent increases in blood levels of NAD. 70 The use of NR is being evaluated in pre-clinical studies, in various areas, such as diabetic neuropathy and liver steatosis associated with diabetes 71 and insulin sensitivity.…”

“…31 Experimental studies have shown that the use of these nutraceuticals may induce a protective effect on the RGCs, independent of IOP control. 32,33 Clinical trials evaluating NR and NAM supplementation have shown a slight improvement in the visual function of some glaucomatous patients. 34 Furthermore, a recent report evaluating the publicly available data from the 2005 to 2008 National Health and Nutrition Examination Survey (NHANES), showed that the odds of having glaucoma were lower when the consumption of vitamin B3 was higher.…”

New strategies for neuro protection in glaucoma

“…In animal models of glaucoma, various diet-related treatments were found as non-IOP-related neuroprotective mechanisms. High VitK1 intake ( Deng et al, 2020 ) , Coenzyme Q10 + Vitamin E ( Zhang et al, 2017 ; Ekicier Acar et al, 2020 ), Nicotinamide riboside of the vitamin B3 family ( Zhang X. et al, 2021 ), probiotic bacteria ( Fafure et al, 2021 ) and other dietary supplementation ( Cammalleri et al, 2020 ) were proved to attenuate the loss of RGCs by regulating glia-mediated neuroinflammatory or BDNF activity, etc.…”