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CQMUH-011 Inhibits LPS-Induced Microglia Activation and Ameliorates Brain Ischemic Injury in Mice

Excessive microglial activation-mediated neuroinflammation is closely involved in the pathogenesis of several neurological diseases. CQMUH-011, as a novel adamantane sulfonamide compound, has been shown anti-inflammatory properties in activated macrophages (RAW264.7). However, the role of CQMUH-011...

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Autores principales: Liu, Hailin, Hu, Xiangnan, Jiang, Rong, Cai, Jianghui, Lin, Qiao, Fan, Zhiguo, Zhao, Pan, Wang, Song, Zou, Chunqiao, Du, Weimin, Dong, Zhi, Liu, Yingju
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285337/
https://www.ncbi.nlm.nih.gov/pubmed/33528726
http://dx.doi.org/10.1007/s10753-021-01420-3
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author Liu, Hailin
Hu, Xiangnan
Jiang, Rong
Cai, Jianghui
Lin, Qiao
Fan, Zhiguo
Zhao, Pan
Wang, Song
Zou, Chunqiao
Du, Weimin
Dong, Zhi
Liu, Yingju
author_facet Liu, Hailin
Hu, Xiangnan
Jiang, Rong
Cai, Jianghui
Lin, Qiao
Fan, Zhiguo
Zhao, Pan
Wang, Song
Zou, Chunqiao
Du, Weimin
Dong, Zhi
Liu, Yingju
author_sort Liu, Hailin
collection PubMed
description Excessive microglial activation-mediated neuroinflammation is closely involved in the pathogenesis of several neurological diseases. CQMUH-011, as a novel adamantane sulfonamide compound, has been shown anti-inflammatory properties in activated macrophages (RAW264.7). However, the role of CQMUH-011 in microglial activation-induced neuroinflammation and neuroprotective properties has yet to be elucidated. In the present study, we investigated the potential effects and mechanisms of CQMUH-011 on lipopolysaccharide (LPS)-stimulated primary microglia in vitro and transient middle cerebral artery occlusion (t-MCAO)–induced acute cerebral ischemia/reperfusion (I/R) injury in vivo. The results demonstrated that CQMUH-011 significantly suppressed the production of tumor necrosis factor (TNF)-α and interleukin (IL)-1β by LPS-stimulated primary microglia. In addition, CQMUH-011 inhibited the proliferation of activated microglia by arresting the cell cycle at the G(1)/S phase accompanied by downregulating the expression of cell cycle regulatory proteins such as proliferating cell nuclear antigen (PCNA) and cyclin D1. CQMUH-011 was seen to induce apoptosis in activated microglia by regulating the expression of Bax and Bcl-2. Furthermore, CQMUH-011 markedly attenuated the protein expression of Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) as well as the phosphorylation levels of nuclear factor-kappa (NF-κB) subunit p65, inhibitory kappa B-alpha (IκBα), and mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinase (ERK) and p38 kinases. In vivo, CQMUH-011 administration significantly improved neurological function and infarct volume, and ameliorated the inflammatory cytokines and microglia amount around the injury site of mice. In conclusion, these results suggested that CQMUH-011 has a notable anti-inflammatory effect and protects mice from I/R injure. Thus, CQMUH-011 may be a candidate drug for the treatment of cerebral ischemia patients.
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spelling pubmed-82853372021-07-20 CQMUH-011 Inhibits LPS-Induced Microglia Activation and Ameliorates Brain Ischemic Injury in Mice Liu, Hailin Hu, Xiangnan Jiang, Rong Cai, Jianghui Lin, Qiao Fan, Zhiguo Zhao, Pan Wang, Song Zou, Chunqiao Du, Weimin Dong, Zhi Liu, Yingju Inflammation Original Article Excessive microglial activation-mediated neuroinflammation is closely involved in the pathogenesis of several neurological diseases. CQMUH-011, as a novel adamantane sulfonamide compound, has been shown anti-inflammatory properties in activated macrophages (RAW264.7). However, the role of CQMUH-011 in microglial activation-induced neuroinflammation and neuroprotective properties has yet to be elucidated. In the present study, we investigated the potential effects and mechanisms of CQMUH-011 on lipopolysaccharide (LPS)-stimulated primary microglia in vitro and transient middle cerebral artery occlusion (t-MCAO)–induced acute cerebral ischemia/reperfusion (I/R) injury in vivo. The results demonstrated that CQMUH-011 significantly suppressed the production of tumor necrosis factor (TNF)-α and interleukin (IL)-1β by LPS-stimulated primary microglia. In addition, CQMUH-011 inhibited the proliferation of activated microglia by arresting the cell cycle at the G(1)/S phase accompanied by downregulating the expression of cell cycle regulatory proteins such as proliferating cell nuclear antigen (PCNA) and cyclin D1. CQMUH-011 was seen to induce apoptosis in activated microglia by regulating the expression of Bax and Bcl-2. Furthermore, CQMUH-011 markedly attenuated the protein expression of Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) as well as the phosphorylation levels of nuclear factor-kappa (NF-κB) subunit p65, inhibitory kappa B-alpha (IκBα), and mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinase (ERK) and p38 kinases. In vivo, CQMUH-011 administration significantly improved neurological function and infarct volume, and ameliorated the inflammatory cytokines and microglia amount around the injury site of mice. In conclusion, these results suggested that CQMUH-011 has a notable anti-inflammatory effect and protects mice from I/R injure. Thus, CQMUH-011 may be a candidate drug for the treatment of cerebral ischemia patients. Springer US 2021-02-02 2021 /pmc/articles/PMC8285337/ /pubmed/33528726 http://dx.doi.org/10.1007/s10753-021-01420-3 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Article
Liu, Hailin
Hu, Xiangnan
Jiang, Rong
Cai, Jianghui
Lin, Qiao
Fan, Zhiguo
Zhao, Pan
Wang, Song
Zou, Chunqiao
Du, Weimin
Dong, Zhi
Liu, Yingju
CQMUH-011 Inhibits LPS-Induced Microglia Activation and Ameliorates Brain Ischemic Injury in Mice
title CQMUH-011 Inhibits LPS-Induced Microglia Activation and Ameliorates Brain Ischemic Injury in Mice
title_full CQMUH-011 Inhibits LPS-Induced Microglia Activation and Ameliorates Brain Ischemic Injury in Mice
title_fullStr CQMUH-011 Inhibits LPS-Induced Microglia Activation and Ameliorates Brain Ischemic Injury in Mice
title_full_unstemmed CQMUH-011 Inhibits LPS-Induced Microglia Activation and Ameliorates Brain Ischemic Injury in Mice
title_short CQMUH-011 Inhibits LPS-Induced Microglia Activation and Ameliorates Brain Ischemic Injury in Mice
title_sort cqmuh-011 inhibits lps-induced microglia activation and ameliorates brain ischemic injury in mice
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285337/
https://www.ncbi.nlm.nih.gov/pubmed/33528726
http://dx.doi.org/10.1007/s10753-021-01420-3
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