Neuroprotection in Glaucoma: NAD+/NADH Redox State as a Potential Biomarker and Therapeutic Target

Abstract

Glaucoma is the leading cause of irreversible blindness worldwide. Its prevalence and incidence increase exponentially with age and the level of intraocular pressure (IOP). IOP reduction is currently the only therapeutic modality shown to slow glaucoma progression. However, patients still lose vision despite best treatment, suggesting that other factors confer susceptibility. Several studies indicate that mitochondrial function may underlie both susceptibility and resistance to developing glaucoma. Mitochondria meet high energy demand, in the form of ATP, that is required for the maintenance of optimum retinal ganglion cell (RGC) function. Reduced nicotinamide adenine dinucleotide (NAD+) levels have been closely correlated to mitochondrial dysfunction and have been implicated in several neurodegenerative diseases including glaucoma. NAD+ is at the centre of various metabolic reactions culminating in ATP production—essential for RGC function. In this review we present various pathways that influence the NAD+(H) redox state, affecting mitochondrial function and making RGCs susceptible to degeneration. Such disruptions of the NAD+(H) redox state are generalised and not solely induced in RGCs because of high IOP. This places the NAD+(H) redox state as a potential systemic biomarker for glaucoma susceptibility and progression; a hypothesis which may be tested in clinical trials and then translated to clinical practice.

Therapeutic Significance of microRNA-Mediated Regulation of PARP-1 in SARS-CoV-2 Infection

“…Based on these observations, we postulate that deficiency of NAD+ due to increased PARP activation may be a key factor related to the SARS-CoV-2 associated disease spectrum. Oxidative stress induces PARP1, whose hyper activation depletes NAD+ and ATP levels, culminating in energy loss and subsequent cell death [49][50][51]. Overall, these processes enhance pro-inflammatory signaling.…”

The Causal Association Between Obesity and Primary Open-Angle Glaucoma: A Two-Sample Mendelian Randomization Study

“…Glaucoma is a leading cause of irreversible blindness worldwide and is mostly characterized by the progressive loss of retinal ganglion cells and their axons ( Chang and Goldberg, 2012 ). Among them, primary open-angle glaucoma (POAG) is the most common type of glaucoma, affecting nearly 80 million people worldwide ( Petriti et al, 2021 ). At present, its pathogenesis has not been fully elucidated, but it is well known that multifactorial events are involved in the development of POAG ( Lichter, 2003 ; Jonas et al, 2017 ).…”

The Role of Axonal Transport in Glaucoma

“…Supplying metabolic substrates is protective to axonal degeneration in glaucoma models, as shown after induction of hyperglycemia in rats [ 156 ]. NAD+/NADH are cofactors central to several metabolic pathways for ATP production, and also to cell signaling [ 157 , 158 ]. Alterations in NAD metabolism are associated to neurodegenerative diseases, and NAD+ supplementation was neuroprotective in different neurodegenerative contexts, including models of Parkinson’s disease, Alzheimer’s disease, and glaucoma [ 158 , 159 , 160 ].…”

“…NAD+/NADH are cofactors central to several metabolic pathways for ATP production, and also to cell signaling [ 157 , 158 ]. Alterations in NAD metabolism are associated to neurodegenerative diseases, and NAD+ supplementation was neuroprotective in different neurodegenerative contexts, including models of Parkinson’s disease, Alzheimer’s disease, and glaucoma [ 158 , 159 , 160 ]. Nicotinamide, a precursor of NAD+, was protective in the glaucoma model of microbead injection and after optic nerve axotomy [ 155 , 161 , 162 ].…”