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http://hdl.handle.net/2445/178883
Title: | A bicyclic α-iminophosphonate improves cognitive decline in 5xFAD murine model of neurodegeneration |
Author: | 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- |
Keywords: | Malaltia d'Alzheimer Malalties neurodegeneratives Envelliment Alzheimer's disease Neurodegenerative Diseases Aging |
Issue Date: | 22-Jun-2021 |
Publisher: | The Federation of American Society of Experimental Biology |
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. |
Note: | Versió preprint del document publicat a: https://doi.org/10.1096/fasebj.2021.35.S1.04974 |
It is part of: | The FASEB Journal , 2021, vol. 35, num. S1 |
URI: | http://hdl.handle.net/2445/178883 |
Related resource: | https://doi.org/10.1096/fasebj.2021.35.S1.04974 |
ISSN: | 0892-6638 |
Appears in Collections: | Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica) |
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