A Combined Chronic Low-Dose Soluble Epoxide Hydrolase and Acetylcholinesterase Pharmacological Inhibition Promotes Memory Reinstatement in Alzheimer's Disease Mice Models

Alzheimer's disease (AD) is a progressive neurological disorder with multifactorial and heterogeneous causes. AD involves several etiopathogenic mechanisms such as aberrant protein accumulation, neurotransmitter deficits, synaptic dysfunction and neuroinflammation, which lead to cognitive decli...

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Autores: Jarne Ferrer, Júlia, Griñán Ferré, Christian, Bellver Sanchis, Aina, Vázquez Cruz, Santiago, Muñoz-Torrero López-Ibarra, Diego, Pallàs i Llibería, Mercè, 1964-
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/189390
Acceso en línea:https://hdl.handle.net/2445/189390
Access Level:acceso abierto
Palabra clave:Malaltia d'Alzheimer
Malalties neurodegeneratives
Química farmacèutica
Alzheimer's disease
Neurodegenerative Diseases
Pharmaceutical chemistry
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spelling A Combined Chronic Low-Dose Soluble Epoxide Hydrolase and Acetylcholinesterase Pharmacological Inhibition Promotes Memory Reinstatement in Alzheimer's Disease Mice ModelsJarne Ferrer, JúliaGriñán Ferré, ChristianBellver Sanchis, AinaVázquez Cruz, SantiagoMuñoz-Torrero López-Ibarra, DiegoPallàs i Llibería, Mercè, 1964-Malaltia d'AlzheimerMalalties neurodegenerativesQuímica farmacèuticaAlzheimer's diseaseNeurodegenerative DiseasesPharmaceutical chemistryAlzheimer's disease (AD) is a progressive neurological disorder with multifactorial and heterogeneous causes. AD involves several etiopathogenic mechanisms such as aberrant protein accumulation, neurotransmitter deficits, synaptic dysfunction and neuroinflammation, which lead to cognitive decline. Unfortunately, the currently available anti-AD drugs only alleviate the symptoms temporarily and provide a limited therapeutic effect. Thus, new therapeutic strategies, including multitarget approaches, are urgently needed. It has been demonstrated that a co-treatment of acetylcholinesterase (AChE) inhibitor with other neuroprotective agents has beneficial effects on cognition. Here, we have assessed the neuroprotective effects of chronic dual treatment with a soluble epoxide hydrolase (sEH) inhibitor (TPPU) and an AChE inhibitor (6-chlorotacrine or rivastigmine) in in vivo studies. Interestingly, we have found beneficial effects after chronic low-dose co-treatment with TPPU and 6-chlorotacrine in the senescence-accelerated mouse prone 8 (SAMP8) mouse model as well as with TPPU and rivastigmine co-treatment in the 5XFAD mouse model, in comparison with the corresponding monotherapy treatments. In the SAMP8 model, no substantial improvements in synaptic plasticity markers were found, but the co-treatment of TPPU and 6-chlorotacrine led to a significantly reduced gene expression of neuroinflammatory markers, such as interleukin 6 (Il-6), triggering receptor expressed on myeloid cell 2 (Trem2) and glial fibrillary acidic protein (Gfap). In 5XFAD mice, chronic low-dose co-treatment of TPPU and rivastigmine led to enhanced protein levels of synaptic plasticity markers, such as the phospho-cAMP response element-binding protein (p- CREB) ratio, brain-derived neurotrophic factor (BDNF) and postsynaptic density protein 95 (PSD95), and also to a reduction in neuroinflammatory gene expression. Collectively, these results support the neuroprotectant role of chronic low-dose co-treatment strategy with sEH and AChE inhibitors in AD mouse models, opening new avenues for effective AD treatment.MDPI2022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/189390Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.3390/ph15080908Pharmaceuticals, 2022, vol. 15, num. 8, p. 908https://doi.org/10.3390/ph15080908cc-by (c) Jarné-Ferrer, Júlia et al., 2022https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1893902026-05-27T06:46:51Z
dc.title.none.fl_str_mv A Combined Chronic Low-Dose Soluble Epoxide Hydrolase and Acetylcholinesterase Pharmacological Inhibition Promotes Memory Reinstatement in Alzheimer's Disease Mice Models
title A Combined Chronic Low-Dose Soluble Epoxide Hydrolase and Acetylcholinesterase Pharmacological Inhibition Promotes Memory Reinstatement in Alzheimer's Disease Mice Models
spellingShingle A Combined Chronic Low-Dose Soluble Epoxide Hydrolase and Acetylcholinesterase Pharmacological Inhibition Promotes Memory Reinstatement in Alzheimer's Disease Mice Models
Jarne Ferrer, Júlia
Malaltia d'Alzheimer
Malalties neurodegeneratives
Química farmacèutica
Alzheimer's disease
Neurodegenerative Diseases
Pharmaceutical chemistry
title_short A Combined Chronic Low-Dose Soluble Epoxide Hydrolase and Acetylcholinesterase Pharmacological Inhibition Promotes Memory Reinstatement in Alzheimer's Disease Mice Models
title_full A Combined Chronic Low-Dose Soluble Epoxide Hydrolase and Acetylcholinesterase Pharmacological Inhibition Promotes Memory Reinstatement in Alzheimer's Disease Mice Models
title_fullStr A Combined Chronic Low-Dose Soluble Epoxide Hydrolase and Acetylcholinesterase Pharmacological Inhibition Promotes Memory Reinstatement in Alzheimer's Disease Mice Models
title_full_unstemmed A Combined Chronic Low-Dose Soluble Epoxide Hydrolase and Acetylcholinesterase Pharmacological Inhibition Promotes Memory Reinstatement in Alzheimer's Disease Mice Models
title_sort A Combined Chronic Low-Dose Soluble Epoxide Hydrolase and Acetylcholinesterase Pharmacological Inhibition Promotes Memory Reinstatement in Alzheimer's Disease Mice Models
dc.creator.none.fl_str_mv Jarne Ferrer, Júlia
Griñán Ferré, Christian
Bellver Sanchis, Aina
Vázquez Cruz, Santiago
Muñoz-Torrero López-Ibarra, Diego
Pallàs i Llibería, Mercè, 1964-
author Jarne Ferrer, Júlia
author_facet Jarne Ferrer, Júlia
Griñán Ferré, Christian
Bellver Sanchis, Aina
Vázquez Cruz, Santiago
Muñoz-Torrero López-Ibarra, Diego
Pallàs i Llibería, Mercè, 1964-
author_role author
author2 Griñán Ferré, Christian
Bellver Sanchis, Aina
Vázquez Cruz, Santiago
Muñoz-Torrero López-Ibarra, Diego
Pallàs i Llibería, Mercè, 1964-
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv Malaltia d'Alzheimer
Malalties neurodegeneratives
Química farmacèutica
Alzheimer's disease
Neurodegenerative Diseases
Pharmaceutical chemistry
topic Malaltia d'Alzheimer
Malalties neurodegeneratives
Química farmacèutica
Alzheimer's disease
Neurodegenerative Diseases
Pharmaceutical chemistry
description Alzheimer's disease (AD) is a progressive neurological disorder with multifactorial and heterogeneous causes. AD involves several etiopathogenic mechanisms such as aberrant protein accumulation, neurotransmitter deficits, synaptic dysfunction and neuroinflammation, which lead to cognitive decline. Unfortunately, the currently available anti-AD drugs only alleviate the symptoms temporarily and provide a limited therapeutic effect. Thus, new therapeutic strategies, including multitarget approaches, are urgently needed. It has been demonstrated that a co-treatment of acetylcholinesterase (AChE) inhibitor with other neuroprotective agents has beneficial effects on cognition. Here, we have assessed the neuroprotective effects of chronic dual treatment with a soluble epoxide hydrolase (sEH) inhibitor (TPPU) and an AChE inhibitor (6-chlorotacrine or rivastigmine) in in vivo studies. Interestingly, we have found beneficial effects after chronic low-dose co-treatment with TPPU and 6-chlorotacrine in the senescence-accelerated mouse prone 8 (SAMP8) mouse model as well as with TPPU and rivastigmine co-treatment in the 5XFAD mouse model, in comparison with the corresponding monotherapy treatments. In the SAMP8 model, no substantial improvements in synaptic plasticity markers were found, but the co-treatment of TPPU and 6-chlorotacrine led to a significantly reduced gene expression of neuroinflammatory markers, such as interleukin 6 (Il-6), triggering receptor expressed on myeloid cell 2 (Trem2) and glial fibrillary acidic protein (Gfap). In 5XFAD mice, chronic low-dose co-treatment of TPPU and rivastigmine led to enhanced protein levels of synaptic plasticity markers, such as the phospho-cAMP response element-binding protein (p- CREB) ratio, brain-derived neurotrophic factor (BDNF) and postsynaptic density protein 95 (PSD95), and also to a reduction in neuroinflammatory gene expression. Collectively, these results support the neuroprotectant role of chronic low-dose co-treatment strategy with sEH and AChE inhibitors in AD mouse models, opening new avenues for effective AD treatment.
publishDate 2022
dc.date.none.fl_str_mv 2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/189390
url https://hdl.handle.net/2445/189390
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.3390/ph15080908
Pharmaceuticals, 2022, vol. 15, num. 8, p. 908
https://doi.org/10.3390/ph15080908
dc.rights.none.fl_str_mv cc-by (c) Jarné-Ferrer, Júlia et al., 2022
https://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Jarné-Ferrer, Júlia et al., 2022
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300724

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