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CETP inhibitor evacetrapib enters mouse brain tissue

High levels of plasma cholesterol, especially high levels of low-density lipoprotein cholesterol (LDL-C), have been associated with an increased risk of Alzheimer’s disease. The cholesteryl ester transfer protein (CETP) in plasma distributes cholesteryl esters between lipoproteins and increases LDL-...

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Autores principales: Phénix, Jasmine, Côté, Jonathan, Dieme, Denis, Recinto, Sherilyn J., Oestereich, Felix, Efrem, Sasen, Haddad, Sami, Bouchard, Michèle, Munter, Lisa Marie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10390775/
https://www.ncbi.nlm.nih.gov/pubmed/37533630
http://dx.doi.org/10.3389/fphar.2023.1171937
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author Phénix, Jasmine
Côté, Jonathan
Dieme, Denis
Recinto, Sherilyn J.
Oestereich, Felix
Efrem, Sasen
Haddad, Sami
Bouchard, Michèle
Munter, Lisa Marie
author_facet Phénix, Jasmine
Côté, Jonathan
Dieme, Denis
Recinto, Sherilyn J.
Oestereich, Felix
Efrem, Sasen
Haddad, Sami
Bouchard, Michèle
Munter, Lisa Marie
author_sort Phénix, Jasmine
collection PubMed
description High levels of plasma cholesterol, especially high levels of low-density lipoprotein cholesterol (LDL-C), have been associated with an increased risk of Alzheimer’s disease. The cholesteryl ester transfer protein (CETP) in plasma distributes cholesteryl esters between lipoproteins and increases LDL-C in plasma. Epidemiologically, decreased CETP activity has been associated with sustained cognitive performance during aging, longevity, and a lower risk of Alzheimer’s disease. Thus, pharmacological CETP inhibitors could be repurposed for the treatment of Alzheimer’s disease as they are safe and effective at lowering CETP activity and LDL-C. Although CETP is mostly expressed by the liver and secreted into the bloodstream, it is also expressed by astrocytes in the brain. Therefore, it is important to determine whether CETP inhibitors can enter the brain. Here, we describe the pharmacokinetic parameters of the CETP inhibitor evacetrapib in the plasma, liver, and brain tissues of CETP transgenic mice. We show that evacetrapib crosses the blood–brain barrier and is detectable in brain tissue 0.5 h after a 40 mg/kg i.v. injection in a non-linear function. We conclude that evacetrapib may prove to be a good candidate to treat CETP-mediated cholesterol dysregulation in Alzheimer’s disease.
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spelling pubmed-103907752023-08-02 CETP inhibitor evacetrapib enters mouse brain tissue Phénix, Jasmine Côté, Jonathan Dieme, Denis Recinto, Sherilyn J. Oestereich, Felix Efrem, Sasen Haddad, Sami Bouchard, Michèle Munter, Lisa Marie Front Pharmacol Pharmacology High levels of plasma cholesterol, especially high levels of low-density lipoprotein cholesterol (LDL-C), have been associated with an increased risk of Alzheimer’s disease. The cholesteryl ester transfer protein (CETP) in plasma distributes cholesteryl esters between lipoproteins and increases LDL-C in plasma. Epidemiologically, decreased CETP activity has been associated with sustained cognitive performance during aging, longevity, and a lower risk of Alzheimer’s disease. Thus, pharmacological CETP inhibitors could be repurposed for the treatment of Alzheimer’s disease as they are safe and effective at lowering CETP activity and LDL-C. Although CETP is mostly expressed by the liver and secreted into the bloodstream, it is also expressed by astrocytes in the brain. Therefore, it is important to determine whether CETP inhibitors can enter the brain. Here, we describe the pharmacokinetic parameters of the CETP inhibitor evacetrapib in the plasma, liver, and brain tissues of CETP transgenic mice. We show that evacetrapib crosses the blood–brain barrier and is detectable in brain tissue 0.5 h after a 40 mg/kg i.v. injection in a non-linear function. We conclude that evacetrapib may prove to be a good candidate to treat CETP-mediated cholesterol dysregulation in Alzheimer’s disease. Frontiers Media S.A. 2023-07-18 /pmc/articles/PMC10390775/ /pubmed/37533630 http://dx.doi.org/10.3389/fphar.2023.1171937 Text en Copyright © 2023 Phénix, Côté, Dieme, Recinto, Oestereich, Efrem, Haddad, Bouchard and Munter. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Phénix, Jasmine
Côté, Jonathan
Dieme, Denis
Recinto, Sherilyn J.
Oestereich, Felix
Efrem, Sasen
Haddad, Sami
Bouchard, Michèle
Munter, Lisa Marie
CETP inhibitor evacetrapib enters mouse brain tissue
title CETP inhibitor evacetrapib enters mouse brain tissue
title_full CETP inhibitor evacetrapib enters mouse brain tissue
title_fullStr CETP inhibitor evacetrapib enters mouse brain tissue
title_full_unstemmed CETP inhibitor evacetrapib enters mouse brain tissue
title_short CETP inhibitor evacetrapib enters mouse brain tissue
title_sort cetp inhibitor evacetrapib enters mouse brain tissue
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10390775/
https://www.ncbi.nlm.nih.gov/pubmed/37533630
http://dx.doi.org/10.3389/fphar.2023.1171937
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