Antioxidant Alternatives in the Treatment of Amyotrophic Lateral Sclerosis: A Comprehensive Review

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that produces a selective loss of the motor neurons of the spinal cord, brain stem and motor cortex. Oxidative stress (OS) associated with mitochondrial dysfunction and the deterioration of the electron transport chain has been shown to be a factor that contributes to neurodegeneration and plays a potential role in the pathogenesis of ALS. The regions of the central nervous system affected have high levels of reactive oxygen species (ROS) and reduced antioxidant defenses. Scientific studies propose treatment with antioxidants to combat the characteristic OS and the regeneration of nicotinamide adenine dinucleotide (NAD⁺) levels by the use of precursors. This review examines the possible roles of nicotinamide riboside and pterostilbene as therapeutic strategies in ALS.

Keywords: amyotrophic lateral sclerosis; mitochondrial dysfunction; neurodegenerative diseases; nicotinamide riboside; oxidative stress; pterostilbene.

FIGURE 1

Physiopathogenesis of ALS. Oxidative stress is caused by an imbalance between antioxidant defenses and RONS in favor of these second ones. The endogenous production of ROS is secondary to different prooxidant agents: mitochondrial and cytochrome p-450 metabolism, prostaglandins synthesis, phagocytosis, NADPH oxidases, XO, LOX and COX. Among the endogenous sources of RNS it should be noted the activity of epithelial, neuronal and inducible NOS. Exogenous sources also can produce RONS: stress, tobacco, UV-light, pesticides, environmental pollution and malnutrition. OS affects the normal functioning of the ETC, producing mitochondrial dysfunction that generates more ROS, which leads to a “vicious-cycle” that increases metabolic stress. This situation characterizes neurodegenerative diseases such as: ALS, AD, PD, MS, HD, and SA. In the case of ALS, OS and mitochondrial dysfunction have been identified as two mechanisms involved in its pathogenesis. They are related to neuroinflammation, aggregation of TDP-43, mutations in the mtDNA that produce characteristic OS biomarkers such as 8-OHdG, aggregation of SOD1 which impairs energy metabolism and cellular respiration, affectation of ATP supply to neurons and disturbance of the intracellular calcium homeostasis that results in excitotoxicity. The formation of highly reactive end products such as MDA and 4-HNE, both secondary to the lipoperoxidation of the neuronal membranes, is also observed.

FIGURE 2

Nicotinamide riboside action mechanism. NR gets into the cell and there, it is converted into NAD⁺ through two mechanisms. One of them is Nrk1 and Nrk2 and the other is PNP and NAMPT. NAD⁺ is a cosubstrate of PARPS which is related to repair of DNA damage by ROS. NAD⁺ is also SIRT cosubstrate which is associated with energy metabolism, inflammation regulation, DNA repair and mitochondrial metabolism. The activation of SIRT increases the resistance against OS through an increase in metabolic pathways that detoxify ROS, like SOD2 and Cat. SIRT1 activates PGC-1α which involves an increase of antioxidant defense through SOD2 and GSH. SIRT3 activates SOD2 and Cat. Thus, SIRT regulates mitochondrial function and aging processes as well as is involved in ROS detoxification.

FIGURE 3

Pterostilbene properties and action mechanism. The antioxidant mechanism of Pter is associated with Cat, GSH, SOD, Nrf2 and SIRT1 pathways, which leads to an inhibition of the oxidation and lipoperoxidation processes, decreasing the levels of MDA, HNE, 8-OHdG and carbonilated proteins. Its action on NF-kß involves an anti-inflammatory effect due to the decrease in the levels of TNF-α and interleukins such as IL-1β, IL-6 and IL-18. Its role on NF-kß, LPS and PPAR-α mediates the cognitive function of Pter, which is expressed through cognition modulation, inhibition of microglia activation and protection against neuronal damage. In addition, Pter presents protection against excitotoxicity due to the increase in cellular restoration and the reduction of the recovery time after cellular depolarization.