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NAD+ Precursors and Antioxidants for the Treatment of Amyotrophic Lateral Sclerosis

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NAD+ Precursors and Antioxidants for the Treatment of Amyotrophic Lateral Sclerosis biomedicines Review NAD+ Precursors and Antioxidants for the Treatment of Amyotrophic Lateral Sclerosis Elena Obrador 1 , Rosario Salvador-Palmer 1 , Rafael López-Blanch 1, Ryan W. Dellinger 2 and José M. Estrela 1,* 1 Department of Physiology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain; [email protected] (E.O.); [email protected] (R.S.-P.); [email protected] (R.L.-B.) 2 Elysium Health Inc., New York, NY 10013, USA; [email protected] * Correspondence: [email protected]; Tel.: +34-963-864-646 Abstract: Charcot first described amyotrophic lateral sclerosis (ALS) between 1865 and 1874 as a sporadic adult disease resulting from the idiopathic progressive degeneration of the motor neuronal system, resulting in rapid, progressive, and generalized muscle weakness and atrophy. There is no cure for ALS and no proven therapy to prevent it or reverse its course. There are two drugs specifically approved for the treatment of ALS, riluzol and edaravone, and many others have already been tested or are following clinical trials. However, at the present moment, we still cannot glimpse a true breakthrough in the treatment of this devastating disease. Nevertheless, our understanding of the pathophysiology of ALS is constantly growing. Based on this background, we know that oxidative stress, alterations in the NAD+-dependent metabolism and redox status, and abnormal mitochondrial dynamics and function in the motor neurons are at the core of the problem. Thus, different antioxidant molecules or NAD+ generators have been proposed for the therapy of ALS. This review analyzes Citation: Obrador, E.; these options not only in light of their use as individual molecules, but with special emphasis on Salvador-Palmer, R.; their potential association, and even as part of broader combined multi-therapies. López-Blanch, R.; Dellinger, R.W.; + Estrela, J.M. NAD+ Precursors and Keywords: amyotrophic lateral sclerosis; motor neurons; oxidative stress; NAD ; antioxidants Antioxidants for the Treatment of Amyotrophic Lateral Sclerosis. Biomedicines 2021, 9, 1000. https://doi.org/10.3390/ 1. Introduction biomedicines9081000 ALS, often referred to as “Lou Gehrig’s disease”, is a progressive neurodegenerative disease that damages motor neurons (MNs) in the brain and the spinal cord [1]. This loss of Academic Editor: Jacopo Meldolesi MNs is responsible for progressive weakness and paralysis. It is the third most prevalent neurodegenerative disease, after Alzheimer’s and Parkinson’s disease. It affects approxi- Received: 30 July 2021 mately 30,000 people in the U.S. and 450,000 worldwide [2]. ALS usually occurs in people Accepted: 10 August 2021 Published: 12 August 2021 over 50, although in a minority of cases it appears at younger ages. Men are slightly more likely to have ALS than women; however, as age increases, this difference disappears [3]. Publisher’s Note: MDPI stays neutral A recent study including approximately 3000 ALS patients concluded that the onset and with regard to jurisdictional claims in progression of ALS is characterized by a different susceptibility of motor cortex and lower published maps and institutional affil- MNs to the ALS-associated damage, and is influenced by age, sex, and gene variants [4]. iations. Although it is still considered a rare disease, approximately 20 people in the world are diagnosed with ALS every hour. Most cases of ALS (>90%) are considered sporadic (SALS), which means that the disease appears to occur randomly, without a clear family history of the disease. Only 5–10% of cases are associated with known genetic mutations (familial-type ALS, FALS) [1]. In patients with FALS, the symptoms usually appear earlier Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. (approximately 5 years) than in those diagnosed with SALS, a fact apparently related to This article is an open access article Mendelian gene variants lowering the age of onset [5]. The mean survival from the first distributed under the terms and symptom is 3–5 years, although approximately 10% of patients live longer than 10 years [6]. conditions of the Creative Commons The reasons for this exceptional survival remain poorly understood. Attribution (CC BY) license (https:// Despite recent advances in the understanding of ALS, respiratory and nutritional creativecommons.org/licenses/by/ interventions remain the treatments showing the highest efficacy in extending the patient’s 4.0/). survival. ALS has no effective treatment or cure to date [7]. Biomedicines 2021, 9, 1000. https://doi.org/10.3390/biomedicines9081000 https://www.mdpi.com/journal/biomedicines Biomedicines 2021, 9, 1000 2 of 13 There is mounting evidence involving oxidative stress as a main pathophysiological mechanism leading to MN damage and death [8]. Conceptually, oxidative stress is an imbalance of oxygen-derived free radicals and antioxidants in the body, which can lead to cell and organ damage [9]. Reactive oxygen species (ROS) contain an uneven number of electrons and, at high non-physiological levels, can cause oxidative damages to nucleic acids, lipids, and proteins [9]. Moreover, the generation of NO and H2O2 (induced by proinflammatory cytokines in e.g., endothelial cells) can lead to the formation of highly damaging –OONO radicals [10,11]. Antioxidants are molecules that can donate an electron to a free radical without making themselves unstable. Therefore, enhancers of our physi- ological antioxidant defenses or the administration of molecules with direct antioxidant activity are potential therapeutic strategies against ALS [12,13]. On the other hand, NAD+ is involved in cell bioenergetics, redox regulation, signaling, homeostasis, adaptive response to stress, and survival [14,15]. Specifically, different NAD+- dependent enzymes are implicated in mechanisms regulating synaptic plasticity [16,17] and neuronal resilience to stress [18,19]. Therefore, either the inhibition of NAD+ consuming enzymes or the supplementation with NAD+ precursors also appears to be potentially useful in the therapy of ALS [20,21]. Oxidative stress and alterations in redox status, bioenergetics, and NAD+ metabolism are clearly linked to the pathophysiology of ALS [8]. Thus, the aim of this review is to discuss the possibility of using both NAD+ promoters and antioxidants as complementary therapies to slow down the progression of MN damage. 2. NAD+ and Physiological Antioxidant Levels in ALS NAD+ is a coenzyme in redox reactions, a donor of ADP-ribose for ADP-ribosylation reactions, a precursor of cyclic ADP-ribose, and a substrate for sirtuins (SIRTs) that use the cofactor to remove acetyl groups from proteins. SIRTs link NAD+ levels to mitochondrial function, dynamics and biogenesis, and to cellular antioxidant defenses [8,22]. Interest- ingly, under the conditions of reduced cellular energy (as it occurs in the MNs during the progression of ALS), SIRTs may not consume sufficient NAD+ to preclude any cell survival-promoting effects of its deacetylase action on protein substrates [23]. For instance, poly(ADP-ribose) polymerase 1 (PARP1) is involved in DNA replication, transcription, DNA repair, apoptosis, and genome stability. However, DNA damage may overactivate PARP1 and lead to cell death and inflammation [24]. SIRT1 function (nucleus and cyto- plasm) can facilitate cell survival under stress conditions by the deacetylation-dependent deactivation of PARP1 [25]. However, SIRT1 also consumes NAD+. Thus, inducing an increase in SIRT levels and activity (at least above an undefined threshold) could be coun- terproductive to neuronal survival, particularly to those energetically compromised. As an example, the nicotinamide-induced inhibition of SIRT1 was shown to protect neurons from death under acute anoxic injury [26]. Moreover, in SIRT1 knockout mice, their brains showed low levels of oxidative stress-related markers (i.e., carbonylated proteins and isoprostanes) [27]. These facts suggest a delicate balance between SIRT1 activity and the survival of neurons subjected to stress-associated insults. Despite the controversial facts regarding the activity of SIRT1, it is widely accepted that the maintenance of high NAD+ levels promotes cell homeostasis and survival [28]. Consequently, the consumption of NAD+ without an adequate method of replenishment is deleterious for the cell physiology. In mammalian cells, NAD+ can be synthesized de novo from tryptophan (a multi-step enzymatic process which is fairly inefficient), or from nicotinic acid, nicotinamide (NAM), nicotinamide mononucleotide (NMN), or nicotinamide riboside (NR) [29,30]. For instance, it has been shown that NAM prevents NAD+ depletion and protects neurons against excitotoxicity and cerebral ischemia [31]. NR and NMN were shown to confer axonal protection in a Wallerian degeneration model of neuronal explant cultures [32]. Interest- ingly, the mechanism that neurons undergoing axonal degeneration use for protection is to upregulate the expression of nicotinamide riboside kinase (NRK) and nicotinamide mononucleotide adenylyl transferase 1 (NNMAT1), the enzymes required to convert NR Biomedicines 2021, 9, 1000 3 of 13 (or NMN) to NAD+ [32]. Further, NR rescues mitochondrial defects and neuronal loss in models of Parkinson’s diseases [33], or increasing cytosolic and mitochondrial NAD+ content in ALS astrocytes increases the oxidative stress resistance and reverts their toxicity towards MNs [34]. Furthermore, it has been shown that SARM1 (sterile α and TIR motif– containing 1) is a key factor in triggering
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