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Antipurinergic Therapy Corrects the Autism-Like Features in the Poly(IC) Mouse Model

BACKGROUND: Autism spectrum disorders (ASDs) are caused by both genetic and environmental factors. Mitochondria act to connect genes and environment by regulating gene-encoded metabolic networks according to changes in the chemistry of the cell and its environment. Mitochondrial ATP and other metabo...

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Autores principales: Naviaux, Robert K., Zolkipli, Zarazuela, Wang, Lin, Nakayama, Tomohiro, Naviaux, Jane C., Le, Thuy P., Schuchbauer, Michael A., Rogac, Mihael, Tang, Qingbo, Dugan, Laura L., Powell, Susan B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3596371/
https://www.ncbi.nlm.nih.gov/pubmed/23516405
http://dx.doi.org/10.1371/journal.pone.0057380
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author Naviaux, Robert K.
Zolkipli, Zarazuela
Wang, Lin
Nakayama, Tomohiro
Naviaux, Jane C.
Le, Thuy P.
Schuchbauer, Michael A.
Rogac, Mihael
Tang, Qingbo
Dugan, Laura L.
Powell, Susan B.
author_facet Naviaux, Robert K.
Zolkipli, Zarazuela
Wang, Lin
Nakayama, Tomohiro
Naviaux, Jane C.
Le, Thuy P.
Schuchbauer, Michael A.
Rogac, Mihael
Tang, Qingbo
Dugan, Laura L.
Powell, Susan B.
author_sort Naviaux, Robert K.
collection PubMed
description BACKGROUND: Autism spectrum disorders (ASDs) are caused by both genetic and environmental factors. Mitochondria act to connect genes and environment by regulating gene-encoded metabolic networks according to changes in the chemistry of the cell and its environment. Mitochondrial ATP and other metabolites are mitokines—signaling molecules made in mitochondria—that undergo regulated release from cells to communicate cellular health and danger to neighboring cells via purinergic signaling. The role of purinergic signaling has not yet been explored in autism spectrum disorders. OBJECTIVES AND METHODS: We used the maternal immune activation (MIA) mouse model of gestational poly(IC) exposure and treatment with the non-selective purinergic antagonist suramin to test the role of purinergic signaling in C57BL/6J mice. RESULTS: We found that antipurinergic therapy (APT) corrected 16 multisystem abnormalities that defined the ASD-like phenotype in this model. These included correction of the core social deficits and sensorimotor coordination abnormalities, prevention of cerebellar Purkinje cell loss, correction of the ultrastructural synaptic dysmorphology, and correction of the hypothermia, metabolic, mitochondrial, P2Y2 and P2X7 purinergic receptor expression, and ERK1/2 and CAMKII signal transduction abnormalities. CONCLUSIONS: Hyperpurinergia is a fundamental and treatable feature of the multisystem abnormalities in the poly(IC) mouse model of autism spectrum disorders. Antipurinergic therapy provides a new tool for refining current concepts of pathogenesis in autism and related spectrum disorders, and represents a fresh path forward for new drug development.
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spelling pubmed-35963712013-03-20 Antipurinergic Therapy Corrects the Autism-Like Features in the Poly(IC) Mouse Model Naviaux, Robert K. Zolkipli, Zarazuela Wang, Lin Nakayama, Tomohiro Naviaux, Jane C. Le, Thuy P. Schuchbauer, Michael A. Rogac, Mihael Tang, Qingbo Dugan, Laura L. Powell, Susan B. PLoS One Research Article BACKGROUND: Autism spectrum disorders (ASDs) are caused by both genetic and environmental factors. Mitochondria act to connect genes and environment by regulating gene-encoded metabolic networks according to changes in the chemistry of the cell and its environment. Mitochondrial ATP and other metabolites are mitokines—signaling molecules made in mitochondria—that undergo regulated release from cells to communicate cellular health and danger to neighboring cells via purinergic signaling. The role of purinergic signaling has not yet been explored in autism spectrum disorders. OBJECTIVES AND METHODS: We used the maternal immune activation (MIA) mouse model of gestational poly(IC) exposure and treatment with the non-selective purinergic antagonist suramin to test the role of purinergic signaling in C57BL/6J mice. RESULTS: We found that antipurinergic therapy (APT) corrected 16 multisystem abnormalities that defined the ASD-like phenotype in this model. These included correction of the core social deficits and sensorimotor coordination abnormalities, prevention of cerebellar Purkinje cell loss, correction of the ultrastructural synaptic dysmorphology, and correction of the hypothermia, metabolic, mitochondrial, P2Y2 and P2X7 purinergic receptor expression, and ERK1/2 and CAMKII signal transduction abnormalities. CONCLUSIONS: Hyperpurinergia is a fundamental and treatable feature of the multisystem abnormalities in the poly(IC) mouse model of autism spectrum disorders. Antipurinergic therapy provides a new tool for refining current concepts of pathogenesis in autism and related spectrum disorders, and represents a fresh path forward for new drug development. Public Library of Science 2013-03-13 /pmc/articles/PMC3596371/ /pubmed/23516405 http://dx.doi.org/10.1371/journal.pone.0057380 Text en © 2013 Naviaux 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
Naviaux, Robert K.
Zolkipli, Zarazuela
Wang, Lin
Nakayama, Tomohiro
Naviaux, Jane C.
Le, Thuy P.
Schuchbauer, Michael A.
Rogac, Mihael
Tang, Qingbo
Dugan, Laura L.
Powell, Susan B.
Antipurinergic Therapy Corrects the Autism-Like Features in the Poly(IC) Mouse Model
title Antipurinergic Therapy Corrects the Autism-Like Features in the Poly(IC) Mouse Model
title_full Antipurinergic Therapy Corrects the Autism-Like Features in the Poly(IC) Mouse Model
title_fullStr Antipurinergic Therapy Corrects the Autism-Like Features in the Poly(IC) Mouse Model
title_full_unstemmed Antipurinergic Therapy Corrects the Autism-Like Features in the Poly(IC) Mouse Model
title_short Antipurinergic Therapy Corrects the Autism-Like Features in the Poly(IC) Mouse Model
title_sort antipurinergic therapy corrects the autism-like features in the poly(ic) mouse model
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3596371/
https://www.ncbi.nlm.nih.gov/pubmed/23516405
http://dx.doi.org/10.1371/journal.pone.0057380
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