I 2 imidazoline receptor modulation protects aged SAMP8 mice against cognitive decline by suppressing the calcineurin pa
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ORIGINAL ARTICLE
I2 imidazoline receptor modulation protects aged SAMP8 mice against cognitive decline by suppressing the calcineurin pathway Foteini Vasilopoulou & Christian Griñán-Ferré & Sergio Rodríguez-Arévalo & Andrea Bagán & Sònia Abás & Carmen Escolano & Mercè Pallàs Received: 16 December 2019 / Accepted: 28 September 2020 # American Aging Association 2020
Abstract Brain aging and dementia are current problems that must be solved. The levels of imidazoline 2 receptors (I 2 -IRs) are increased in the brain in Alzheimer’s disease (AD) and other neurodegenerative diseases. We tested the action of the specific and selective I2-IR ligand B06 in a mouse model of accelerated aging and AD, the senescence-accelerated mouse prone 8 (SAMP8) model. Oral administration of B06 for 4 weeks improved SAMP8 mouse behavior and cognition and reduced AD hallmarks, oxidative stress, and apoptotic and neuroinflammation markers. Likewise, B06 regulated glial excitatory amino acid transporter 2 and N-methyl-D aspartate 2A and 2B receptor subunit protein levels. Calcineurin (CaN) is a phosphatase that controls the phosphorylation levels of cAMP response element-binding (CREB), apoptotic
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11357-020-00281-2) contains supplementary material, which is available to authorized users. F. Vasilopoulou : C. Griñán-Ferré : M. Pallàs (*) Pharmacology Section, Department of Pharmacology, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, and Institute of Neurociencies, University of Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, Spain e-mail: [email protected] S. Rodríguez-Arévalo : A. Bagán : S. Abás : C. Escolano Laboratory of Medicinal Chemistry (Associated Unit to CSIC), Department of Pharmacology, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, Spain
mediator BCL-2-associated agonist of cell death (BAD) and GSK3β, among other molecules. Interestingly, B06 was able to reduce the levels of the CaN active form (CaN A). Likewise, CREB phosphorylation, BAD gene expression, and other factors were modified after B06 treatment. Moreover, phosphorylation of a target of CaN, nuclear factor of activated Tcells, cytoplasmic 1 (NFATC1), was increased in B06treated mice, impeding the transcription of genes related to neuroinflammation and neural plasticity. In summary, this I2 imidazoline ligand can exert its beneficial effects on age-related conditions by modulating CaN pathway action and affecting several molecular pathways, playing a neuroprotective role in SAMP8 mice. Keywords I2 imidazoline receptors . Aging . Behavior . Neuroinflammation . NFAT . Neuroprotection . Alzheimer’s disease Abbreviations AD Alzheimer’s disease Aldh2 Aldehyde dehydrogenase 2 APP Amyloid precursor protein BAD BCL-2-Associated agonist of cell death Bdnf Brain-derived neurotrophic factor CaMKII Calcium calmodulin kinase II C
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