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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
Alzheimer's disease
Neurodegenerative Diseases
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:
It is part of: The FASEB Journal , 2021, vol. 35, num. S1
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ISSN: 0892-6638
Appears in Collections:Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)

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