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The small molecule CA140 inhibits the neuroinflammatory response in wild-type mice and a mouse model of AD
BACKGROUND: Neuroinflammation is associated with neurodegenerative diseases, including Alzheimer’s disease (AD). Thus, modulating the neuroinflammatory response represents a potential therapeutic strategy for treating neurodegenerative diseases. Several recent studies have shown that dopamine (DA) a...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182807/ https://www.ncbi.nlm.nih.gov/pubmed/30309372 http://dx.doi.org/10.1186/s12974-018-1321-3 |
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author | Lee, Ju-Young Nam, Jin Han Nam, Youngpyo Nam, Hye Yeon Yoon, Gwangho Ko, Eunhwa Kim, Sang-Bum Bautista, Mahealani R Capule, Christina C Koyanagi, Takaoki Leriche, Geoffray Choi, Hwan Geun Yang, Jerry Kim, Jeongyeon Hoe, Hyang-Sook |
author_facet | Lee, Ju-Young Nam, Jin Han Nam, Youngpyo Nam, Hye Yeon Yoon, Gwangho Ko, Eunhwa Kim, Sang-Bum Bautista, Mahealani R Capule, Christina C Koyanagi, Takaoki Leriche, Geoffray Choi, Hwan Geun Yang, Jerry Kim, Jeongyeon Hoe, Hyang-Sook |
author_sort | Lee, Ju-Young |
collection | PubMed |
description | BACKGROUND: Neuroinflammation is associated with neurodegenerative diseases, including Alzheimer’s disease (AD). Thus, modulating the neuroinflammatory response represents a potential therapeutic strategy for treating neurodegenerative diseases. Several recent studies have shown that dopamine (DA) and its receptors are expressed in immune cells and are involved in the neuroinflammatory response. Thus, we recently developed and synthesized a non-self-polymerizing analog of DA (CA140) and examined the effect of CA140 on neuroinflammation. METHODS: To determine the effects of CA140 on the neuroinflammatory response, BV2 microglial cells were pretreated with lipopolysaccharide (LPS, 1 μg/mL), followed by treatment with CA140 (10 μM) and analysis by reverse transcription-polymerase chain reaction (RT-PCR). To examine whether CA140 alters the neuroinflammatory response in vivo, wild-type mice were injected with both LPS (10 mg/kg, intraperitoneally (i.p.)) and CA140 (30 mg/kg, i.p.), and immunohistochemistry was performed. In addition, familial AD (5xFAD) mice were injected with CA140 or vehicle daily for 2 weeks and examined for microglial and astrocyte activation. RESULTS: Pre- or post-treatment with CA140 differentially regulated proinflammatory responses in LPS-stimulated microglia and astrocytes. Interestingly, CA140 regulated D1R levels to alter LPS-induced proinflammatory responses. CA140 significantly downregulated LPS-induced phosphorylation of ERK and STAT3 in BV2 microglia cells. In addition, CA140-injected wild-type mice exhibited significantly decreased LPS-induced microglial and astrocyte activation. Moreover, CA140-injected 5xFAD mice exhibited significantly reduced microglial and astrocyte activation. CONCLUSIONS: CA140 may be beneficial for preventing and treating neuroinflammatory-related diseases, including AD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12974-018-1321-3) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6182807 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-61828072018-10-18 The small molecule CA140 inhibits the neuroinflammatory response in wild-type mice and a mouse model of AD Lee, Ju-Young Nam, Jin Han Nam, Youngpyo Nam, Hye Yeon Yoon, Gwangho Ko, Eunhwa Kim, Sang-Bum Bautista, Mahealani R Capule, Christina C Koyanagi, Takaoki Leriche, Geoffray Choi, Hwan Geun Yang, Jerry Kim, Jeongyeon Hoe, Hyang-Sook J Neuroinflammation Research BACKGROUND: Neuroinflammation is associated with neurodegenerative diseases, including Alzheimer’s disease (AD). Thus, modulating the neuroinflammatory response represents a potential therapeutic strategy for treating neurodegenerative diseases. Several recent studies have shown that dopamine (DA) and its receptors are expressed in immune cells and are involved in the neuroinflammatory response. Thus, we recently developed and synthesized a non-self-polymerizing analog of DA (CA140) and examined the effect of CA140 on neuroinflammation. METHODS: To determine the effects of CA140 on the neuroinflammatory response, BV2 microglial cells were pretreated with lipopolysaccharide (LPS, 1 μg/mL), followed by treatment with CA140 (10 μM) and analysis by reverse transcription-polymerase chain reaction (RT-PCR). To examine whether CA140 alters the neuroinflammatory response in vivo, wild-type mice were injected with both LPS (10 mg/kg, intraperitoneally (i.p.)) and CA140 (30 mg/kg, i.p.), and immunohistochemistry was performed. In addition, familial AD (5xFAD) mice were injected with CA140 or vehicle daily for 2 weeks and examined for microglial and astrocyte activation. RESULTS: Pre- or post-treatment with CA140 differentially regulated proinflammatory responses in LPS-stimulated microglia and astrocytes. Interestingly, CA140 regulated D1R levels to alter LPS-induced proinflammatory responses. CA140 significantly downregulated LPS-induced phosphorylation of ERK and STAT3 in BV2 microglia cells. In addition, CA140-injected wild-type mice exhibited significantly decreased LPS-induced microglial and astrocyte activation. Moreover, CA140-injected 5xFAD mice exhibited significantly reduced microglial and astrocyte activation. CONCLUSIONS: CA140 may be beneficial for preventing and treating neuroinflammatory-related diseases, including AD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12974-018-1321-3) contains supplementary material, which is available to authorized users. BioMed Central 2018-10-11 /pmc/articles/PMC6182807/ /pubmed/30309372 http://dx.doi.org/10.1186/s12974-018-1321-3 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Lee, Ju-Young Nam, Jin Han Nam, Youngpyo Nam, Hye Yeon Yoon, Gwangho Ko, Eunhwa Kim, Sang-Bum Bautista, Mahealani R Capule, Christina C Koyanagi, Takaoki Leriche, Geoffray Choi, Hwan Geun Yang, Jerry Kim, Jeongyeon Hoe, Hyang-Sook The small molecule CA140 inhibits the neuroinflammatory response in wild-type mice and a mouse model of AD |
title | The small molecule CA140 inhibits the neuroinflammatory response in wild-type mice and a mouse model of AD |
title_full | The small molecule CA140 inhibits the neuroinflammatory response in wild-type mice and a mouse model of AD |
title_fullStr | The small molecule CA140 inhibits the neuroinflammatory response in wild-type mice and a mouse model of AD |
title_full_unstemmed | The small molecule CA140 inhibits the neuroinflammatory response in wild-type mice and a mouse model of AD |
title_short | The small molecule CA140 inhibits the neuroinflammatory response in wild-type mice and a mouse model of AD |
title_sort | small molecule ca140 inhibits the neuroinflammatory response in wild-type mice and a mouse model of ad |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182807/ https://www.ncbi.nlm.nih.gov/pubmed/30309372 http://dx.doi.org/10.1186/s12974-018-1321-3 |
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