In the news: Vitamin B3 Prevents Disease In Mouse Model of Glaucoma

RGCs More Vulnerable to Damage with Age

Glaucoma is characterized by the progressive dysfunction and loss of retinal ganglion cells (RGCs). High intraocular pressure (IOP) and increasing age are important risk factors for glaucoma. However, specific mechanisms that render retinal ganglion cells (RGCs) more vulnerable to damage with age are unknown.

A research team led by Simon W.M. John of the Jackson Laboratory set out to identify key age-related susceptibility factors that change with age and increase vulnerability to neuronal disease. The team used DBA/2J (D2) mice, a widely used model of chronic age-related inherited glaucoma, and age, sex, and strain-matched D2-Gpnmb+ mice (which do not develop high IOP or glaucoma) as controls to address how increasing age and high IOP interact to drive neurodegeneration.

The findings, published in the journal Science (1), could lead to vitamin B3 therapy in glaucoma and potentially other age-related neuronal diseases.

NAD+ & Mitochondrial Function in Aging RGCs

Conducting a variety of elegantly designed genomic, metabolic, neurobiological, and other experiments, the researchers found that mitochondrial disturbances are among the very first changes occurring within RGCs during glaucoma.

They next assessed metabolites in retinas of the D2 and control mice as they aged and as the disease developed. They detected early decreases in the levels of a molecule central to cellular energy metabolism, niacinamide adenine dinucleotide (NAD+), as well as antioxidant enzyme glutathione.

According to the researchers, the data supported a model of age-dependent declines of total NAD and glutathione in the retina, making RGCs vulnerable to damage from elevated IOP. Theorizing that increasing NAD+ levels would allow the RGCs to better resist IOP-induced stress, the team administered oral vitamin B3 (niacinamide, a precursor of NAD+) to D2 mice.

Vitamin B3 Increases NAD, Prevents Disease

Oral administration of vitamin B3 prevented the decline of NAD+ levels up to 12 months of age (a standard end stage for assessing neurodegeneration in this model of glaucoma). Electron microscopy revealed that vitamin B3 administration inhibited the formation of dysfunctional mitochondria. Vitamin B3 also limited the synapse loss that occurs in this model; less perturbed cellular metabolism was also seen (decreased PARP activation, decreased levels of DNA damage, and transcriptional induction of HIF 1-alpha).

Administration of a 3.6 fold higher dose of vitamin B was observed to be extremely protective: 93% of treated eyes did not develop glaucoma and had no optic nerve damage. “The degree of protection afforded by administering this single molecule is unprecedented and unanticipated,” the authors stated.

In further experiments, it was also determined that single gene therapy (driving expression of Nmnat1, a key NAD+-producing enzyme) was protective both prophylactically and as a treatment in the D2 model.

Future, Current Research with Vitamin B3

The authors indicate that they plan to evaluate the effect of vitamin B3 in glaucoma patients, which would likely entail testing high doses. There are two forms of vitamin B3: niacinamide (nicotinamide), and nicotinic acid (niacin). While nicotinic acid causes vasodilatory side effects such as headache, flushing and hypo-tension, niacinamide lacks these adverse effects.

A recent phase III study (2) found that a high daily dose of vitamin B3 safely reduced the risk for recurrence of non-melanoma skin cancers. Niacinamide (NAD precursor) replenishes ATP levels in human keratinocytes after UV exposure, an effect thought to be a key mechanism by which the vitamin enhances DNA repair and reduces skin cancer risk.

References

1. Williams PA, et al. Vitamin B3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice. Science; 355(6326):756-60, Feb 17, 2017.
2. Chen AC, Martin AJ, Choy B, et al. A phase 3 randomized trial of nicotinamide for skin cancer chemoprevention. NEJM; 373:1618-26, 2015.