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PQM130, a Novel Feruloyl–Donepezil Hybrid Compound, Effectively Ameliorates the Cognitive Impairments and Pathology in a Mouse Model of Alzheimer’s Disease
Alzheimer’s disease (AD) is the most frequent type of dementia in older people. The complex nature of AD calls for the development of multitarget agents addressing key pathogenic processes. Donepezil, an acetylcholinesterase inhibitor, is a first-line acetylcholinesterase inhibitor used for the trea...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581760/ https://www.ncbi.nlm.nih.gov/pubmed/31244664 http://dx.doi.org/10.3389/fphar.2019.00658 |
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author | Morroni, Fabiana Sita, Giulia Graziosi, Agnese Ravegnini, Gloria Molteni, Raffaella Paladini, Maria Serena Dias, Kris Simone Tranches dos Santos, Ariele Faria Viegas, Claudio Camps, Ihosvany Pruccoli, Letizia Tarozzi, Andrea Hrelia, Patrizia |
author_facet | Morroni, Fabiana Sita, Giulia Graziosi, Agnese Ravegnini, Gloria Molteni, Raffaella Paladini, Maria Serena Dias, Kris Simone Tranches dos Santos, Ariele Faria Viegas, Claudio Camps, Ihosvany Pruccoli, Letizia Tarozzi, Andrea Hrelia, Patrizia |
author_sort | Morroni, Fabiana |
collection | PubMed |
description | Alzheimer’s disease (AD) is the most frequent type of dementia in older people. The complex nature of AD calls for the development of multitarget agents addressing key pathogenic processes. Donepezil, an acetylcholinesterase inhibitor, is a first-line acetylcholinesterase inhibitor used for the treatment of AD. Although several studies have demonstrated the symptomatic efficacy of donepezil treatment in AD patients, the possible effects of donepezil on the AD process are not yet known. In this study, a novel feruloyl–donepezil hybrid compound (PQM130) was synthesized and evaluated as a multitarget drug candidate against the neurotoxicity induced by Aβ(1-42) oligomer (AβO) injection in mice. Interestingly, PQM130 had already shown anti-inflammatory activity in different in vivo models and neuroprotective activity in human neuronal cells. The intracerebroventricular (i.c.v.) injection of AβO in mice caused the increase of memory impairment, oxidative stress, neurodegeneration, and neuroinflammation. Instead, PQM130 (0.5–1 mg/kg) treatment after the i.c.v. AβO injection reduced oxidative damage and neuroinflammation and induced cell survival and protein synthesis through the modulation of glycogen synthase kinase 3β (GSK3β) and extracellular signal–regulated kinases (ERK1/2). Moreover, PQM130 increased brain plasticity and protected mice against the decline in spatial cognition. Even more interesting is that PQM130 modulated different pathways compared to donepezil, and it is much more effective in counteracting AβO damage. Therefore, our findings highlighted that PQM130 is a potent multi-functional agent against AD and could act as a promising neuroprotective compound for anti-AD drug development. |
format | Online Article Text |
id | pubmed-6581760 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-65817602019-06-26 PQM130, a Novel Feruloyl–Donepezil Hybrid Compound, Effectively Ameliorates the Cognitive Impairments and Pathology in a Mouse Model of Alzheimer’s Disease Morroni, Fabiana Sita, Giulia Graziosi, Agnese Ravegnini, Gloria Molteni, Raffaella Paladini, Maria Serena Dias, Kris Simone Tranches dos Santos, Ariele Faria Viegas, Claudio Camps, Ihosvany Pruccoli, Letizia Tarozzi, Andrea Hrelia, Patrizia Front Pharmacol Pharmacology Alzheimer’s disease (AD) is the most frequent type of dementia in older people. The complex nature of AD calls for the development of multitarget agents addressing key pathogenic processes. Donepezil, an acetylcholinesterase inhibitor, is a first-line acetylcholinesterase inhibitor used for the treatment of AD. Although several studies have demonstrated the symptomatic efficacy of donepezil treatment in AD patients, the possible effects of donepezil on the AD process are not yet known. In this study, a novel feruloyl–donepezil hybrid compound (PQM130) was synthesized and evaluated as a multitarget drug candidate against the neurotoxicity induced by Aβ(1-42) oligomer (AβO) injection in mice. Interestingly, PQM130 had already shown anti-inflammatory activity in different in vivo models and neuroprotective activity in human neuronal cells. The intracerebroventricular (i.c.v.) injection of AβO in mice caused the increase of memory impairment, oxidative stress, neurodegeneration, and neuroinflammation. Instead, PQM130 (0.5–1 mg/kg) treatment after the i.c.v. AβO injection reduced oxidative damage and neuroinflammation and induced cell survival and protein synthesis through the modulation of glycogen synthase kinase 3β (GSK3β) and extracellular signal–regulated kinases (ERK1/2). Moreover, PQM130 increased brain plasticity and protected mice against the decline in spatial cognition. Even more interesting is that PQM130 modulated different pathways compared to donepezil, and it is much more effective in counteracting AβO damage. Therefore, our findings highlighted that PQM130 is a potent multi-functional agent against AD and could act as a promising neuroprotective compound for anti-AD drug development. Frontiers Media S.A. 2019-06-12 /pmc/articles/PMC6581760/ /pubmed/31244664 http://dx.doi.org/10.3389/fphar.2019.00658 Text en Copyright © 2019 Morroni, Sita, Graziosi, Ravegnini, Molteni, Paladini, Dias, dos Santos, Viegas, Camps, Pruccoli, Tarozzi and Hrelia http://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 Morroni, Fabiana Sita, Giulia Graziosi, Agnese Ravegnini, Gloria Molteni, Raffaella Paladini, Maria Serena Dias, Kris Simone Tranches dos Santos, Ariele Faria Viegas, Claudio Camps, Ihosvany Pruccoli, Letizia Tarozzi, Andrea Hrelia, Patrizia PQM130, a Novel Feruloyl–Donepezil Hybrid Compound, Effectively Ameliorates the Cognitive Impairments and Pathology in a Mouse Model of Alzheimer’s Disease |
title | PQM130, a Novel Feruloyl–Donepezil Hybrid Compound, Effectively Ameliorates the Cognitive Impairments and Pathology in a Mouse Model of Alzheimer’s Disease |
title_full | PQM130, a Novel Feruloyl–Donepezil Hybrid Compound, Effectively Ameliorates the Cognitive Impairments and Pathology in a Mouse Model of Alzheimer’s Disease |
title_fullStr | PQM130, a Novel Feruloyl–Donepezil Hybrid Compound, Effectively Ameliorates the Cognitive Impairments and Pathology in a Mouse Model of Alzheimer’s Disease |
title_full_unstemmed | PQM130, a Novel Feruloyl–Donepezil Hybrid Compound, Effectively Ameliorates the Cognitive Impairments and Pathology in a Mouse Model of Alzheimer’s Disease |
title_short | PQM130, a Novel Feruloyl–Donepezil Hybrid Compound, Effectively Ameliorates the Cognitive Impairments and Pathology in a Mouse Model of Alzheimer’s Disease |
title_sort | pqm130, a novel feruloyl–donepezil hybrid compound, effectively ameliorates the cognitive impairments and pathology in a mouse model of alzheimer’s disease |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581760/ https://www.ncbi.nlm.nih.gov/pubmed/31244664 http://dx.doi.org/10.3389/fphar.2019.00658 |
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