Nicotinamide and WLDS Act Together to Prevent Neurodegeneration in Glaucoma

Abstract

Glaucoma is a complex neurodegenerative disease characterized by progressive visual dysfunction leading to vision loss. Retinal ganglion cells are the primary affected neuronal population, with a critical insult damaging their axons in the optic nerve head. This insult is typically secondary to harmfully high levels of intraocular pressure (IOP). We have previously determined that early mitochondrial abnormalities within retinal ganglion cells lead to neuronal dysfunction, with age-related declines in NAD (NAD+ and NADH) rendering retinal ganglion cell mitochondria vulnerable to IOP-dependent stresses. The Wallerian degeneration slow allele, WldS, decreases the vulnerability of retinal ganglion cells in eyes with elevated IOP, but the exact mechanism(s) of protection from glaucoma are not determined. Here, we demonstrate that WldS increases retinal NAD levels. Coupled with nicotinamide administration (an NAD precursor), it robustly protects from glaucomatous neurodegeneration in a mouse model of glaucoma (94% of eyes having no glaucoma, more than WldS or nicotinamide alone). Importantly, nicotinamide and WldS protect somal, synaptic, and axonal compartments, prevent loss of anterograde axoplasmic transport, and protect from visual dysfunction as assessed by pattern electroretinogram. Boosting NAD production generally benefits major compartments of retinal ganglion cells, and may be of value in other complex, age-related, axonopathies where multiple neuronal compartments are ultimately affected.

Glaucoma as a Metabolic Optic Neuropathy: Making the Case for Nicotinamide Treatment in Glaucoma

“…D2 mice with the Wld S allele were protected from glaucoma to a similar degree as mice with nicotinamide treatment alone (~70% of eyes not developing glaucoma) 24 . We also tested the effect of combining both enzyme and precursor ( i.e.…”

“…WLD S plus nicotinamide). This robustly prevented development of glaucoma more than either treatment alone (94% of eyes not developing glaucoma) 24 . Importantly, these treatments protected from RGC synapse loss and prevented dendrite pruning out to the oldest ages tested 24, 29 .…”

“…This robustly prevented development of glaucoma more than either treatment alone (94% of eyes not developing glaucoma) 24 . Importantly, these treatments protected from RGC synapse loss and prevented dendrite pruning out to the oldest ages tested 24, 29 . Although further experiments with a variety of animal models are needed to assess how widespread and robust such NAD based protection may be in glaucoma, we also demonstrated protection against two experimentally induced models of RGC death and protection has been shown in other models by other groups 23 .…”

“…1). This treatment protected all assessed RGC compartments including the axon, soma, and synapses 23, 24 . Additionally, it protected from declines in the very early and sensitive measures of RGC dysfunction; PERG and axoplasmic transport.…”

“…Therapies to increase NAD levels and improve metabolic reliability under stress may be effective against glaucoma 23, 24, 29, 58 . Thus, the administration of NAD precursors offers promise for improving glaucoma prevention and care.…”