Disease-modifying treatment with I2 imidazoline receptor ligand LSL60101 in an Alzheimer's disease mouse model: A Comparative study with donepezil

Background and Purpose: The development of effective therapeutic strategies against Alzheimer's disease (AD) remains a challenge. I2 Imidazoline receptors (I2-IR) ligands have a neuroprotective role in AD. Moreover, co-treatment of acetylcholinesterase inhibitors with neuroprotective agents has...

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Authors: Vasilopoulou, Foteini, Rodríguez-Arévalo, Sergio, Bagan Polonio, Andrea, Escolano Mirón, Carmen, Griñán Ferré, Christian, Pallàs i Llibería, Mercè, 1964-
Format: article
Status:Versión aceptada para publicación
Publication Date:2021
Country:España
Institution:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repository:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/178766
Online Access:https://hdl.handle.net/2445/178766
Access Level:Open access
Keyword:Malaltia d'Alzheimer
Malalties neurodegeneratives
Envelliment
Alzheimer's disease
Neurodegenerative Diseases
Aging
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spelling Disease-modifying treatment with I2 imidazoline receptor ligand LSL60101 in an Alzheimer's disease mouse model: A Comparative study with donepezilVasilopoulou, FoteiniRodríguez-Arévalo, SergioBagan Polonio, AndreaEscolano Mirón, CarmenGriñán Ferré, ChristianPallàs i Llibería, Mercè, 1964-Malaltia d'AlzheimerMalalties neurodegenerativesEnvellimentAlzheimer's diseaseNeurodegenerative DiseasesAgingBackground and Purpose: The development of effective therapeutic strategies against Alzheimer's disease (AD) remains a challenge. I2 Imidazoline receptors (I2-IR) ligands have a neuroprotective role in AD. Moreover, co-treatment of acetylcholinesterase inhibitors with neuroprotective agents has shown better effects on the prevention of dementia. Here, we assessed the potential therapeutic effect of the I2-IR ligand LSL60101, donepezil, and their combination in 5XFAD mice. Experimental Approach: 5XFAD female mice were treated with low doses of LSL60101 (1 mg kg-1 day-1), donepezil (1 mg kg -1 day-1), and donepezil plus LSL60101 (1+1 mg kg-1 day-1), during 4 weeks per os. Novel object recognition, Morris water maze, open field, elevated plus maze, and three-chamber tests were employed to evaluate the cognitive and behavioural status after treatment. The effects of the treatments on AD-like pathology were assessed with immunohistochemistry, Western blot and qPCR. Key results: Chronic low-dose treatment with LSL60101 and donepezil reversed cognitive deficits and impaired social behaviour. LSL60101 treatment did not affect anxiety-like behaviour in contrast to donepezil. In the 5XFAD brains, LSL60101 and donepezil/LSL60101 treatments decreased Aβ-pathology and Tau hyperphosphorylation, and these alterations were accompanied by reduced microglia marker Iba-1 levels and increased Trem2 gene expression. LSL60601 and donepezil decreased glial fibrillary acidic protein (GFAP) astrocytic marker reactivity. However, only LSL60601 treatment significantly increased the synaptic markers' levels post-density 95 (PSD95) and synaptophysin (SYN). Conclusion and implications: Our results suggest that chronic low dose treatment with selective I2-IR ligands can be an effective treatment for AD and provide insights into combination treatments of symptomatic and disease-modifying drugs.Blackwell2021202220212021info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersion17 p.application/pdfhttps://hdl.handle.net/2445/178766Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésVersió postprint del document publicat a: https://doi.org/10.1111/bph.15478British Journal of Pharmacology, 2021, p. 1-17https://doi.org/10.1111/bph.15478(c) The British Pharmacological Society, 2021info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1787662026-05-29T05:05:01Z
dc.title.none.fl_str_mv Disease-modifying treatment with I2 imidazoline receptor ligand LSL60101 in an Alzheimer's disease mouse model: A Comparative study with donepezil
title Disease-modifying treatment with I2 imidazoline receptor ligand LSL60101 in an Alzheimer's disease mouse model: A Comparative study with donepezil
spellingShingle Disease-modifying treatment with I2 imidazoline receptor ligand LSL60101 in an Alzheimer's disease mouse model: A Comparative study with donepezil
Vasilopoulou, Foteini
Malaltia d'Alzheimer
Malalties neurodegeneratives
Envelliment
Alzheimer's disease
Neurodegenerative Diseases
Aging
title_short Disease-modifying treatment with I2 imidazoline receptor ligand LSL60101 in an Alzheimer's disease mouse model: A Comparative study with donepezil
title_full Disease-modifying treatment with I2 imidazoline receptor ligand LSL60101 in an Alzheimer's disease mouse model: A Comparative study with donepezil
title_fullStr Disease-modifying treatment with I2 imidazoline receptor ligand LSL60101 in an Alzheimer's disease mouse model: A Comparative study with donepezil
title_full_unstemmed Disease-modifying treatment with I2 imidazoline receptor ligand LSL60101 in an Alzheimer's disease mouse model: A Comparative study with donepezil
title_sort Disease-modifying treatment with I2 imidazoline receptor ligand LSL60101 in an Alzheimer's disease mouse model: A Comparative study with donepezil
dc.creator.none.fl_str_mv Vasilopoulou, Foteini
Rodríguez-Arévalo, Sergio
Bagan Polonio, Andrea
Escolano Mirón, Carmen
Griñán Ferré, Christian
Pallàs i Llibería, Mercè, 1964-
author Vasilopoulou, Foteini
author_facet Vasilopoulou, Foteini
Rodríguez-Arévalo, Sergio
Bagan Polonio, Andrea
Escolano Mirón, Carmen
Griñán Ferré, Christian
Pallàs i Llibería, Mercè, 1964-
author_role author
author2 Rodríguez-Arévalo, Sergio
Bagan Polonio, Andrea
Escolano Mirón, Carmen
Griñán Ferré, Christian
Pallàs i Llibería, Mercè, 1964-
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv Malaltia d'Alzheimer
Malalties neurodegeneratives
Envelliment
Alzheimer's disease
Neurodegenerative Diseases
Aging
topic Malaltia d'Alzheimer
Malalties neurodegeneratives
Envelliment
Alzheimer's disease
Neurodegenerative Diseases
Aging
description Background and Purpose: The development of effective therapeutic strategies against Alzheimer's disease (AD) remains a challenge. I2 Imidazoline receptors (I2-IR) ligands have a neuroprotective role in AD. Moreover, co-treatment of acetylcholinesterase inhibitors with neuroprotective agents has shown better effects on the prevention of dementia. Here, we assessed the potential therapeutic effect of the I2-IR ligand LSL60101, donepezil, and their combination in 5XFAD mice. Experimental Approach: 5XFAD female mice were treated with low doses of LSL60101 (1 mg kg-1 day-1), donepezil (1 mg kg -1 day-1), and donepezil plus LSL60101 (1+1 mg kg-1 day-1), during 4 weeks per os. Novel object recognition, Morris water maze, open field, elevated plus maze, and three-chamber tests were employed to evaluate the cognitive and behavioural status after treatment. The effects of the treatments on AD-like pathology were assessed with immunohistochemistry, Western blot and qPCR. Key results: Chronic low-dose treatment with LSL60101 and donepezil reversed cognitive deficits and impaired social behaviour. LSL60101 treatment did not affect anxiety-like behaviour in contrast to donepezil. In the 5XFAD brains, LSL60101 and donepezil/LSL60101 treatments decreased Aβ-pathology and Tau hyperphosphorylation, and these alterations were accompanied by reduced microglia marker Iba-1 levels and increased Trem2 gene expression. LSL60601 and donepezil decreased glial fibrillary acidic protein (GFAP) astrocytic marker reactivity. However, only LSL60601 treatment significantly increased the synaptic markers' levels post-density 95 (PSD95) and synaptophysin (SYN). Conclusion and implications: Our results suggest that chronic low dose treatment with selective I2-IR ligands can be an effective treatment for AD and provide insights into combination treatments of symptomatic and disease-modifying drugs.
publishDate 2021
dc.date.none.fl_str_mv 2021
2021
2021
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/178766
url https://hdl.handle.net/2445/178766
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Versió postprint del document publicat a: https://doi.org/10.1111/bph.15478
British Journal of Pharmacology, 2021, p. 1-17
https://doi.org/10.1111/bph.15478
dc.rights.none.fl_str_mv (c) The British Pharmacological Society, 2021
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) The British Pharmacological Society, 2021
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 17 p.
application/pdf
dc.publisher.none.fl_str_mv Blackwell
publisher.none.fl_str_mv Blackwell
dc.source.none.fl_str_mv Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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