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 (Universitat Autònoma de Barcelona. Institut de Neurociències)
Del Valle, Jaume (Universitat Autònoma de Barcelona. Institut de Neurociències)
Morell, Marta (Universitat Autònoma de Barcelona. Institut de Neurociències)
Pallàs, Mercè (Universitat de Barcelona. Institut de Biomedicina)
Osta, Rosario (Universidad de Zaragoza)
Navarro, X. (Xavier) (Xavier) (Universitat Autònoma de Barcelona. Institut de Neurociències)
Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia

Date:	2014
Abstract:	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. We determined the locomotor performance of the animals by rotarod test and evaluated spinal motoneuron function using electrophysiological tests. 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. 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.
Grants:	Ministerio de Ciencia e Innovación SAF2009-12495
Note:	Altres ajuts: Action COST-B30 of the EC
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Motoneuron disease ; Amyotrophic lateral sclerosis ; Resveratrol ; Sirtuin 1 ; AMPK ; SOD1 G93A mice ; Sigma-1 receptor ; PRE-084 ; Combined therapy
Published in:	Orphanet Journal of Rare Diseases, Vol. 9 (May 2014) , art. 78, ISSN 1750-1172

DOI: 10.1186/1750-1172-9-78
PMID: 24885036

11 p, 1.2 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Neurociències (INc)
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Articles > Published articles