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Resveratrol Improves Motoneuron Function and Extends Survival in SOD1G93A ALS Mice

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Neurotherapeutics

Abstract

Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease that causes progressive paralysis and death due to degeneration of motoneurons in spinal cord, brainstem and motor cortex. Nowadays, there is no effective therapy and patients die 2–5 years after diagnosis. Resveratrol (trans-3,4′,5-trihydroxystilbene) is a natural polyphenol found in grapes, with promising neuroprotective effects since it induces expression and activation of several neuroprotective pathways involving Sirtuin1 and AMPK. The objective of this work was to assess the effect of resveratrol administration on SOD1G93A ALS mice. We determined the onset of symptoms by rotarod test and evaluated upper and lower motoneuron function using electrophysiological tests. We assessed the survival of the animals and determined the number of spinal motoneurons. Finally, we further investigated resveratrol mechanism of action by means of western blot and immunohistochemical analysis. Resveratrol treatment from 8 weeks of age significantly delayed disease onset and preserved lower and upper motoneuron function in female and male animals. Moreover, resveratrol significantly extended SOD1G93A mice lifespan and promoted survival of spinal motoneurons. Delayed resveratrol administration from 12 weeks of age also improved spinal motoneuron function preservation and survival. Further experiments revealed that resveratrol protective effects were associated with increased expression and activation of Sirtuin 1 and AMPK in the ventral spinal cord. Both mediators promoted normalization of the autophagic flux and, more importantly, increased mitochondrial biogenesis in the SOD1G93A spinal cord. Taken together, our findings suggest that resveratrol may represent a promising therapy for ALS.

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Acknowledgments

This work was supported by grants PI1001787 and PI111532, TERCEL and CIBERNED funds from the Fondo de Investigación Sanitaria of Spain, grant SAF2009-12495 from the Ministerio de Ciencia e Innovación of Spain, FEDER funds, and Action COST-B30 of the EC. We thank the technical help of Jessica Jaramillo and Marta Morell. RM is the recipient of a predoctoral fellowship from the Ministerio de Educación of Spain.

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The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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Authors and Affiliations

  1. Institute of Neurosciences and Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Spain

    Renzo Mancuso, Jaume del Valle, Laura Modol, Anna Martinez & Xavier Navarro

  2. Department of Experimental Medicine, Faculty of Medicine, Universitat de Lleida-IRBLleida, Lleida, Spain

    Ana B Granado-Serrano, Omar Ramirez-Núñez & Manel Portero-Otin

  3. Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Institut de Biomedicina (IBUB), Universitat de Barcelona, and CIBERNED, Barcelona, Spain

    Mercé Pallás

  4. Laboratory of Genetic Biochemistry (LAGENBIO-I3A), Aragon Institute of Health Sciences, Universidad de Zaragoza, Zaragoza, Spain

    Rosario Osta

  5. Unitat de Fisiologia Mèdica, Facultat de Medicina, Universitat Autònoma de Barcelona, E-08193, Bellaterra, Spain

    Xavier Navarro

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  1. Renzo Mancuso
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  2. Jaume del Valle
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  10. Xavier Navarro
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Correspondence to Xavier Navarro.

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Mancuso, R., del Valle, J., Modol, L. et al. Resveratrol Improves Motoneuron Function and Extends Survival in SOD1G93A ALS Mice. Neurotherapeutics 11, 419–432 (2014). https://doi.org/10.1007/s13311-013-0253-y

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