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RL-118 and 11β-HSD1 target engagement through TAPS assay: behaviour and molecular analysis

View ORCID ProfileD. Puigoriol-Illamola, J. Companys-Alemany, N. Homer, R. Leiva, S. Vázquez, D. Mole, View ORCID ProfileC. Griñán-Ferré, View ORCID ProfileM. Pallàs
doi: https://doi.org/10.1101/2020.10.27.356881
D. Puigoriol-Illamola
1Department of Pharmacology, Toxicology and Therapeutic Chemistry. Pharmacology Section. Faculty of Pharmacy and Food Sciences. University of Barcelona, Av Joan XXIII 27-31, 08028 Barcelona, Spain
2Institute of Neuroscience, University of Barcelona (NeuroUB), Passeig de la Vall d’Hebron 171, Barcelona, Spain
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J. Companys-Alemany
1Department of Pharmacology, Toxicology and Therapeutic Chemistry. Pharmacology Section. Faculty of Pharmacy and Food Sciences. University of Barcelona, Av Joan XXIII 27-31, 08028 Barcelona, Spain
2Institute of Neuroscience, University of Barcelona (NeuroUB), Passeig de la Vall d’Hebron 171, Barcelona, Spain
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N. Homer
3Mass Spectrometry Core, Edinburgh Clinical Research Facility, Queen’s Medical Research Institute, Edinburgh, United Kingdom
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R. Leiva
4Medicinal Chemistry Section. Department of Pharmacology, Toxicology and Therapeutic Chemistry. Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. Joan XXIII, 27-31, 08028 Barcelona, Spain
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S. Vázquez
4Medicinal Chemistry Section. Department of Pharmacology, Toxicology and Therapeutic Chemistry. Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. Joan XXIII, 27-31, 08028 Barcelona, Spain
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D. Mole
5MRC Centre for Inflammation Research, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
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C. Griñán-Ferré
1Department of Pharmacology, Toxicology and Therapeutic Chemistry. Pharmacology Section. Faculty of Pharmacy and Food Sciences. University of Barcelona, Av Joan XXIII 27-31, 08028 Barcelona, Spain
2Institute of Neuroscience, University of Barcelona (NeuroUB), Passeig de la Vall d’Hebron 171, Barcelona, Spain
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M. Pallàs
1Department of Pharmacology, Toxicology and Therapeutic Chemistry. Pharmacology Section. Faculty of Pharmacy and Food Sciences. University of Barcelona, Av Joan XXIII 27-31, 08028 Barcelona, Spain
2Institute of Neuroscience, University of Barcelona (NeuroUB), Passeig de la Vall d’Hebron 171, Barcelona, Spain
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  • For correspondence: pallas@ub.edu
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1. Abstract

Taking into consideration the convergence of ageing, stress and neurodegenerative diseases, such as AD, there is impaired GC signalling. Therefore, the study of GC-mediated stress response to chronic moderate stressful situations, as account in daily life, becomes of huge interest to design pharmacological strategies to prevent neurodegeneration.

To address this issue, SAMP8 were exposed for 4 weeks to the CMS paradigm and treated with RL-118, an 11β-HSD1 inhibitor. In fact, several pieces of evidence link the inhibition of this enzyme with reduction of GC levels and cognitive improvement, while CMS exposure has been associated with reduced cognitive performance. The aim of this project was to assess whether RL-118 treatment could restore the deleterious effects of CMS on cognition and behavioural abilities, but also on molecular mechanisms that compromise healthy ageing in SAMP8 mice.

On the one hand, we determined the target engagement between RL-118 and 11β-HSD1. Therefore all the beneficial effects previously described in SAMP8 treated with the drug can undoubtedly be attributed to the inhibition of this enzyme. Besides, herein we observed decreased DNA methylation, hydroxymethylation and histone phosphorylation induced by CMS but, on the contrary, increased after RL-118 treatment. In addition, CMS exposure produced ROS damage accumulation, and increments of pro-oxidant enzymes as well as pro-inflammatory mediators through NF-κB pathway and astrogliosis markers, like Gfap. Of note, those modifications were recovered by 11β-HSD1 inhibition. Remarkably, although CMS altered mTORC1 signalling, autophagy was increased in SAMP8 treated with RL-118 mice. Also, we found amyloidogenic APP processing pathway favoured and decreased synaptic plasticity and neuronal remodelling markers in mice under CMS, but changed after RL-118 treatment. In consequence, detrimental effects on behaviour and cognitive performance were detected in CMS exposed mice, but restored after concomitant 11β-HSD1 inhibition by RL-118.

Overall, CMS is a feasible intervention to understand the influence of stress on epigenetic mechanisms underlying cognition and accelerating senescence. However and most important, 11β-HSD1 inhibition through RL-118 turned up to restore the majority of these detrimental effects caused by CMS, indicating that GC excess attenuation may become a potential therapeutic strategy for age-related cognitive decline and AD.

Competing Interest Statement

The authors have declared no competing interest.

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RL-118 and 11β-HSD1 target engagement through TAPS assay: behaviour and molecular analysis
D. Puigoriol-Illamola, J. Companys-Alemany, N. Homer, R. Leiva, S. Vázquez, D. Mole, C. Griñán-Ferré, M. Pallàs
bioRxiv 2020.10.27.356881; doi: https://doi.org/10.1101/2020.10.27.356881
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RL-118 and 11β-HSD1 target engagement through TAPS assay: behaviour and molecular analysis
D. Puigoriol-Illamola, J. Companys-Alemany, N. Homer, R. Leiva, S. Vázquez, D. Mole, C. Griñán-Ferré, M. Pallàs
bioRxiv 2020.10.27.356881; doi: https://doi.org/10.1101/2020.10.27.356881

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