Abstract
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. We assess the effects of nicotinamide (a precursor to NAD) on retinal ganglion cells (the affected neuron in glaucoma) in normal physiological conditions and across a range of glaucoma relevant insults including mitochondrial stress and axon degenerative insults. We demonstrate retinal ganglion cell somal, axonal, and dendritic neuroprotection by nicotinamide in rodent models which represent isolated ocular hypertensive, axon degenerative, and mitochondrial degenerative insults. We performed metabolomics enriched for small molecular weight metabolites for the retina, optic nerve, and superior colliculus which demonstrates that ocular hypertension induces widespread metabolic disruption, including consistent changes to α-ketoglutaric acid, creatine/creatinine, homocysteine, and glycerophosphocholine. This metabolic disruption is prevented by nicotinamide. Nicotinamide provides further 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 nicotinamide treatment as a neuroprotective therapy for human glaucoma.
Highlights
Glaucoma is one of the most common neurodegenerative diseases, and the leading cause of irreversible blindness, affecting ~80 million people worldwide [1]
Nicotinamide is protective in a genetic mouse model (DBA/2J) that recapitulates features of a human pigmentary glaucoma and demon strates an age-related decline in retinal Nicotinamide adenine dinucleotide (NAD) [5]
To further determine how nicotinamide (NAM) protects retinal ganglion cells (RGCs), we induced RGC degeneration in two separate glaucoma relevant insults in the absence of an age related effect: elevated intraocular pressure (IOP) and optic nerve degeneration induced by axotomy
Summary
Glaucoma is one of the most common neurodegenerative diseases, and the leading cause of irreversible blindness, affecting ~80 million people worldwide [1]. Genetics, and elevated intraocular pressure (IOP) are major risk factors, but to date, the only clinically available therapies target the reduction of IOP. For the many patients which are refractory to IOP lowering treatments, surgical interventions are commonly used in order to limit the progressive neurodegeneration and visual impairment [2]. No therapy currently targets the neuronal pop ulation that degenerates in glaucoma. 42% of treated glau coma patients progress to blindness in at least one eye [3]. With an increasingly aged population, glaucoma will continue to be a significant health and economic burden and neuroprotective strategies tar geting the retina and optic nerve are of great therapeutic need
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