title: Neuroprotective Effect of Bexarotene in the SOD1(G93A) Mouse Model of Amyotrophic Lateral Sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive weakness and muscle atrophy related to the loss of upper and lower motor neurons (MNs) without a curative treatment. There is experimental evidence suggesting that retinoids may be involved in ALS pathogenesis. Bexarotene (Bxt) is a retinoid-X receptor agonist used in the treatment of cutaneous lymphoma with a favorable safety profile whose effects have been recently investigated in other neurodegenerative diseases. In this study, we analyze the potential therapeutic effect of Bxt in the SOD1(G93A) mouse model of ALS. Mice were treated with Bxt or vehicle five times per week from day 60 onward. Survival, weight, and neuromuscular function studies together with histological and biochemical analyses were performed. Bxt significantly delayed motor function deterioration, ameliorated the loss of body weight, and extended mice survival up to 30% of the symptomatic period. Histological analyses of the lumbosacral spinal cord revealed that Bxt markedly delayed the early motor-neuron degeneration occurring at presymptomatic stages in ALS-transgenic mice. Bxt treatment contributed to preserve the MN homeostasis in the SOD1(G93A) mice. Particularly, it reduced the neuronal loss and the chromatolytic response, induced nucleolar hypertrophy, decreased the formation of ubiquitylated inclusions, and modulated the lysosomal response. As an agonist of the retinoic-X receptor (RXR) pathway, Bxt notably increased the nuclear expression of the RXRα throughout transcriptionally active euchromatin domains. Bxt also contributed to protect the MN environment by reducing reactive astrogliosis and preserving perisomatic synapsis. Overall, these neuroprotective effects suggest that treatment with Bxt could be useful in ALS, particularly in those cases related to SOD1 mutations.
authors.affiliation: Neurology Service, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Investigación Marqués de Valdecilla (IDIVAL), University Hospital Marqués de Valdecilla, University of Cantabria , Santander , Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Riancho
authors.affiliation: Department of Anatomy and Cell Biology, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Investigación Marqués de Valdecilla (IDIVAL), University of Cantabria , Santander , Spain.
authors.forename: María
authors.initials: M
authors.lastname: Ruiz-Soto
authors.affiliation: Department of Anatomy and Cell Biology, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Investigación Marqués de Valdecilla (IDIVAL), University of Cantabria , Santander , Spain.
authors.forename: María T
authors.initials: MT
authors.lastname: Berciano
authors.affiliation: Neurology Service, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Investigación Marqués de Valdecilla (IDIVAL), University Hospital Marqués de Valdecilla, University of Cantabria , Santander , Spain.
authors.forename: José
authors.initials: J
authors.lastname: Berciano
authors.affiliation: Department of Anatomy and Cell Biology, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Investigación Marqués de Valdecilla (IDIVAL), University of Cantabria , Santander , Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Lafarga
keywords: G93ASOD1; amyotrophic lateral sclerosis; bexarotene; mouse; proteostasis; retinoid-X receptor