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A bicyclic α-iminophosphonate improves cognitive decline in 5xFAD murine model of neurodegeneration
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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.
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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. A bicyclic α-iminophosphonate improves cognitive decline in 5xFAD murine model of neurodegeneration. _The FASEB Journal _. 2021. Vol. 35, núm. S1. [consulta: 14 de gener de 2026]. ISSN: 0892-6638. [Disponible a: https://hdl.handle.net/2445/178883]