Nicotinamide Riboside and Pterostilbene Cooperatively Delay Motor Neuron Failure in ALS SOD1 G93A Mice
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Nicotinamide Riboside and Pterostilbene Cooperatively Delay Motor Neuron Failure in ALS SOD1G93A Mice Elena Obrador 1 & Rosario Salvador 1 & Patricia Marchio 1 & Rafael López-Blanch 1 & Ali Jihad-Jebbar 1 & Pilar Rivera 1 & Soraya L. Vallés 1 & Salvador Banacloche 1 & Javier Alcácer 2 & Nuria Colomer 2 & Javier A. Coronado 2 & Sandra Alandes 2 & Eraci Drehmer 3 & María Benlloch 3 & José M. Estrela 1 Received: 29 July 2020 / Accepted: 27 October 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Oxidative stress-induced damage is a major mechanism in the pathophysiology of amyotrophic lateral sclerosis (ALS). A recent human clinical trial showed that the combination of nicotinamide riboside (NR) and pterostilbene (PT), molecules with potential to interfere in that mechanism, was efficacious in ALS patients. We examined the effect of these molecules in SOD1G93A transgenic mice, a well-stablished model of ALS. Assessment of neuromotor activity and coordination was correlated with histopathology, and measurement of proinflammatory cytokines in the cerebrospinal fluid. Cell death, Nrf2- and redoxdependent enzymes and metabolites, and sirtuin activities were studied in isolated motor neurons. NR and PT increased survival and ameliorated ALS-associated loss of neuromotor functions in SOD1G93A transgenic mice. NR and PT also decreased the microgliosis and astrogliosis associated with ALS progression. Increased levels of proinflammatory cytokines were observed in the cerebrospinal fluid of mice and humans with ALS. NR and PT ameliorated TNFα-induced oxidative stress and motor neuron death in vitro. Our results support the involvement of oxidative stress, specific Nrf2-dependent antioxidant defenses, and sirtuins in the pathophysiology of ALS. NR and PT interfere with the mechanisms leading to the release of proapoptotic molecular signals by mitochondria, and also promote mitophagy. Keywords Amyotrophic lateral sclerosis . Motor neuron . SOD1G93A . Oxidative stress . Neuroinflammation . Nicotinamide riboside . Pterostilbene . Antioxidant defenses . Glutathione . Sirtuins
* José M. Estrela [email protected]
Javier Alcácer [email protected]
Elena Obrador [email protected]
Nuria Colomer [email protected]
Rosario Salvador [email protected]
Javier A. Coronado [email protected]
Patricia Marchio [email protected]
Sandra Alandes [email protected]
Rafael López-Blanch [email protected]
Eraci Drehmer [email protected]
Ali Jihad-Jebbar [email protected] Pilar Rivera [email protected] Soraya L. Vallés [email protected] Salvador Banacloche [email protected]
María Benlloch [email protected] 1
Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 15 Av. Blasco Ibañez, 46010 Valencia, Spain
2
Pathology Laboratory, Quirón Hospital, 46010 Valencia, Spain
3
Department of Health and Functional Valorization, Catholic University of San Vicente Martir, 46001 Valencia, Spain
Mol Neurobiol
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