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Resveratrol improves motoneuron function and extends survival in SOD1G93A ALS mice

Resveratrol improves motoneuron function and extends survival in SOD1G93A ALS mice
Resveratrol improves motoneuron function and extends survival in SOD1G93A ALS mice
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 SOD1(G93A) 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 SOD1(G93A) 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 SOD1(G93A) spinal cord. Taken together, our findings suggest that resveratrol may represent a promising therapy for ALS
1933-7213
419-432
Mancuso, Renzo
05786562-a993-4e37-926e-3c1fcf50b36d
Del Valle, J.
95b7f785-63d1-4210-ab3e-3c0636570a05
Mòdol, L.
bad7ffd0-2311-4cb5-8bf8-34f394bc6f15
Martinez, A.
08e8e823-41fc-4ad0-b8e3-79d8823eb848
Granado-Serrano, A.B.
dd1e5afc-17df-48ed-92e1-b503064c39f2
Ramirez-Núñez, O.
bef9ddfc-a892-428a-b2bb-55b61af26404
Pallás, M.
894e972c-5fdb-4518-8422-cacdbb640a21
Portero-Otín, M.
f4379fcd-07b8-4091-8366-a67b2e8851aa
Osta, R.
86d1bc86-c43c-41e4-8fde-a1e0758ff737
Navarro, X.
e02f3576-d8d3-495f-ba77-37e4f8769974
Mancuso, Renzo
05786562-a993-4e37-926e-3c1fcf50b36d
Del Valle, J.
95b7f785-63d1-4210-ab3e-3c0636570a05
Mòdol, L.
bad7ffd0-2311-4cb5-8bf8-34f394bc6f15
Martinez, A.
08e8e823-41fc-4ad0-b8e3-79d8823eb848
Granado-Serrano, A.B.
dd1e5afc-17df-48ed-92e1-b503064c39f2
Ramirez-Núñez, O.
bef9ddfc-a892-428a-b2bb-55b61af26404
Pallás, M.
894e972c-5fdb-4518-8422-cacdbb640a21
Portero-Otín, M.
f4379fcd-07b8-4091-8366-a67b2e8851aa
Osta, R.
86d1bc86-c43c-41e4-8fde-a1e0758ff737
Navarro, X.
e02f3576-d8d3-495f-ba77-37e4f8769974

Mancuso, Renzo, Del Valle, J., Mòdol, L., Martinez, A., Granado-Serrano, A.B., Ramirez-Núñez, O., Pallás, M., Portero-Otín, M., Osta, R. and Navarro, X. (2014) Resveratrol improves motoneuron function and extends survival in SOD1G93A ALS mice. Neurotherapeutics, 11 (2), 419-432. (doi:10.1007/s13311-013-0253-y). (PMID:24414863 )

Record type: Article

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 SOD1(G93A) 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 SOD1(G93A) 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 SOD1(G93A) spinal cord. Taken together, our findings suggest that resveratrol may represent a promising therapy for ALS

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Accepted/In Press date: 2014
e-pub ahead of print date: 11 January 2014
Organisations: Centre for Biological Sciences

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Local EPrints ID: 376101
URI: http://eprints.soton.ac.uk/id/eprint/376101
ISSN: 1933-7213
PURE UUID: b6ab2b7c-eabf-4955-94c8-8c6465d9798c

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Date deposited: 27 Apr 2015 08:15
Last modified: 15 Jul 2019 21:23

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Contributors

Author: Renzo Mancuso
Author: J. Del Valle
Author: L. Mòdol
Author: A. Martinez
Author: A.B. Granado-Serrano
Author: O. Ramirez-Núñez
Author: M. Pallás
Author: M. Portero-Otín
Author: R. Osta
Author: X. Navarro

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