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Neurotherapeutics

, Volume 16, Issue 1, pp 203–215 | Cite as

Mitochondrial Modulation by Dichloroacetate Reduces Toxicity of Aberrant Glial Cells and Gliosis in the SOD1G93A Rat Model of Amyotrophic Lateral Sclerosis

  • Laura Martínez-PalmaEmail author
  • Ernesto Miquel
  • Valentina Lagos-Rodríguez
  • Luis Barbeito
  • Adriana Cassina
  • Patricia CassinaEmail author
Original Article

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron (MN) degeneration and gliosis. Neonatal astrocytes obtained from the SOD1G93A rat model of ALS exhibit mitochondrial dysfunction and neurotoxicity that can be reduced by dichloroacetate (DCA), a metabolic modulator that has been used in humans, and shows beneficial effects on disease outcome in SOD1G93A mice. Aberrant glial cells (AbGC) isolated from the spinal cords of adult paralytic SOD1G93A rats exhibit highly proliferative and neurotoxic properties and may contribute to disease progression. Here we analyze the mitochondrial activity of AbGC and whether metabolic modulation would modify their phenotypic profile. Our studies revealed fragmented mitochondria and lower respiratory control ratio in AbGC compared to neonatal SOD1G93A and nontransgenic rat astrocytes. DCA (5 mM) exposure improved AbGC mitochondrial function, reduced their proliferative rate, and importantly, decreased their toxicity to MNs. Furthermore, oral DCA administration (100 mg/kg, 10 days) to symptomatic SOD1G93A rats reduced MN degeneration, gliosis, and the number of GFAP/S100β double-labeled hypertrophic glial cells in the spinal cord. DCA treatment of AbGC reduced extracellular lactate levels indicating that the main recognized DCA action, targeting the pyruvate dehydrogenase kinase/pyruvate dehydrogenase complex, may underlie our findings. Our results show that AbGC metabolic phenotype is related to their toxicity to MNs and indicate that its modulation can reduce glial mediated pathology in the spinal cord. Together with previous findings, these results further support glial metabolic modulation as a valid therapeutic strategy in ALS.

Key Words

Mitochondria metabolic modulation DCA glial toxicity aberrant glial cells ALS 

Notes

Acknowledgments:

The authors thank Drs. Mariela Bollati and Karen Perelmuter from the Cell Biology Unit at the Institut Pasteur de Montevideo for lactate and glucose measurements. This work was supported by Comisión Sectorial de Investigación Científica (CSIC), Universidad de la República, Uruguay; Grupos I+D Program, #1104 to PC and LB.

Compliance with Ethical Standards

Procedures using laboratory animals were in accordance with international guidelines and were approved by the Institutional Animal Committee: Comisión Honoraria de Experimentación Animal de la Universidad de la República (CHEA; https://chea.edu.uy/); protocol no. 070153-000528-14.

Required Author Forms

Disclosure forms provided by the authors are available with the online version of this article.

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

13311_2018_659_MOESM1_ESM.pdf (437 kb)
ESM 1 (PDF 436 kb)
13311_2018_659_MOESM2_ESM.pdf (434 kb)
ESM 2 (PDF 433 kb)

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Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2018

Authors and Affiliations

  1. 1.Departamento de Histología y Embriología, Facultad de MedicinaUniversidad de la RepúblicaMontevideoUruguay
  2. 2.Centro de Investigaciones Biomédicas (CEINBIO), Facultad de MedicinaUniversidad de la RepúblicaMontevideoUruguay
  3. 3.Institut Pasteur de MontevideoMontevideoUruguay
  4. 4.Departamento de Bioquímica, Facultad de MedicinaUniversidad de la RepúblicaMontevideoUruguay

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