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.

Glaucoma and age-related macular degeneration are leading causes of irreversible blindness worldwide with significant health and societal burdens. To date, no clinical cures are available and treatments target only the manageable symptoms and risk factors (but do not remediate the underlying pathology of the disease). Both diseases are neurodegenerative in their pathology of the retina and as such many of the events that trigger cell dysfunction, degeneration, and eventual loss are due to mitochondrial dysfunction, inflammation, and oxidative stress. Here, we critically review how a decreased bioavailability of nicotinamide adenine dinucleotide (NAD; a crucial metabolite in healthy and disease states) may underpin many of these aberrant mechanisms. We propose how exogenous sources of NAD may become a therapeutic standard for the treatment of these conditions.

Nutraceuticals had always been known for their therapeutic effects in ancient medicine and had been the primary healing remedy until the introduction of modern chemistry and pharmacology. However, their use has not been dismissed but actually is acquiring a new acclamation among the scientific community especially for their efficacy on the Central Nervous System (CNS). Molecular mechanisms of the most common neurodegenerative diseases are now being uncovered and along with that the molecules that drive the neurodegenerative processes. It is not surprising that some natural compounds can interact with those molecules and interfere with the pathological pathways halting the cascades that ultimately lead to neuronal cell death. The plant Ruta graveolens has gained increased attention in medicinal chemistry due to its beneficial role to treat a variety of human diseases and also because of the presence of a huge number of compounds belonging to different classes of natural products, including neuroactive compounds potentially able to promote neuroprotection. Among all the components of the plant extract, rutin – which is highly, if not the most, abundant – positively interacts with the neurophysiology of the CNS too, being particularly efficient against neurotoxicity. Rutin, has proven to be protective in a variety of experimental settings of neurodegeneration. Finally, it has been shown that the water extract of Ruta graveolens (RGWE) induces death of glioblastoma cells but not of neuronal cells. Moreover, it also fosters cell cycle re-entry and differentiation of neuronal cells. This peculiarity represents a promising tool to promote neural plasticity in pathological conditions.