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...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2019-06-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2019.00658/full |
| _version_ | 1819086982084558848 |
|---|---|
| author | Fabiana Morroni Giulia Sita Agnese Graziosi Gloria Ravegnini Raffaella Molteni Maria Serena Paladini Kris Simone Tranches Dias Ariele Faria dos Santos Claudio Viegas Ihosvany Camps Letizia Pruccoli Andrea Tarozzi Patrizia Hrelia |
| author_facet | Fabiana Morroni Giulia Sita Agnese Graziosi Gloria Ravegnini Raffaella Molteni Maria Serena Paladini Kris Simone Tranches Dias Ariele Faria dos Santos Claudio Viegas Ihosvany Camps Letizia Pruccoli Andrea Tarozzi Patrizia Hrelia |
| author_sort | Fabiana Morroni |
| collection | DOAJ |
| 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 Aβ1-42 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. |
| first_indexed | 2024-12-21T21:28:54Z |
| format | Article |
| id | doaj.art-5ce18938fa0d4f4798d3c229bc41fda2 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-21T21:28:54Z |
| publishDate | 2019-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-5ce18938fa0d4f4798d3c229bc41fda22022-12-21T18:49:41ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122019-06-011010.3389/fphar.2019.00658461532PQM130, a Novel Feruloyl–Donepezil Hybrid Compound, Effectively Ameliorates the Cognitive Impairments and Pathology in a Mouse Model of Alzheimer’s DiseaseFabiana Morroni0Giulia Sita1Agnese Graziosi2Gloria Ravegnini3Raffaella Molteni4Maria Serena Paladini5Kris Simone Tranches Dias6Ariele Faria dos Santos7Claudio Viegas8Ihosvany Camps9Letizia Pruccoli10Andrea Tarozzi11Patrizia Hrelia12Department of Pharmacy and BioTechnology–FaBiT, Alma Mater Studiorum–University of Bologna, Bologna, ItalyDepartment of Pharmacy and BioTechnology–FaBiT, Alma Mater Studiorum–University of Bologna, Bologna, ItalyDepartment of Pharmacy and BioTechnology–FaBiT, Alma Mater Studiorum–University of Bologna, Bologna, ItalyDepartment of Pharmacy and BioTechnology–FaBiT, Alma Mater Studiorum–University of Bologna, Bologna, ItalyDepartment of Medical Biotechnology and Translational Medicine, University of Milan, Milan, ItalyDepartment of Medical Biotechnology and Translational Medicine, University of Milan, Milan, ItalyInstitute of Chemistry, Federal University of Alfenas, Alfenas, MG, BrazilInstitute of Chemistry, Federal University of Alfenas, Alfenas, MG, BrazilInstitute of Chemistry, Federal University of Alfenas, Alfenas, MG, BrazilInstitute of Exact Sciences, Federal University of Alfenas, Alfenas, MG, BrazilDepartment for Life Quality Studies-QuVi, Alma Mater Studiorum-University of Bologna, Rimini, ItalyDepartment for Life Quality Studies-QuVi, Alma Mater Studiorum-University of Bologna, Rimini, ItalyDepartment of Pharmacy and BioTechnology–FaBiT, Alma Mater Studiorum–University of Bologna, Bologna, ItalyAlzheimer’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 Aβ1-42 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.https://www.frontiersin.org/article/10.3389/fphar.2019.00658/fullAlzheimer’s diseaseamyloid-β oligomersoxidative stressapoptosisneuroprotectionmultitarget ligand |
| spellingShingle | Fabiana Morroni Giulia Sita Agnese Graziosi Gloria Ravegnini Raffaella Molteni Maria Serena Paladini Kris Simone Tranches Dias Ariele Faria dos Santos Claudio Viegas Ihosvany Camps Letizia Pruccoli Andrea Tarozzi Patrizia Hrelia PQM130, a Novel Feruloyl–Donepezil Hybrid Compound, Effectively Ameliorates the Cognitive Impairments and Pathology in a Mouse Model of Alzheimer’s Disease Frontiers in Pharmacology Alzheimer’s disease amyloid-β oligomers oxidative stress apoptosis neuroprotection multitarget ligand |
| 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 | Alzheimer’s disease amyloid-β oligomers oxidative stress apoptosis neuroprotection multitarget ligand |
| url | https://www.frontiersin.org/article/10.3389/fphar.2019.00658/full |
| work_keys_str_mv | AT fabianamorroni pqm130anovelferuloyldonepezilhybridcompoundeffectivelyamelioratesthecognitiveimpairmentsandpathologyinamousemodelofalzheimersdisease AT giuliasita pqm130anovelferuloyldonepezilhybridcompoundeffectivelyamelioratesthecognitiveimpairmentsandpathologyinamousemodelofalzheimersdisease AT agnesegraziosi pqm130anovelferuloyldonepezilhybridcompoundeffectivelyamelioratesthecognitiveimpairmentsandpathologyinamousemodelofalzheimersdisease AT gloriaravegnini pqm130anovelferuloyldonepezilhybridcompoundeffectivelyamelioratesthecognitiveimpairmentsandpathologyinamousemodelofalzheimersdisease AT raffaellamolteni pqm130anovelferuloyldonepezilhybridcompoundeffectivelyamelioratesthecognitiveimpairmentsandpathologyinamousemodelofalzheimersdisease AT mariaserenapaladini pqm130anovelferuloyldonepezilhybridcompoundeffectivelyamelioratesthecognitiveimpairmentsandpathologyinamousemodelofalzheimersdisease AT krissimonetranchesdias pqm130anovelferuloyldonepezilhybridcompoundeffectivelyamelioratesthecognitiveimpairmentsandpathologyinamousemodelofalzheimersdisease AT arielefariadossantos pqm130anovelferuloyldonepezilhybridcompoundeffectivelyamelioratesthecognitiveimpairmentsandpathologyinamousemodelofalzheimersdisease AT claudioviegas pqm130anovelferuloyldonepezilhybridcompoundeffectivelyamelioratesthecognitiveimpairmentsandpathologyinamousemodelofalzheimersdisease AT ihosvanycamps pqm130anovelferuloyldonepezilhybridcompoundeffectivelyamelioratesthecognitiveimpairmentsandpathologyinamousemodelofalzheimersdisease AT letiziapruccoli pqm130anovelferuloyldonepezilhybridcompoundeffectivelyamelioratesthecognitiveimpairmentsandpathologyinamousemodelofalzheimersdisease AT andreatarozzi pqm130anovelferuloyldonepezilhybridcompoundeffectivelyamelioratesthecognitiveimpairmentsandpathologyinamousemodelofalzheimersdisease AT patriziahrelia pqm130anovelferuloyldonepezilhybridcompoundeffectivelyamelioratesthecognitiveimpairmentsandpathologyinamousemodelofalzheimersdisease |