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Blockade of Gap Junction Hemichannel Suppresses Disease Progression in Mouse Models of Amyotrophic Lateral Sclerosis and Alzheimer's Disease

BACKGROUND: Glutamate released by activated microglia induces excitotoxic neuronal death, which likely contributes to non-cell autonomous neuronal death in neurodegenerative diseases, including amyotrophic lateral sclerosis and Alzheimer's disease. Although both blockade of glutamate receptors...

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Autores principales: Takeuchi, Hideyuki, Mizoguchi, Hiroyuki, Doi, Yukiko, Jin, Shijie, Noda, Mariko, Liang, Jianfeng, Li, Hua, Zhou, Yan, Mori, Rarami, Yasuoka, Satoko, Li, Endong, Parajuli, Bijay, Kawanokuchi, Jun, Sonobe, Yoshifumi, Sato, Jun, Yamanaka, Koji, Sobue, Gen, Mizuno, Tetsuya, Suzumura, Akio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3119678/
https://www.ncbi.nlm.nih.gov/pubmed/21712989
http://dx.doi.org/10.1371/journal.pone.0021108
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author Takeuchi, Hideyuki
Mizoguchi, Hiroyuki
Doi, Yukiko
Jin, Shijie
Noda, Mariko
Liang, Jianfeng
Li, Hua
Zhou, Yan
Mori, Rarami
Yasuoka, Satoko
Li, Endong
Parajuli, Bijay
Kawanokuchi, Jun
Sonobe, Yoshifumi
Sato, Jun
Yamanaka, Koji
Sobue, Gen
Mizuno, Tetsuya
Suzumura, Akio
author_facet Takeuchi, Hideyuki
Mizoguchi, Hiroyuki
Doi, Yukiko
Jin, Shijie
Noda, Mariko
Liang, Jianfeng
Li, Hua
Zhou, Yan
Mori, Rarami
Yasuoka, Satoko
Li, Endong
Parajuli, Bijay
Kawanokuchi, Jun
Sonobe, Yoshifumi
Sato, Jun
Yamanaka, Koji
Sobue, Gen
Mizuno, Tetsuya
Suzumura, Akio
author_sort Takeuchi, Hideyuki
collection PubMed
description BACKGROUND: Glutamate released by activated microglia induces excitotoxic neuronal death, which likely contributes to non-cell autonomous neuronal death in neurodegenerative diseases, including amyotrophic lateral sclerosis and Alzheimer's disease. Although both blockade of glutamate receptors and inhibition of microglial activation are the therapeutic candidates for these neurodegenerative diseases, glutamate receptor blockers also perturbed physiological and essential glutamate signals, and inhibitors of microglial activation suppressed both neurotoxic/neuroprotective roles of microglia and hardly affected disease progression. We previously demonstrated that activated microglia release a large amount of glutamate specifically through gap junction hemichannel. Hence, blockade of gap junction hemichannel may be potentially beneficial in treatment of neurodegenerative diseases. METHODS AND FINDINGS: In this study, we generated a novel blood-brain barrier permeable gap junction hemichannel blocker based on glycyrrhetinic acid. We found that pharmacologic blockade of gap junction hemichannel inhibited excessive glutamate release from activated microglia in vitro and in vivo without producing notable toxicity. Blocking gap junction hemichannel significantly suppressed neuronal loss of the spinal cord and extended survival in transgenic mice carrying human superoxide dismutase 1 with G93A or G37R mutation as an amyotrophic lateral sclerosis mouse model. Moreover, blockade of gap junction hemichannel also significantly improved memory impairments without altering amyloid β deposition in double transgenic mice expressing human amyloid precursor protein with K595N and M596L mutations and presenilin 1 with A264E mutation as an Alzheimer's disease mouse model. CONCLUSIONS: Our results suggest that gap junction hemichannel blockers may represent a new therapeutic strategy to target neurotoxic microglia specifically and prevent microglia-mediated neuronal death in various neurodegenerative diseases.
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spelling pubmed-31196782011-06-27 Blockade of Gap Junction Hemichannel Suppresses Disease Progression in Mouse Models of Amyotrophic Lateral Sclerosis and Alzheimer's Disease Takeuchi, Hideyuki Mizoguchi, Hiroyuki Doi, Yukiko Jin, Shijie Noda, Mariko Liang, Jianfeng Li, Hua Zhou, Yan Mori, Rarami Yasuoka, Satoko Li, Endong Parajuli, Bijay Kawanokuchi, Jun Sonobe, Yoshifumi Sato, Jun Yamanaka, Koji Sobue, Gen Mizuno, Tetsuya Suzumura, Akio PLoS One Research Article BACKGROUND: Glutamate released by activated microglia induces excitotoxic neuronal death, which likely contributes to non-cell autonomous neuronal death in neurodegenerative diseases, including amyotrophic lateral sclerosis and Alzheimer's disease. Although both blockade of glutamate receptors and inhibition of microglial activation are the therapeutic candidates for these neurodegenerative diseases, glutamate receptor blockers also perturbed physiological and essential glutamate signals, and inhibitors of microglial activation suppressed both neurotoxic/neuroprotective roles of microglia and hardly affected disease progression. We previously demonstrated that activated microglia release a large amount of glutamate specifically through gap junction hemichannel. Hence, blockade of gap junction hemichannel may be potentially beneficial in treatment of neurodegenerative diseases. METHODS AND FINDINGS: In this study, we generated a novel blood-brain barrier permeable gap junction hemichannel blocker based on glycyrrhetinic acid. We found that pharmacologic blockade of gap junction hemichannel inhibited excessive glutamate release from activated microglia in vitro and in vivo without producing notable toxicity. Blocking gap junction hemichannel significantly suppressed neuronal loss of the spinal cord and extended survival in transgenic mice carrying human superoxide dismutase 1 with G93A or G37R mutation as an amyotrophic lateral sclerosis mouse model. Moreover, blockade of gap junction hemichannel also significantly improved memory impairments without altering amyloid β deposition in double transgenic mice expressing human amyloid precursor protein with K595N and M596L mutations and presenilin 1 with A264E mutation as an Alzheimer's disease mouse model. CONCLUSIONS: Our results suggest that gap junction hemichannel blockers may represent a new therapeutic strategy to target neurotoxic microglia specifically and prevent microglia-mediated neuronal death in various neurodegenerative diseases. Public Library of Science 2011-06-21 /pmc/articles/PMC3119678/ /pubmed/21712989 http://dx.doi.org/10.1371/journal.pone.0021108 Text en Takeuchi 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
Takeuchi, Hideyuki
Mizoguchi, Hiroyuki
Doi, Yukiko
Jin, Shijie
Noda, Mariko
Liang, Jianfeng
Li, Hua
Zhou, Yan
Mori, Rarami
Yasuoka, Satoko
Li, Endong
Parajuli, Bijay
Kawanokuchi, Jun
Sonobe, Yoshifumi
Sato, Jun
Yamanaka, Koji
Sobue, Gen
Mizuno, Tetsuya
Suzumura, Akio
Blockade of Gap Junction Hemichannel Suppresses Disease Progression in Mouse Models of Amyotrophic Lateral Sclerosis and Alzheimer's Disease
title Blockade of Gap Junction Hemichannel Suppresses Disease Progression in Mouse Models of Amyotrophic Lateral Sclerosis and Alzheimer's Disease
title_full Blockade of Gap Junction Hemichannel Suppresses Disease Progression in Mouse Models of Amyotrophic Lateral Sclerosis and Alzheimer's Disease
title_fullStr Blockade of Gap Junction Hemichannel Suppresses Disease Progression in Mouse Models of Amyotrophic Lateral Sclerosis and Alzheimer's Disease
title_full_unstemmed Blockade of Gap Junction Hemichannel Suppresses Disease Progression in Mouse Models of Amyotrophic Lateral Sclerosis and Alzheimer's Disease
title_short Blockade of Gap Junction Hemichannel Suppresses Disease Progression in Mouse Models of Amyotrophic Lateral Sclerosis and Alzheimer's Disease
title_sort blockade of gap junction hemichannel suppresses disease progression in mouse models of amyotrophic lateral sclerosis and alzheimer's disease
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3119678/
https://www.ncbi.nlm.nih.gov/pubmed/21712989
http://dx.doi.org/10.1371/journal.pone.0021108
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