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.

Mitochondrial Dysfunctions: A Red Thread across Neurodegenerative Diseases

“…As previously mentioned, ROS are produced by mitochondria both in physiological and pathological conditions [149] and can be responsible for onset and progression of many neurodegenerative diseases [150,151]. Furthermore, as discussed above, one of the major events related to neurodegenerative diseases, driven by the redox status, is microglial activation-derived neuroinflammation [152]: the induction of the expression of proinflammatory genes leading to the release of cytokines and chemokines can represent a consequence of the uncontrolled ROS production by mitochondria.…”

“…Finally, as reviewed by Reiter et al [176], melatonin is able to counteract oxidative stress not only directly interacting with free radicals [177], but also by stimulating antioxidant enzymes and upregulating GSH synthesis, through an indirect pathway. For these reasons, its use in the treatment of neurodegenerative diseases has been proposed: in vitro it exerted an antiapoptotic activity and in vivo it improved behavioral and cognitive functions and extended the lifespan of AD and ALS mice and rats [151,[178][179][180][181]; furthermore, it enhanced locomotor performances in PD mouse models [182]. Otherwise, meta-analysis and clinical trials on AD and PD patients revealed only an improvement in sleep quality without any ameliorations in terms of cognitive or motor functions and clinical trials testing melatonin in a specific range dose to establish its neuroprotective activity are needed [181][182][183].…”

“…Despite these encouraging outcomes in preclinical stages, further clinical trials are needed to investigate the real effects of Vitamin E supplementation in AD in order to consider all the factors that can influence patients' responsiveness [196]. Even in ALS, Vitamin E intake is debated because the positive outcomes obtained in preclinical trials on ALS onset and progression cannot always be translated to patients [151,197].…”

“…Vitamin E ALS Preclinical in vivo PMID: 8967745 [197] Vit.E determines ALS delay onset and slows its progression Clinical trials information is collected in the following work PMC7016185 [151] Several clinical studies have shown conflicting outcomes in slowing ALS onset and progression, but further studies are needed…”

“…As exhaustively explained by Carrera-Juliá et al [151], NAD+ is a compound involved in many metabolic pathways that are related to neuroprotection and, in turn, its intake could be considered a promising approach to treatment of neurodegenerative diseases. Indeed, acting in glycolysis, Krebs cycle, and oxidative phosphorylation, it can contribute to preserve cognitive functions, representing a promising compound for AD treatment [139,207].…”