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Neonatal Astrocyte Damage Is Sufficient to Trigger Progressive Striatal Degeneration in a Rat Model of Glutaric Acidemia-I
BACKGROUND: We have investigated whether an acute metabolic damage to astrocytes during the neonatal period may critically disrupt subsequent brain development, leading to neurodevelopmental disorders. Astrocytes are vulnerable to glutaric acid (GA), a dicarboxylic acid that accumulates in millimola...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3115973/ https://www.ncbi.nlm.nih.gov/pubmed/21698251 http://dx.doi.org/10.1371/journal.pone.0020831 |
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author | Olivera-Bravo, Silvia Fernández, Anabel Sarlabós, María Noel Rosillo, Juan Carlos Casanova, Gabriela Jiménez, Marcie Barbeito, Luis |
author_facet | Olivera-Bravo, Silvia Fernández, Anabel Sarlabós, María Noel Rosillo, Juan Carlos Casanova, Gabriela Jiménez, Marcie Barbeito, Luis |
author_sort | Olivera-Bravo, Silvia |
collection | PubMed |
description | BACKGROUND: We have investigated whether an acute metabolic damage to astrocytes during the neonatal period may critically disrupt subsequent brain development, leading to neurodevelopmental disorders. Astrocytes are vulnerable to glutaric acid (GA), a dicarboxylic acid that accumulates in millimolar concentrations in Glutaric Acidemia I (GA-I), an inherited neurometabolic childhood disease characterized by degeneration of striatal neurons. While GA induces astrocyte mitochondrial dysfunction, oxidative stress and subsequent increased proliferation, it is presently unknown whether such astrocytic dysfunction is sufficient to trigger striatal neuronal loss. METHODOLOGY/PRINCIPAL FINDINGS: A single intracerebroventricular dose of GA was administered to rat pups at postnatal day 0 (P0) to induce an acute, transient rise of GA levels in the central nervous system (CNS). GA administration potently elicited proliferation of astrocytes expressing S100β followed by GFAP astrocytosis and nitrotyrosine staining lasting until P45. Remarkably, GA did not induce acute neuronal loss assessed by FluoroJade C and NeuN cell count. Instead, neuronal death appeared several days after GA treatment and progressively increased until P45, suggesting a delayed onset of striatal degeneration. The axonal bundles perforating the striatum were disorganized following GA administration. In cell cultures, GA did not affect survival of either striatal astrocytes or neurons, even at high concentrations. However, astrocytes activated by a short exposure to GA caused neuronal death through the production of soluble factors. Iron porphyrin antioxidants prevented GA-induced astrocyte proliferation and striatal degeneration in vivo, as well as astrocyte-mediated neuronal loss in vitro. CONCLUSIONS/SIGNIFICANCE: Taken together, these results indicate that a transient metabolic insult with GA induces long lasting phenotypic changes in astrocytes that cause them to promote striatal neuronal death. Pharmacological protection of astrocytes with antioxidants during encephalopatic crisis may prevent astrocyte dysfunction and the ineluctable progression of disease in children with GA-I. |
format | Online Article Text |
id | pubmed-3115973 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-31159732011-06-22 Neonatal Astrocyte Damage Is Sufficient to Trigger Progressive Striatal Degeneration in a Rat Model of Glutaric Acidemia-I Olivera-Bravo, Silvia Fernández, Anabel Sarlabós, María Noel Rosillo, Juan Carlos Casanova, Gabriela Jiménez, Marcie Barbeito, Luis PLoS One Research Article BACKGROUND: We have investigated whether an acute metabolic damage to astrocytes during the neonatal period may critically disrupt subsequent brain development, leading to neurodevelopmental disorders. Astrocytes are vulnerable to glutaric acid (GA), a dicarboxylic acid that accumulates in millimolar concentrations in Glutaric Acidemia I (GA-I), an inherited neurometabolic childhood disease characterized by degeneration of striatal neurons. While GA induces astrocyte mitochondrial dysfunction, oxidative stress and subsequent increased proliferation, it is presently unknown whether such astrocytic dysfunction is sufficient to trigger striatal neuronal loss. METHODOLOGY/PRINCIPAL FINDINGS: A single intracerebroventricular dose of GA was administered to rat pups at postnatal day 0 (P0) to induce an acute, transient rise of GA levels in the central nervous system (CNS). GA administration potently elicited proliferation of astrocytes expressing S100β followed by GFAP astrocytosis and nitrotyrosine staining lasting until P45. Remarkably, GA did not induce acute neuronal loss assessed by FluoroJade C and NeuN cell count. Instead, neuronal death appeared several days after GA treatment and progressively increased until P45, suggesting a delayed onset of striatal degeneration. The axonal bundles perforating the striatum were disorganized following GA administration. In cell cultures, GA did not affect survival of either striatal astrocytes or neurons, even at high concentrations. However, astrocytes activated by a short exposure to GA caused neuronal death through the production of soluble factors. Iron porphyrin antioxidants prevented GA-induced astrocyte proliferation and striatal degeneration in vivo, as well as astrocyte-mediated neuronal loss in vitro. CONCLUSIONS/SIGNIFICANCE: Taken together, these results indicate that a transient metabolic insult with GA induces long lasting phenotypic changes in astrocytes that cause them to promote striatal neuronal death. Pharmacological protection of astrocytes with antioxidants during encephalopatic crisis may prevent astrocyte dysfunction and the ineluctable progression of disease in children with GA-I. Public Library of Science 2011-06-15 /pmc/articles/PMC3115973/ /pubmed/21698251 http://dx.doi.org/10.1371/journal.pone.0020831 Text en Olivera-Bravo et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Olivera-Bravo, Silvia Fernández, Anabel Sarlabós, María Noel Rosillo, Juan Carlos Casanova, Gabriela Jiménez, Marcie Barbeito, Luis Neonatal Astrocyte Damage Is Sufficient to Trigger Progressive Striatal Degeneration in a Rat Model of Glutaric Acidemia-I |
title | Neonatal Astrocyte Damage Is Sufficient to Trigger Progressive Striatal Degeneration in a Rat Model of Glutaric Acidemia-I |
title_full | Neonatal Astrocyte Damage Is Sufficient to Trigger Progressive Striatal Degeneration in a Rat Model of Glutaric Acidemia-I |
title_fullStr | Neonatal Astrocyte Damage Is Sufficient to Trigger Progressive Striatal Degeneration in a Rat Model of Glutaric Acidemia-I |
title_full_unstemmed | Neonatal Astrocyte Damage Is Sufficient to Trigger Progressive Striatal Degeneration in a Rat Model of Glutaric Acidemia-I |
title_short | Neonatal Astrocyte Damage Is Sufficient to Trigger Progressive Striatal Degeneration in a Rat Model of Glutaric Acidemia-I |
title_sort | neonatal astrocyte damage is sufficient to trigger progressive striatal degeneration in a rat model of glutaric acidemia-i |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3115973/ https://www.ncbi.nlm.nih.gov/pubmed/21698251 http://dx.doi.org/10.1371/journal.pone.0020831 |
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