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A bicyclic α‑iminophosphonate improves cognitive decline in 5xFAD murine model of neurodegeneration

Authors :
Fotini Vasilopoulou
José Brea
Belén Pérez
Christian Griñán-Ferré
Pilar Pérez-Lozano
Jesús A. García-Sevilla
Milica Radan
Sergio Rodríguez-Arévalo
José Pérez del Palacio
Carolina Muguruza
Carmen Ramos
Mercè Pallàs
Luis F. Callado
M.J. García-Fuster
Francisca Vicente
Elena Hernández-Hernández
Carmen Escolano
Elies Molins
Teodora Djikic
María Isabel Loza
Iria Brocos-Mosquera
Andrea Bagán
Katarina Nikolic
Abas Sonia
Caridad Díaz
Source :
The FASEB Journal, Dipòsit Digital de la UB, Universidad de Barcelona
Publication Year :
2021
Publisher :
Wiley, 2021.

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.

Details

Language :
English
Database :
OpenAIRE
Journal :
The FASEB Journal, Dipòsit Digital de la UB, Universidad de Barcelona
Accession number :
edsair.doi.dedup.....add9d2bad79496b1ee91dc68411c7a91