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Laquinimod Modulates Human Astrocyte Function and Dampens Astrocyte-Induced Neurotoxicity during Inflammation

Astrocytes greatly participate to inflammatory and neurotoxic reactions occurring in neurodegenerative diseases and are valuable pharmacological targets to support neuroprotection. Here we used human astrocytes generated from reprogrammed fibroblasts as a cellular model to study the effect of the co...

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Autores principales: Colombo, Emanuela, Pascente, Rosaria, Triolo, Daniela, Bassani, Claudia, De Angelis, Anthea, Ruffini, Francesca, Ottoboni, Linda, Comi, Giancarlo, Martino, Gianvito, Farina, Cinthia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699283/
https://www.ncbi.nlm.nih.gov/pubmed/33218208
http://dx.doi.org/10.3390/molecules25225403
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author Colombo, Emanuela
Pascente, Rosaria
Triolo, Daniela
Bassani, Claudia
De Angelis, Anthea
Ruffini, Francesca
Ottoboni, Linda
Comi, Giancarlo
Martino, Gianvito
Farina, Cinthia
author_facet Colombo, Emanuela
Pascente, Rosaria
Triolo, Daniela
Bassani, Claudia
De Angelis, Anthea
Ruffini, Francesca
Ottoboni, Linda
Comi, Giancarlo
Martino, Gianvito
Farina, Cinthia
author_sort Colombo, Emanuela
collection PubMed
description Astrocytes greatly participate to inflammatory and neurotoxic reactions occurring in neurodegenerative diseases and are valuable pharmacological targets to support neuroprotection. Here we used human astrocytes generated from reprogrammed fibroblasts as a cellular model to study the effect of the compound Laquinimod and its active metabolite de-Laquinimod on astrocyte functions and the astrocyte–neuron interaction. We show that human iAstrocytes expressed the receptor for the inflammatory mediator IL1 and responded to it via nuclear translocation of NFκB, an event that did not occur if cells were treated with Laquinimod, indicating a direct anti-inflammatory activity of the drug on the human astrocyte. Similarly, while exposure to IL1 downregulated glial glutamate transporters GLAST and GLT1, treatment with Laquinimod supported maintenance of physiological levels of these proteins despite the inflammatory milieu. Laquinimod also induced nuclear translocation of the aryl hydrocarbon receptor (AHR), suggesting that drug action was mediated by activation of the AHR pathway. However, the drug was effective despite AHR inhibition via CH223191, indicating that AHR signaling in the astrocyte is dispensable for drug responses. Finally, in vitro experiments with rat spinal neurons showed that laquinimod did not exert neuroprotection directly on the neuron but dampened astrocyte-induced neurodegeneration. Our findings indicate that fibroblast-derived human astrocytes represent a suitable model to study astrocyte–neuron crosstalk and demonstrate indirect, partial neuroprotective efficacy for laquinimod.
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spelling pubmed-76992832020-11-29 Laquinimod Modulates Human Astrocyte Function and Dampens Astrocyte-Induced Neurotoxicity during Inflammation Colombo, Emanuela Pascente, Rosaria Triolo, Daniela Bassani, Claudia De Angelis, Anthea Ruffini, Francesca Ottoboni, Linda Comi, Giancarlo Martino, Gianvito Farina, Cinthia Molecules Article Astrocytes greatly participate to inflammatory and neurotoxic reactions occurring in neurodegenerative diseases and are valuable pharmacological targets to support neuroprotection. Here we used human astrocytes generated from reprogrammed fibroblasts as a cellular model to study the effect of the compound Laquinimod and its active metabolite de-Laquinimod on astrocyte functions and the astrocyte–neuron interaction. We show that human iAstrocytes expressed the receptor for the inflammatory mediator IL1 and responded to it via nuclear translocation of NFκB, an event that did not occur if cells were treated with Laquinimod, indicating a direct anti-inflammatory activity of the drug on the human astrocyte. Similarly, while exposure to IL1 downregulated glial glutamate transporters GLAST and GLT1, treatment with Laquinimod supported maintenance of physiological levels of these proteins despite the inflammatory milieu. Laquinimod also induced nuclear translocation of the aryl hydrocarbon receptor (AHR), suggesting that drug action was mediated by activation of the AHR pathway. However, the drug was effective despite AHR inhibition via CH223191, indicating that AHR signaling in the astrocyte is dispensable for drug responses. Finally, in vitro experiments with rat spinal neurons showed that laquinimod did not exert neuroprotection directly on the neuron but dampened astrocyte-induced neurodegeneration. Our findings indicate that fibroblast-derived human astrocytes represent a suitable model to study astrocyte–neuron crosstalk and demonstrate indirect, partial neuroprotective efficacy for laquinimod. MDPI 2020-11-18 /pmc/articles/PMC7699283/ /pubmed/33218208 http://dx.doi.org/10.3390/molecules25225403 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Colombo, Emanuela
Pascente, Rosaria
Triolo, Daniela
Bassani, Claudia
De Angelis, Anthea
Ruffini, Francesca
Ottoboni, Linda
Comi, Giancarlo
Martino, Gianvito
Farina, Cinthia
Laquinimod Modulates Human Astrocyte Function and Dampens Astrocyte-Induced Neurotoxicity during Inflammation
title Laquinimod Modulates Human Astrocyte Function and Dampens Astrocyte-Induced Neurotoxicity during Inflammation
title_full Laquinimod Modulates Human Astrocyte Function and Dampens Astrocyte-Induced Neurotoxicity during Inflammation
title_fullStr Laquinimod Modulates Human Astrocyte Function and Dampens Astrocyte-Induced Neurotoxicity during Inflammation
title_full_unstemmed Laquinimod Modulates Human Astrocyte Function and Dampens Astrocyte-Induced Neurotoxicity during Inflammation
title_short Laquinimod Modulates Human Astrocyte Function and Dampens Astrocyte-Induced Neurotoxicity during Inflammation
title_sort laquinimod modulates human astrocyte function and dampens astrocyte-induced neurotoxicity during inflammation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699283/
https://www.ncbi.nlm.nih.gov/pubmed/33218208
http://dx.doi.org/10.3390/molecules25225403
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