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http://hdl.handle.net/2445/178883
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DC Field | Value | Language |
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dc.contributor.author | Escolano Mirón, Carmen | - |
dc.contributor.author | Abás Prades, Sònia | - |
dc.contributor.author | Rodríguez-Arévalo, Sergio | - |
dc.contributor.author | Bagan Polonio, Andrea | - |
dc.contributor.author | Griñán Ferré, Christian | - |
dc.contributor.author | Vasilopoulou, Foteini | - |
dc.contributor.author | Brocos-Mosquera, Iria | - |
dc.contributor.author | Muguruza, Carolina | - |
dc.contributor.author | Callado, Luis F. | - |
dc.contributor.author | Pérez, Belén | - |
dc.contributor.author | Pérez Lozano, Pilar | - |
dc.contributor.author | Brea, José | - |
dc.contributor.author | Loza, María Isabel | - |
dc.contributor.author | Hernández-Hernández, Elena | - |
dc.contributor.author | García-Sevilla, Jesús A | - |
dc.contributor.author | García-Fuster, M. Julia | - |
dc.contributor.author | Radan, Milica | - |
dc.contributor.author | Djikic, Teodora | - |
dc.contributor.author | Nikolic, Katarina | - |
dc.contributor.author | Díaz, C. | - |
dc.contributor.author | Pérez, J. | - |
dc.contributor.author | Ramos Guerra, Cristian | - |
dc.contributor.author | Vicente, Filipa | - |
dc.contributor.author | Molins i Grau, Elies | - |
dc.contributor.author | Pallàs i Llibería, Mercè, 1964- | - |
dc.date.accessioned | 2021-07-08T06:49:44Z | - |
dc.date.available | 2021-07-08T06:49:44Z | - |
dc.date.issued | 2021-06-22 | - |
dc.identifier.issn | 0892-6638 | - |
dc.identifier.uri | http://hdl.handle.net/2445/178883 | - |
dc.description.abstract | 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. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | - |
dc.publisher | The Federation of American Society of Experimental Biology | - |
dc.relation.isformatof | Versió preprint del document publicat a: https://doi.org/10.1096/fasebj.2021.35.S1.04974 | - |
dc.relation.ispartof | The FASEB Journal , 2021, vol. 35, num. S1 | - |
dc.relation.uri | https://doi.org/10.1096/fasebj.2021.35.S1.04974 | - |
dc.rights | (c) The Federation of American Society of Experimental Biology, 2021 | - |
dc.source | Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica) | - |
dc.subject.classification | Malaltia d'Alzheimer | - |
dc.subject.classification | Malalties neurodegeneratives | - |
dc.subject.classification | Envelliment | - |
dc.subject.other | Alzheimer's disease | - |
dc.subject.other | Neurodegenerative Diseases | - |
dc.subject.other | Aging | - |
dc.title | A bicyclic α-iminophosphonate improves cognitive decline in 5xFAD murine model of neurodegeneration | - |
dc.type | info:eu-repo/semantics/article | - |
dc.type | info:eu-repo/semantics/submittedVersion | - |
dc.identifier.idgrec | 712951 | - |
dc.date.updated | 2021-07-08T06:49:44Z | - |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | - |
Appears in Collections: | Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica) |
Files in This Item:
File | Description | Size | Format | |
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712951.pdf | 229.47 kB | Adobe PDF | View/Open |
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