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I2-Imidazoline Ligand CR4056 Improves Memory, Increases ApoE Expression and Reduces BBB Leakage in 5xFAD Mice

Recent evidence suggests that I2-imidazoline ligands have neuroprotective properties in animal models of neurodegeneration, such as Alzheimer’s disease (AD). We recently demonstrated that the I2-ligand BU224 reversed memory impairments in AD transgenic mice and this effect was not because of reducti...

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Autores principales: Mota, Bibiana C., Ashburner, Nathan, Abelleira-Hervas, Laura, Liu, Liyueyue, Aleksynas, Robertas, Rovati, Lucio Claudio, Caselli, Gianfranco, Sastre, Magdalena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9266435/
https://www.ncbi.nlm.nih.gov/pubmed/35806327
http://dx.doi.org/10.3390/ijms23137320
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author Mota, Bibiana C.
Ashburner, Nathan
Abelleira-Hervas, Laura
Liu, Liyueyue
Aleksynas, Robertas
Rovati, Lucio Claudio
Caselli, Gianfranco
Sastre, Magdalena
author_facet Mota, Bibiana C.
Ashburner, Nathan
Abelleira-Hervas, Laura
Liu, Liyueyue
Aleksynas, Robertas
Rovati, Lucio Claudio
Caselli, Gianfranco
Sastre, Magdalena
author_sort Mota, Bibiana C.
collection PubMed
description Recent evidence suggests that I2-imidazoline ligands have neuroprotective properties in animal models of neurodegeneration, such as Alzheimer’s disease (AD). We recently demonstrated that the I2-ligand BU224 reversed memory impairments in AD transgenic mice and this effect was not because of reductions in amyloid-β (Aβ) deposition. In this study, our aim was to determine the therapeutic potential of the powerful analgesic I2-imidazoline ligand CR4056 in the 5xFAD model of AD, since this ligand has been proven to be safely tolerated in humans. Sub-chronic oral administration of CR4056 (30 mg/kg for 10 days) led to an improvement in recognition memory in 6-month-old 5xFAD mice, but not in wild-type littermates, without affecting Aβ levels or deposition. Our results also revealed a change in the profile of microglia by CR4056, resulting in a suppression of pro-inflammatory activated microglia, but increased the density of astrocytes and the expression of ApoE, which is mainly produced by these glial cells. In addition, CR4056 restored fibrinogen extravasation, affecting the distribution of markers of astrocytic end feet in blood vessels. Therefore, these results suggest that CR4056 protects against Aβ-mediated neuroinflammation and vascular damage, and offers therapeutic potential at any stage of AD.
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spelling pubmed-92664352022-07-09 I2-Imidazoline Ligand CR4056 Improves Memory, Increases ApoE Expression and Reduces BBB Leakage in 5xFAD Mice Mota, Bibiana C. Ashburner, Nathan Abelleira-Hervas, Laura Liu, Liyueyue Aleksynas, Robertas Rovati, Lucio Claudio Caselli, Gianfranco Sastre, Magdalena Int J Mol Sci Article Recent evidence suggests that I2-imidazoline ligands have neuroprotective properties in animal models of neurodegeneration, such as Alzheimer’s disease (AD). We recently demonstrated that the I2-ligand BU224 reversed memory impairments in AD transgenic mice and this effect was not because of reductions in amyloid-β (Aβ) deposition. In this study, our aim was to determine the therapeutic potential of the powerful analgesic I2-imidazoline ligand CR4056 in the 5xFAD model of AD, since this ligand has been proven to be safely tolerated in humans. Sub-chronic oral administration of CR4056 (30 mg/kg for 10 days) led to an improvement in recognition memory in 6-month-old 5xFAD mice, but not in wild-type littermates, without affecting Aβ levels or deposition. Our results also revealed a change in the profile of microglia by CR4056, resulting in a suppression of pro-inflammatory activated microglia, but increased the density of astrocytes and the expression of ApoE, which is mainly produced by these glial cells. In addition, CR4056 restored fibrinogen extravasation, affecting the distribution of markers of astrocytic end feet in blood vessels. Therefore, these results suggest that CR4056 protects against Aβ-mediated neuroinflammation and vascular damage, and offers therapeutic potential at any stage of AD. MDPI 2022-06-30 /pmc/articles/PMC9266435/ /pubmed/35806327 http://dx.doi.org/10.3390/ijms23137320 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Mota, Bibiana C.
Ashburner, Nathan
Abelleira-Hervas, Laura
Liu, Liyueyue
Aleksynas, Robertas
Rovati, Lucio Claudio
Caselli, Gianfranco
Sastre, Magdalena
I2-Imidazoline Ligand CR4056 Improves Memory, Increases ApoE Expression and Reduces BBB Leakage in 5xFAD Mice
title I2-Imidazoline Ligand CR4056 Improves Memory, Increases ApoE Expression and Reduces BBB Leakage in 5xFAD Mice
title_full I2-Imidazoline Ligand CR4056 Improves Memory, Increases ApoE Expression and Reduces BBB Leakage in 5xFAD Mice
title_fullStr I2-Imidazoline Ligand CR4056 Improves Memory, Increases ApoE Expression and Reduces BBB Leakage in 5xFAD Mice
title_full_unstemmed I2-Imidazoline Ligand CR4056 Improves Memory, Increases ApoE Expression and Reduces BBB Leakage in 5xFAD Mice
title_short I2-Imidazoline Ligand CR4056 Improves Memory, Increases ApoE Expression and Reduces BBB Leakage in 5xFAD Mice
title_sort i2-imidazoline ligand cr4056 improves memory, increases apoe expression and reduces bbb leakage in 5xfad mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9266435/
https://www.ncbi.nlm.nih.gov/pubmed/35806327
http://dx.doi.org/10.3390/ijms23137320
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