Neuroprotective Effect of Bexarotene in the SOD1(G93A) Mouse Model of Amyotrophic Lateral Sclerosis.

Javier Riancho,Miguel Lafarga,María T Berciano,José Berciano,María Ruiz-Soto

doi:10.3389/fncel.2015.00250

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 SOD1G93A 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 SOD1G93A 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.

Highlights

Amyotrophic lateral sclerosis (ALS) is the most common disease affecting the motor neurons (MNs) with an annual incidence that ranges from 2 to 4 cases per 100,000 people
Amyotrophic lateral sclerosis is one of the most disabling and ominous neurodegenerative diseases, being Riluzole, with a modest effect on survival, the only drug that can be currently offered to patients
Our results indicate that Bxt has a beneficial effect in transgenic SOD1G93A mice

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is the most common disease affecting the motor neurons (MNs) with an annual incidence that ranges from 2 to 4 cases per 100,000 people. Bexarotene in SOD1G93A mice several therapies have been tried, riluzole (a glutamate antagonist) is the only drug currently approved by the U.S Food and Drug Administration (FDA) for ALS treatment. It has shown a very poor effect in patients’ survival (Cheah et al, 2010; Miller et al, 2012). Up to 20% of fALS cases are due to mutations of the gene encoding superoxide dismutase 1 (SOD1) (Pasinelli and Brown, 2006; Rothstein, 2009; Ferraiuolo et al, 2011) This is the basis of a commonly used transgenic mouse model expressing the human SOD1 gene with the G93A mutation (Gurney et al, 1994). A relationship between SOD1 mutations and sALS has recently been reported supporting the translational value of studies using transgenic SOD1 mice (Bosco et al, 2010)

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Conclusion