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Sigma-1R Agonist Improves Motor Function and Motoneuron Survival in ALS Mice

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Neurotherapeutics

Abstract

Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by progressive weakness, muscle atrophy, and paralysis due to the loss of upper and lower motoneurons (MNs). Sigma-1 receptor (sigma-1R) activation promotes neuroprotection after ischemic and traumatic injuries to the central nervous system. We recently reported that sigma-1R agonist (PRE-084) improves the survival of MNs after root avulsion injury in rats. Moreover, a mutation of the sigma-1R leading to frontotemporal lobar degeneration/amyotrophic lateral sclerosis (ALS) was recently described in human patients. In the present study, we analyzed the potential therapeutic effect of the sigma-1R agonist (PRE-084) in the SOD1G93A mouse model of ALS. Mice were daily administered with PRE-084 (0.25 mg/kg) from 8 to 16 weeks of age. Functional outcome was assessed by electrophysiological tests and computerized analysis of locomotion. Histological, immunohistochemical analyses and Western blot of the spinal cord were performed. PRE-084 administration from 8 weeks of age improved the function of MNs, which was manifested by maintenance of the amplitude of muscle action potentials and locomotor behavior, and preserved neuromuscular connections and MNs in the spinal cord. Moreover, it extended survival in both female and male mice by more than 15 %. Delayed administration of PRE-084 from 12 weeks of age also significantly improved functional outcome and preservation of the MNs. There was an induction of protein kinase C-specific phosphorylation of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor in SOD1G93A animals, and a reduction of the microglial reactivity compared with untreated mice. PRE-084 exerts a dual therapeutic contribution, modulating NMDA Ca2+ influx to protect MNs, and the microglial reactivity to ameliorate the MN environment. In conclusion, sigma-1R agonists, such as PRE-084, may be promising candidates for a therapeutical strategy of ALS.

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Acknowledgments

This work was supported by Red de Terapia Celular (TERCEL) and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) funds, the Fondo de Investigación Sanitaria of Spain (grant no. PI1001787); the Ministerio de Ciencia e Innovación of Spain (grant SAF2009-12495), FEDER funds, and Action COST-B30 of the EC. We thank the technical help of Jessica Jaramillo and Marta Morell. RM is recipient of a predoctoral fellowship from the Ministerio de Educación of Spain.

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Authors and Affiliations

  1. Group of Neuroplasticity and Regeneration, Institute of Neurosciences and Department of Cell Biology, Physiology, and Immunology, Universitat Autònoma de Barcelona, Bellaterra, 08193, Spain

    Renzo Mancuso, Caty Casas & Xavier Navarro

  2. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, 08193, Spain

    Renzo Mancuso, Caty Casas & Xavier Navarro

  3. Laboratory of Genetic Biochemistry (LAGENBIO-I3A), Aragon Institute of Health Sciences, Universidad de Zaragoza, Zaragoza, 50013, Spain

    Sara Oliván, Amaya Rando & Rosario Osta

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  1. Renzo Mancuso
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  2. Sara Oliván
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Correspondence to Xavier Navarro.

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Mancuso, R., Oliván, S., Rando, A. et al. Sigma-1R Agonist Improves Motor Function and Motoneuron Survival in ALS Mice. Neurotherapeutics 9, 814–826 (2012). https://doi.org/10.1007/s13311-012-0140-y

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