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5-HT3 Antagonist Ondansetron Increases apoE Secretion by Modulating the LXR-ABCA1 Pathway
Apolipoprotein E (apoE) is linked to the risk for Alzheimer’s disease (AD) and thus has been suggested to be an important therapeutic target. In our drug screening effort, we identified Ondansetron (OS), an FDA-approved 5-HT3 antagonist, as an apoE-modulating drug. OS at low micromolar concentration...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471172/ https://www.ncbi.nlm.nih.gov/pubmed/30934555 http://dx.doi.org/10.3390/ijms20061488 |
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author | Shinohara, Motoko Shinohara, Mitsuru Zhao, Jing Fu, Yuan Liu, Chia-Chen Kanekiyo, Takahisa Bu, Guojun |
author_facet | Shinohara, Motoko Shinohara, Mitsuru Zhao, Jing Fu, Yuan Liu, Chia-Chen Kanekiyo, Takahisa Bu, Guojun |
author_sort | Shinohara, Motoko |
collection | PubMed |
description | Apolipoprotein E (apoE) is linked to the risk for Alzheimer’s disease (AD) and thus has been suggested to be an important therapeutic target. In our drug screening effort, we identified Ondansetron (OS), an FDA-approved 5-HT3 antagonist, as an apoE-modulating drug. OS at low micromolar concentrations significantly increased apoE secretion from immortalized astrocytes and primary astrocytes derived from apoE3 and apoE4-targeted replacement mice without generating cellular toxicity. Other 5-HT3 antagonists also had similar effects as OS, though their effects were milder and required higher concentrations. Antagonists for other 5-HT receptors did not increase apoE secretion. OS also increased mRNA and protein levels of the ATB-binding cassette protein A1 (ABCA1), which is involved in lipidation and secretion of apoE. Accordingly, OS increased high molecular weight apoE. Moreover, the liver X receptor (LXR) and ABCA1 antagonists blocked the OS-induced increase of apoE secretion, indicating that the LXR-ABCA1 pathway is involved in the OS-mediated facilitation of apoE secretion from astrocytes. The effects of OS on apoE and ABCA1 were also observed in human astrocytes derived from induced pluripotent stem cells (iPSC) carrying the APOE ε3/ε3 and APOE ε4/ε4 genotypes. Oral administration of OS at clinically-relevant doses affected apoE levels in the liver, though the effects in the brain were not observed. Collectively, though further studies are needed to probe its effects in vivo, OS could be a potential therapeutic drug for AD by modulating poE metabolism through the LXR-ABCA1 pathway. |
format | Online Article Text |
id | pubmed-6471172 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-64711722019-04-26 5-HT3 Antagonist Ondansetron Increases apoE Secretion by Modulating the LXR-ABCA1 Pathway Shinohara, Motoko Shinohara, Mitsuru Zhao, Jing Fu, Yuan Liu, Chia-Chen Kanekiyo, Takahisa Bu, Guojun Int J Mol Sci Article Apolipoprotein E (apoE) is linked to the risk for Alzheimer’s disease (AD) and thus has been suggested to be an important therapeutic target. In our drug screening effort, we identified Ondansetron (OS), an FDA-approved 5-HT3 antagonist, as an apoE-modulating drug. OS at low micromolar concentrations significantly increased apoE secretion from immortalized astrocytes and primary astrocytes derived from apoE3 and apoE4-targeted replacement mice without generating cellular toxicity. Other 5-HT3 antagonists also had similar effects as OS, though their effects were milder and required higher concentrations. Antagonists for other 5-HT receptors did not increase apoE secretion. OS also increased mRNA and protein levels of the ATB-binding cassette protein A1 (ABCA1), which is involved in lipidation and secretion of apoE. Accordingly, OS increased high molecular weight apoE. Moreover, the liver X receptor (LXR) and ABCA1 antagonists blocked the OS-induced increase of apoE secretion, indicating that the LXR-ABCA1 pathway is involved in the OS-mediated facilitation of apoE secretion from astrocytes. The effects of OS on apoE and ABCA1 were also observed in human astrocytes derived from induced pluripotent stem cells (iPSC) carrying the APOE ε3/ε3 and APOE ε4/ε4 genotypes. Oral administration of OS at clinically-relevant doses affected apoE levels in the liver, though the effects in the brain were not observed. Collectively, though further studies are needed to probe its effects in vivo, OS could be a potential therapeutic drug for AD by modulating poE metabolism through the LXR-ABCA1 pathway. MDPI 2019-03-25 /pmc/articles/PMC6471172/ /pubmed/30934555 http://dx.doi.org/10.3390/ijms20061488 Text en © 2019 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Shinohara, Motoko Shinohara, Mitsuru Zhao, Jing Fu, Yuan Liu, Chia-Chen Kanekiyo, Takahisa Bu, Guojun 5-HT3 Antagonist Ondansetron Increases apoE Secretion by Modulating the LXR-ABCA1 Pathway |
title | 5-HT3 Antagonist Ondansetron Increases apoE Secretion by Modulating the LXR-ABCA1 Pathway |
title_full | 5-HT3 Antagonist Ondansetron Increases apoE Secretion by Modulating the LXR-ABCA1 Pathway |
title_fullStr | 5-HT3 Antagonist Ondansetron Increases apoE Secretion by Modulating the LXR-ABCA1 Pathway |
title_full_unstemmed | 5-HT3 Antagonist Ondansetron Increases apoE Secretion by Modulating the LXR-ABCA1 Pathway |
title_short | 5-HT3 Antagonist Ondansetron Increases apoE Secretion by Modulating the LXR-ABCA1 Pathway |
title_sort | 5-ht3 antagonist ondansetron increases apoe secretion by modulating the lxr-abca1 pathway |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471172/ https://www.ncbi.nlm.nih.gov/pubmed/30934555 http://dx.doi.org/10.3390/ijms20061488 |
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