A bicyclic α-iminophosphonate improves cognitive decline in 5xFAD murine model of neurodegeneration
I2 receptors (I2-IR) are widely distributed in the central nervous system. I2-IR ligands are associated with a neuroprotective effect but, as I2-IR structure remains unknown, the discovery of better and more selective ligands is necessary to understand the pharmacological and molecular implications...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Estado: | Versión enviada para evaluación y publicación |
| Fecha de publicación: | 2021 |
| País: | España |
| Institución: | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| Repositorio: | Recercat. Dipósit de la Recerca de Catalunya |
| OAI Identifier: | oai:recercat.cat:2445/178883 |
| Acceso en línea: | https://hdl.handle.net/2445/178883 |
| Access Level: | acceso abierto |
| Palabra clave: | Malaltia d'Alzheimer Malalties neurodegeneratives Envelliment Alzheimer's disease Neurodegenerative Diseases Aging |
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A bicyclic α-iminophosphonate improves cognitive decline in 5xFAD murine model of neurodegenerationEscolano Mirón, CarmenAbás Prades, SòniaRodríguez-Arévalo, SergioBagan Polonio, AndreaGriñán Ferré, ChristianVasilopoulou, FoteiniBrocos-Mosquera, IriaMuguruza, CarolinaCallado, Luis F.Pérez, BelénPérez Lozano, PilarBrea, JoséLoza, María IsabelHernández-Hernández, ElenaGarcía-Sevilla, Jesús AGarcía-Fuster, M. JuliaRadan, MilicaDjikic, TeodoraNikolic, KatarinaDíaz, C.Pérez, J.Ramos Guerra, CristianVicente, FilipaMolins i Grau, EliesPallàs i Llibería, Mercè, 1964-Malaltia d'AlzheimerMalalties neurodegenerativesEnvellimentAlzheimer's diseaseNeurodegenerative DiseasesAgingI2 receptors (I2-IR) are widely distributed in the central nervous system. I2-IR ligands are associated with a neuroprotective effect but, as I2-IR structure remains unknown, the discovery of better and more selective ligands is necessary to understand the pharmacological and molecular implications of I2-IR. Recently, we described a new imidazoline-structure family which showed high affinity and selectivity for I2-IR. In vivo studies in mice indicated a neuroprotective role and revealed beneficial effects in behaviour and cognition with a murine model of neurodegeneration, senescence-accelerated prone mouse (SAMP8). Herein, we report a novel non-imidazoline-structure of bicyclic α-iminophosphonates family with high affinities for I2-IR. In vivo studies in 5X-FAD mice (a transgenic representative model of AD) and SAMP8 mice (a model of neurodegeneration linked to aging) showed an improvement in behaviour and cognition, a reduction of AD hallmarks and of neuroinflammation markers for the mice treated with the lead compound B06. After evaluating several pathways associated with neurodegeneration, we demonstrated that CaN pathway plays a critical role on the neuroprotective effects of I2-IR ligands on SAMP8 mice model. To rule out warnings of the novel family, we calculated DMPK and physicochemical properties for the novel bicyclic α-iminophosphonates. As well, we carried out drug metabolism, safety studies and in vivo pharmacokinetics for lead compound B06. In summary, we present a novel family of I2-IR ligands, its effectiveness in in vivo models and the possible neuroprotective molecular mechanism mediated by them. This highlights that the modulation of I2-IR by bicyclic α-iminophosphonates may open a new therapeutic venue for unmet neurodegenerative conditions.The Federation of American Society of Experimental Biology2021202120212021info:eu-repo/semantics/articleinfo:eu-repo/semantics/submittedVersionapplication/pdfhttps://hdl.handle.net/2445/178883Articles 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 preprint del document publicat a: https://doi.org/10.1096/fasebj.2021.35.S1.04974The FASEB Journal , 2021, vol. 35, num. S1https://doi.org/10.1096/fasebj.2021.35.S1.04974(c) The Federation of American Society of Experimental Biology, 2021info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1788832026-05-29T05:05:01Z |
| dc.title.none.fl_str_mv |
A bicyclic α-iminophosphonate improves cognitive decline in 5xFAD murine model of neurodegeneration |
| title |
A bicyclic α-iminophosphonate improves cognitive decline in 5xFAD murine model of neurodegeneration |
| spellingShingle |
A bicyclic α-iminophosphonate improves cognitive decline in 5xFAD murine model of neurodegeneration Escolano Mirón, Carmen Malaltia d'Alzheimer Malalties neurodegeneratives Envelliment Alzheimer's disease Neurodegenerative Diseases Aging |
| title_short |
A bicyclic α-iminophosphonate improves cognitive decline in 5xFAD murine model of neurodegeneration |
| title_full |
A bicyclic α-iminophosphonate improves cognitive decline in 5xFAD murine model of neurodegeneration |
| title_fullStr |
A bicyclic α-iminophosphonate improves cognitive decline in 5xFAD murine model of neurodegeneration |
| title_full_unstemmed |
A bicyclic α-iminophosphonate improves cognitive decline in 5xFAD murine model of neurodegeneration |
| title_sort |
A bicyclic α-iminophosphonate improves cognitive decline in 5xFAD murine model of neurodegeneration |
| dc.creator.none.fl_str_mv |
Escolano Mirón, Carmen Abás Prades, Sònia Rodríguez-Arévalo, Sergio Bagan Polonio, Andrea Griñán Ferré, Christian Vasilopoulou, Foteini Brocos-Mosquera, Iria Muguruza, Carolina Callado, Luis F. Pérez, Belén Pérez Lozano, Pilar Brea, José Loza, María Isabel Hernández-Hernández, Elena García-Sevilla, Jesús A García-Fuster, M. Julia Radan, Milica Djikic, Teodora Nikolic, Katarina Díaz, C. Pérez, J. Ramos Guerra, Cristian Vicente, Filipa Molins i Grau, Elies Pallàs i Llibería, Mercè, 1964- |
| author |
Escolano Mirón, Carmen |
| author_facet |
Escolano Mirón, Carmen Abás Prades, Sònia Rodríguez-Arévalo, Sergio Bagan Polonio, Andrea Griñán Ferré, Christian Vasilopoulou, Foteini Brocos-Mosquera, Iria Muguruza, Carolina Callado, Luis F. Pérez, Belén Pérez Lozano, Pilar Brea, José Loza, María Isabel Hernández-Hernández, Elena García-Sevilla, Jesús A García-Fuster, M. Julia Radan, Milica Djikic, Teodora Nikolic, Katarina Díaz, C. Pérez, J. Ramos Guerra, Cristian Vicente, Filipa Molins i Grau, Elies Pallàs i Llibería, Mercè, 1964- |
| author_role |
author |
| author2 |
Abás Prades, Sònia Rodríguez-Arévalo, Sergio Bagan Polonio, Andrea Griñán Ferré, Christian Vasilopoulou, Foteini Brocos-Mosquera, Iria Muguruza, Carolina Callado, Luis F. Pérez, Belén Pérez Lozano, Pilar Brea, José Loza, María Isabel Hernández-Hernández, Elena García-Sevilla, Jesús A García-Fuster, M. Julia Radan, Milica Djikic, Teodora Nikolic, Katarina Díaz, C. Pérez, J. Ramos Guerra, Cristian Vicente, Filipa Molins i Grau, Elies Pallàs i Llibería, Mercè, 1964- |
| author2_role |
author author author author author author author author author author author author author author author author author author author 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 |
I2 receptors (I2-IR) are widely distributed in the central nervous system. I2-IR ligands are associated with a neuroprotective effect but, as I2-IR structure remains unknown, the discovery of better and more selective ligands is necessary to understand the pharmacological and molecular implications of I2-IR. Recently, we described a new imidazoline-structure family which showed high affinity and selectivity for I2-IR. In vivo studies in mice indicated a neuroprotective role and revealed beneficial effects in behaviour and cognition with a murine model of neurodegeneration, senescence-accelerated prone mouse (SAMP8). Herein, we report a novel non-imidazoline-structure of bicyclic α-iminophosphonates family with high affinities for I2-IR. In vivo studies in 5X-FAD mice (a transgenic representative model of AD) and SAMP8 mice (a model of neurodegeneration linked to aging) showed an improvement in behaviour and cognition, a reduction of AD hallmarks and of neuroinflammation markers for the mice treated with the lead compound B06. After evaluating several pathways associated with neurodegeneration, we demonstrated that CaN pathway plays a critical role on the neuroprotective effects of I2-IR ligands on SAMP8 mice model. To rule out warnings of the novel family, we calculated DMPK and physicochemical properties for the novel bicyclic α-iminophosphonates. As well, we carried out drug metabolism, safety studies and in vivo pharmacokinetics for lead compound B06. In summary, we present a novel family of I2-IR ligands, its effectiveness in in vivo models and the possible neuroprotective molecular mechanism mediated by them. This highlights that the modulation of I2-IR by bicyclic α-iminophosphonates may open a new therapeutic venue for unmet neurodegenerative conditions. |
| publishDate |
2021 |
| dc.date.none.fl_str_mv |
2021 2021 2021 2021 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/submittedVersion |
| format |
article |
| status_str |
submittedVersion |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/2445/178883 |
| url |
https://hdl.handle.net/2445/178883 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
Versió preprint del document publicat a: https://doi.org/10.1096/fasebj.2021.35.S1.04974 The FASEB Journal , 2021, vol. 35, num. S1 https://doi.org/10.1096/fasebj.2021.35.S1.04974 |
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(c) The Federation of American Society of Experimental Biology, 2021 info:eu-repo/semantics/openAccess |
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(c) The Federation of American Society of Experimental Biology, 2021 |
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openAccess |
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application/pdf |
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The Federation of American Society of Experimental Biology |
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The Federation of American Society of Experimental Biology |
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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) |
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Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
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Recercat. Dipósit de la Recerca de Catalunya |
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