Nicotinamide treatment robustly protects from inherited mouse glaucoma

Abstract

Nicotinamide adenine dinucleotide (NAD) is a key molecule in several cellular processes and is essential for healthy mitochondrial metabolism. We recently reported that mitochondrial dysfunction is among the very first changes to occur within retinal ganglion cells during initiation of glaucoma in DBA/2J mice. Furthermore, we demonstrated that an age-dependent decline of NAD contributes to mitochondrial dysfunction and vulnerability to glaucoma. The decrease in NAD renders retinal ganglion cells vulnerable to a metabolic crisis following periods of high intraocular pressure. Treating mice with the NAD precursor nicotinamide (the amide form of vitamin B3) inhibited many age- and high intraocular pressure- dependent changes with the highest tested dose decreasing the likelihood of developing glaucoma by ∼10-fold. In this communication, we present further evidence of the neuroprotective effects of nicotinamide against glaucoma in mice, including its prevention of optic nerve excavation and axon loss as assessed by histologic analysis and axon counting. We also show analyses of age- and intraocular pressure- dependent changes in transcripts of NAD producing enzymes within retinal ganglion cells and that nicotinamide treatment prevents these transcriptomic changes.

Nicotinamide Deficiency in Primary Open-Angle Glaucoma

“…Further studies with larger cohorts are also required, as well as investigations in populations with various cultural dietary habits, to find out whether this deficiency is consistently associated with POAG and eventually with other forms of glaucoma. Finally, the convergence between recent studies showing that oral administration of nicotinamide prevents glaucoma in the DBA/2J mouse model 6,7,20 and our study on patients with POAG, opens promising therapeutic perspectives based on nicotinamide supplementation.…”

“…Mitochondrial dysfunctions and decreased NAD content are hallmarks of aging in most organs 13,14 and many experimental studies, essentially performed on mouse models, have revealed that strategies based on NAD repletion effectively reverse age-related phenotypes and disorders 15,16 , such as those affecting the skeletal muscles 17 , the brain 18 , and the endothelium 19 . Recent studies on the DBA/2J mouse model of glaucoma, have further confirmed a dose-dependent protective effect of NAD repletion on the optic nerve, reaching a protection level of 93% at the highest nicotinamide dose tested (2000 mg/kg/day), despite a continuously elevated IOP 6,7,20 . More importantly, the age-dependent vulnerability of the RGCs in these mice is correlated with the decreased concentration of NAD in the retina.…”

Catalyst‐Substrate Effects on Biocompatible SABRE Hyperpolarization

“…d 2 ‐Nam has previously been shown to give 4.1 % 1 H polarisation using [IrCl(COD)(IMes)] in [D4]methanol under 3 bar p ‐H 2 . Nicotinamide has been previously used at high doses in humans whilst a more recent in vivo study of inherited mouse glaucoma showed potential neuroprotective effects . In this study, we prepared a sample containing [IrCl(COD)(IMes)] (5 m m ), d 2 ‐Nam (20 m m ) in 30 % [D6]ethanol in D 2 O and exposed it to 3 bar p ‐H 2 in a 65 G polarization transfer field.…”

“…Despite limited cell death being observed with this substrate, we would not envisage in vivo administration of the SABRE reaction mixture without first reducing the iridium content to below recommended exposure limits. [32] When [IrCl (COD)(d 22 -IMes)] was used as the catalyst, exposing the sample containing d 2 -Nam to p-H 2 in a 65 G polarization transfer field gave a 606-fold signal gain in the biocompatible solvent mixture. Upon replacing the IMes ligand with a caffeine derivative, the cytotoxicity profile did not change.…”

“…This is due to heavy metal exposure, which for iridium has a parenteral permitted daily exposure limit in humans of 10 mg/day. [32] If a nominal, 1 g dosage of the contrast agent is used, this equates to a maximum 10 ppm iridium concentration in a single bolus. A number of methods for depleting the iridium content in solution have been reported, including bi-phasic catalysis, [28] ion-exchange chromatography [26] and solid phase scavengers.…”