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Lack of synergistic effect of resveratrol and sigma-1 receptor agonist (PRE-084) in SOD1(G93A) ALS mice: overlapping effects or limited therapeutic opportunity?

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease characterized by the loss of motoneurons (MNs) in the spinal cord, brainstem and motor cortex, causing progressive paralysis and death. Nowadays, there is no effective therapy and most patients die 2–5 years...

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Autores principales: Mancuso, Renzo, del Valle, Jaume, Morell, Marta, Pallás, Mercé, Osta, Rosario, Navarro, Xavier
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4035830/
https://www.ncbi.nlm.nih.gov/pubmed/24885036
http://dx.doi.org/10.1186/1750-1172-9-78
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author Mancuso, Renzo
del Valle, Jaume
Morell, Marta
Pallás, Mercé
Osta, Rosario
Navarro, Xavier
author_facet Mancuso, Renzo
del Valle, Jaume
Morell, Marta
Pallás, Mercé
Osta, Rosario
Navarro, Xavier
author_sort Mancuso, Renzo
collection PubMed
description BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease characterized by the loss of motoneurons (MNs) in the spinal cord, brainstem and motor cortex, causing progressive paralysis and death. Nowadays, there is no effective therapy and most patients die 2–5 years after diagnosis. Sigma-1R is a transmembrane protein highly expressed in the CNS and specially enriched in MNs. Mutations on the Sigma-1R leading to frontotemporal lobar degeneration-ALS were recently described in human patients. We previously reported the therapeutic role of the selective sigma-1R agonist 2-(4-morpholi-nethyl)1-phenylcyclohexanecarboxylate (PRE-084) in SOD1(G93A) ALS mice, that promoted spinal MN preservation and extended animal survival by controlling NMDA receptor calcium influx. Resveratrol (RSV, trans-3,4′,5-trihydroxystilbene) is a natural polyphenol with promising neuroprotective effects. We recently found that RSV administration to SOD1(G93A) mice preserves spinal MN function and increases mice survival. These beneficial effects were associated to activation of Sirtuin 1 (Sirt1) and AMP-activated protein kinase (AMPK) pathways, leading to the modulation of autophagy and an increase of mitochondrial biogenesis. The main goal of this work was to assess the effect of combined RSV and PRE-084 administration in SOD1(G93A) ALS mice. METHODS: We determined the locomotor performance of the animals by rotarod test and evaluated spinal motoneuron function using electrophysiological tests. RESULTS: RSV plus PRE-084 treatment from 8 weeks of age significantly improved locomotor performance and spinal MN function, accompanied by a significant reduction of MN degeneration and an extension of mice lifespan. In agreement with our previous findings, there was an induction of PKC-specific phosphorylation of the NMDA-NR1 subunit and an increased expression and activation of Sirt1 and AMPK in the ventral spinal cord of treated SOD1(G93A) animals. CONCLUSIONS: Although combined PRE and RSV treatment significantly ameliorated SOD1(G93A) mice, it did not show a synergistic effect compared to RSV-only and PRE-084-only treated groups.
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spelling pubmed-40358302014-05-29 Lack of synergistic effect of resveratrol and sigma-1 receptor agonist (PRE-084) in SOD1(G93A) ALS mice: overlapping effects or limited therapeutic opportunity? Mancuso, Renzo del Valle, Jaume Morell, Marta Pallás, Mercé Osta, Rosario Navarro, Xavier Orphanet J Rare Dis Research BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease characterized by the loss of motoneurons (MNs) in the spinal cord, brainstem and motor cortex, causing progressive paralysis and death. Nowadays, there is no effective therapy and most patients die 2–5 years after diagnosis. Sigma-1R is a transmembrane protein highly expressed in the CNS and specially enriched in MNs. Mutations on the Sigma-1R leading to frontotemporal lobar degeneration-ALS were recently described in human patients. We previously reported the therapeutic role of the selective sigma-1R agonist 2-(4-morpholi-nethyl)1-phenylcyclohexanecarboxylate (PRE-084) in SOD1(G93A) ALS mice, that promoted spinal MN preservation and extended animal survival by controlling NMDA receptor calcium influx. Resveratrol (RSV, trans-3,4′,5-trihydroxystilbene) is a natural polyphenol with promising neuroprotective effects. We recently found that RSV administration to SOD1(G93A) mice preserves spinal MN function and increases mice survival. These beneficial effects were associated to activation of Sirtuin 1 (Sirt1) and AMP-activated protein kinase (AMPK) pathways, leading to the modulation of autophagy and an increase of mitochondrial biogenesis. The main goal of this work was to assess the effect of combined RSV and PRE-084 administration in SOD1(G93A) ALS mice. METHODS: We determined the locomotor performance of the animals by rotarod test and evaluated spinal motoneuron function using electrophysiological tests. RESULTS: RSV plus PRE-084 treatment from 8 weeks of age significantly improved locomotor performance and spinal MN function, accompanied by a significant reduction of MN degeneration and an extension of mice lifespan. In agreement with our previous findings, there was an induction of PKC-specific phosphorylation of the NMDA-NR1 subunit and an increased expression and activation of Sirt1 and AMPK in the ventral spinal cord of treated SOD1(G93A) animals. CONCLUSIONS: Although combined PRE and RSV treatment significantly ameliorated SOD1(G93A) mice, it did not show a synergistic effect compared to RSV-only and PRE-084-only treated groups. BioMed Central 2014-05-21 /pmc/articles/PMC4035830/ /pubmed/24885036 http://dx.doi.org/10.1186/1750-1172-9-78 Text en Copyright © 2014 Mancuso et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Mancuso, Renzo
del Valle, Jaume
Morell, Marta
Pallás, Mercé
Osta, Rosario
Navarro, Xavier
Lack of synergistic effect of resveratrol and sigma-1 receptor agonist (PRE-084) in SOD1(G93A) ALS mice: overlapping effects or limited therapeutic opportunity?
title Lack of synergistic effect of resveratrol and sigma-1 receptor agonist (PRE-084) in SOD1(G93A) ALS mice: overlapping effects or limited therapeutic opportunity?
title_full Lack of synergistic effect of resveratrol and sigma-1 receptor agonist (PRE-084) in SOD1(G93A) ALS mice: overlapping effects or limited therapeutic opportunity?
title_fullStr Lack of synergistic effect of resveratrol and sigma-1 receptor agonist (PRE-084) in SOD1(G93A) ALS mice: overlapping effects or limited therapeutic opportunity?
title_full_unstemmed Lack of synergistic effect of resveratrol and sigma-1 receptor agonist (PRE-084) in SOD1(G93A) ALS mice: overlapping effects or limited therapeutic opportunity?
title_short Lack of synergistic effect of resveratrol and sigma-1 receptor agonist (PRE-084) in SOD1(G93A) ALS mice: overlapping effects or limited therapeutic opportunity?
title_sort lack of synergistic effect of resveratrol and sigma-1 receptor agonist (pre-084) in sod1(g93a) als mice: overlapping effects or limited therapeutic opportunity?
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4035830/
https://www.ncbi.nlm.nih.gov/pubmed/24885036
http://dx.doi.org/10.1186/1750-1172-9-78
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