cells Review Neuroprotection in Glaucoma: NAD + /NADH Redox State as a Potential Biomarker and Therapeutic Target Bledi Petriti 1,2 , Pete A. Williams 3 , Gerassimos Lascaratos 4 , Kai-Yin Chau 2 and David F. Garway-Heath 1, *   Citation: Petriti, B.; Williams, P.A.; Lascaratos, G.; Chau, K.-Y.; Garway-Heath, D.F. Neuroprotection in Glaucoma: NAD + /NADH Redox State as a Potential Biomarker and Therapeutic Target. Cells 2021, 10, 1402. https://doi.org/10.3390/ cells10061402 Academic Editors: Stanislav I. Tomarev and Ben Mead Received: 30 April 2021 Accepted: 27 May 2021 Published: 5 June 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 NIHR Biomedical Research Centre, Moorfields Eye Hospital and UCL Institute of Ophthalmology, London EC1V 9EL, UK; b.petriti@ucl.ac.uk 2 Department of Clinical & Movement Neurosciences, UCL Queens Square Institute of Neurology, London NW3 2PF, UK; k.chau@ucl.ac.uk 3 Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital, Karolinska Institutet, 171 64 Stockholm, Sweden; Pete.williams@ki.se 4 King’s College Hospital NHS Foundation Trust, London and King’s College London, London SE5 9RS, UK; gerassimos.lascaratos@nhs.net * Correspondence: d.garwayheath@nhs.net 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. Keywords: glaucoma; mitochondrial dysfunction; retinal ganglion cell (RGC); nicotinamide adenine dinucleotide (NAD + ); NAD + /NADH redox state; ATP; neurodegenerative disease 1. Introduction Glaucoma is one of the most common neurodegenerative diseases and the leading cause of irreversible blindness worldwide. Its prevalence increases with age and affects ~80 million people worldwide, with primary open–angle glaucoma (POAG) being the most frequent form. Due to the rapid increase in ageing populations worldwide, it is estimated that the number affected will increase to 111.8 million in 2040 [1]. The number of hospital related glaucoma visits surpasses one million per year in England and Wales alone, putting a significant strain on health services [2]. The disease is often associated with fear of vision loss, consequent social withdrawal, and depression from impaired vision causing a significant psychological burden to the patient as vision decreases [3]. Thus, glaucoma is a significant social and economic burden. This underlines the need to prioritise research in this area and to develop new treatments for glaucoma. Progressive neurodegeneration of retinal ganglion cells (RGCs; the output neurons of the retina) and their axons, which make up the optic nerve, is the hallmark of glaucoma. The optic nerve is particularly sensitive to mitochondrial dysfunction and bioenergetic Cells 2021, 10, 1402. https://doi.org/10.3390/cells10061402 https://www.mdpi.com/journal/cells