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Novel P2X7 Antagonist Ameliorates the Early Phase of ALS Disease and Decreases Inflammation and Autophagy in SOD1-G93A Mouse Model

Amyotrophic lateral sclerosis (ALS) is a disease with a resilient neuroinflammatory component caused by activated microglia and infiltrated immune cells. How to successfully balance neuroprotective versus neurotoxic actions through the use of anti-inflammatory agents is still under debate. There has...

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Autores principales: Apolloni, Savina, Fabbrizio, Paola, Amadio, Susanna, Napoli, Giulia, Freschi, Mattia, Sironi, Francesca, Pevarello, Paolo, Tarroni, Paola, Liberati, Chiara, Bendotti, Caterina, Volonté, Cinzia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508678/
https://www.ncbi.nlm.nih.gov/pubmed/34638992
http://dx.doi.org/10.3390/ijms221910649
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author Apolloni, Savina
Fabbrizio, Paola
Amadio, Susanna
Napoli, Giulia
Freschi, Mattia
Sironi, Francesca
Pevarello, Paolo
Tarroni, Paola
Liberati, Chiara
Bendotti, Caterina
Volonté, Cinzia
author_facet Apolloni, Savina
Fabbrizio, Paola
Amadio, Susanna
Napoli, Giulia
Freschi, Mattia
Sironi, Francesca
Pevarello, Paolo
Tarroni, Paola
Liberati, Chiara
Bendotti, Caterina
Volonté, Cinzia
author_sort Apolloni, Savina
collection PubMed
description Amyotrophic lateral sclerosis (ALS) is a disease with a resilient neuroinflammatory component caused by activated microglia and infiltrated immune cells. How to successfully balance neuroprotective versus neurotoxic actions through the use of anti-inflammatory agents is still under debate. There has been a boost of awareness regarding the role of extracellular ATP and purinergic receptors in modulating the physiological and pathological mechanisms in the nervous system. Particularly in ALS, it is known that the purinergic ionotropic P2X7 receptor plays a dual role in disease progression by acting at different cellular and molecular levels. In this context, we previously demonstrated that the P2X7 receptor antagonist, brilliant blue G, reduces neuroinflammation and ameliorates some of the pathological features of ALS in the SOD1-G93A mouse model. Here, we test the novel, noncommercially available, and centrally permeant Axxam proprietary P2X7 antagonist, AXX71, in SOD1-G93A mice, by assessing some behavioral and molecular parameters, among which are disease progression, survival, gliosis, and motor neuron wealth. We demonstrate that AXX71 affects the early symptomatic phase of the disease by reducing microglia-related proinflammatory markers and autophagy without affecting the anti-inflammatory markers or motor neuron survival. Our results suggest that P2X7 modulation can be further investigated as a therapeutic strategy in preclinical studies, and exploited in ALS clinical trials.
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spelling pubmed-85086782021-10-13 Novel P2X7 Antagonist Ameliorates the Early Phase of ALS Disease and Decreases Inflammation and Autophagy in SOD1-G93A Mouse Model Apolloni, Savina Fabbrizio, Paola Amadio, Susanna Napoli, Giulia Freschi, Mattia Sironi, Francesca Pevarello, Paolo Tarroni, Paola Liberati, Chiara Bendotti, Caterina Volonté, Cinzia Int J Mol Sci Article Amyotrophic lateral sclerosis (ALS) is a disease with a resilient neuroinflammatory component caused by activated microglia and infiltrated immune cells. How to successfully balance neuroprotective versus neurotoxic actions through the use of anti-inflammatory agents is still under debate. There has been a boost of awareness regarding the role of extracellular ATP and purinergic receptors in modulating the physiological and pathological mechanisms in the nervous system. Particularly in ALS, it is known that the purinergic ionotropic P2X7 receptor plays a dual role in disease progression by acting at different cellular and molecular levels. In this context, we previously demonstrated that the P2X7 receptor antagonist, brilliant blue G, reduces neuroinflammation and ameliorates some of the pathological features of ALS in the SOD1-G93A mouse model. Here, we test the novel, noncommercially available, and centrally permeant Axxam proprietary P2X7 antagonist, AXX71, in SOD1-G93A mice, by assessing some behavioral and molecular parameters, among which are disease progression, survival, gliosis, and motor neuron wealth. We demonstrate that AXX71 affects the early symptomatic phase of the disease by reducing microglia-related proinflammatory markers and autophagy without affecting the anti-inflammatory markers or motor neuron survival. Our results suggest that P2X7 modulation can be further investigated as a therapeutic strategy in preclinical studies, and exploited in ALS clinical trials. MDPI 2021-09-30 /pmc/articles/PMC8508678/ /pubmed/34638992 http://dx.doi.org/10.3390/ijms221910649 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Apolloni, Savina
Fabbrizio, Paola
Amadio, Susanna
Napoli, Giulia
Freschi, Mattia
Sironi, Francesca
Pevarello, Paolo
Tarroni, Paola
Liberati, Chiara
Bendotti, Caterina
Volonté, Cinzia
Novel P2X7 Antagonist Ameliorates the Early Phase of ALS Disease and Decreases Inflammation and Autophagy in SOD1-G93A Mouse Model
title Novel P2X7 Antagonist Ameliorates the Early Phase of ALS Disease and Decreases Inflammation and Autophagy in SOD1-G93A Mouse Model
title_full Novel P2X7 Antagonist Ameliorates the Early Phase of ALS Disease and Decreases Inflammation and Autophagy in SOD1-G93A Mouse Model
title_fullStr Novel P2X7 Antagonist Ameliorates the Early Phase of ALS Disease and Decreases Inflammation and Autophagy in SOD1-G93A Mouse Model
title_full_unstemmed Novel P2X7 Antagonist Ameliorates the Early Phase of ALS Disease and Decreases Inflammation and Autophagy in SOD1-G93A Mouse Model
title_short Novel P2X7 Antagonist Ameliorates the Early Phase of ALS Disease and Decreases Inflammation and Autophagy in SOD1-G93A Mouse Model
title_sort novel p2x7 antagonist ameliorates the early phase of als disease and decreases inflammation and autophagy in sod1-g93a mouse model
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508678/
https://www.ncbi.nlm.nih.gov/pubmed/34638992
http://dx.doi.org/10.3390/ijms221910649
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