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Nicotinamide adenine dinucleotide (NAD) is a REDOX cofactor and metabolite essential for neuronal survival. Glaucoma is a common neurodegenerative disease in which neuronal levels of NAD decline. Repleting NAD via dietary supplementation of nicotinamide (a precursor to NAD) is effective in preventing retinal ganglion cell neurodegeneration in mouse models. Supporting this, short-term oral nicotinamide treatment in human glaucoma patients provides a recovery of retinal ganglion cell function implying a protection of visual function. Despite this, the mechanism of neuroprotection and full effects of nicotinamide on retinal ganglion cells is unclear. Glaucoma is a complex neurodegenerative disease in which a mix of healthy, stressed, and degenerating retinal ganglion cells co-exist, and in which retinal ganglion cells display compartmentalized degeneration across their visual trajectory. Therefore, we assess the effects of nicotinamide on retinal ganglion cells in normal physiological conditions and across a range of glaucoma relevant insults. We confirm neuroprotection afforded by nicotinamide in rodent models which represent isolated ocular hypertensive, axon degenerative, and mitochondrial degenerative insults. We define a small molecular weight metabolome for the retina, optic nerve, and superior colliculus which demonstrates that ocular hypertension induces widespread metabolic disruption that can be prevented by nicotinamide. Nicotinamide provides these neuroprotective effects by increasing oxidative phosphorylation, buffering and preventing metabolic stress, and increasing mitochondrial size and motility whilst simultaneously dampening action potential firing frequency. These data support continued determination of the utility of long-term NAM treatment as a neuroprotective therapy for human glaucoma.

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Background: Glaucoma remains a leading cause of irreversible blindness worldwide. Multiple animal models show retinal ganglion cell injuries that replicate features of glaucoma. In these experiments the contralateral eye is commonly used as an internal control. As in humans, in rodents and non-human primates there is significant cross-over of retinal ganglion cell axons from the ipsilateral to the contralateral side at the level of the optic chiasm which may confound findings when damage is restricted to one eye. While neuroinflammation may be a critical event that damages retinal ganglion cells and their axons during glaucoma progression the effect of unilateral damage on the contralateral visual pathway has largely been unexplored.Methods: Ocular hypertensive glaucoma was induced unilaterally or bilaterally by intracameral injection of paramagnetic beads in adult Brown Norway rats. Retinal ganglion cell neurodegeneration and dysfunction were assessed. Neuroinflammation was quantified in the retina, optic nerve head, optic nerve, lateral geniculate nucleus, and superior colliculus by high resolution imaging, and in the retina by flow cytometry and protein arrays.Results: Following ocular hypertensive stress the retinal vasculature remodels, peripheral monocytes enter the retina, and microglia become highly reactive. This effect is more marked in animals with bilateral induction of ocular hypertensive glaucoma. In rats where glaucoma was induced unilaterally there was significant microglia activation in the contralateral (control) eye. Microglial activation extended into the optic nerve and terminal visual thalami, where it was similar across hemispheres irrespective of whether ocular hypertension was unilateral or bilateral. Conclusions:Ocular hypertensive glaucoma in the rat recapitulates many of the features of human glaucoma. In this model microglia become reactive throughout the visual pathway during glaucoma pathogenesis. These effects are not isolated to the experimental eye and its pathway and significant neuroinflammation occurs in the contralateral 'control' eye and pathway. These data suggest that caution is warranted when using the contralateral eye as control in unilateral models of glaucomatous damage.