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Article

Inhibition of 11β-HSD1 Ameliorates Cognition and Molecular Detrimental Changes after Chronic Mild Stress in SAMP8 Mice

1
Pharmacology 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
2
Institute of Neuroscience, University of Barcelona (NeuroUB), Passeig Vall d’Hebron 171, 08028 Barcelona, Spain
3
MRC Centre for Inflammation Research, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK
4
Mass Spectrometry Core, Edinburgh Clinical Research Facility, Queen’s Medical Research Institute, Edinburgh EH16 4TJ, UK
5
Medicinal 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
*
Author to whom correspondence should be addressed.
Academic Editors: Stefano Puglisi-Allegra and Francesco Fornai
Pharmaceuticals 2021, 14(10), 1040; https://doi.org/10.3390/ph14101040
Received: 10 September 2021 / Revised: 28 September 2021 / Accepted: 8 October 2021 / Published: 13 October 2021
(This article belongs to the Special Issue Stress, Neurotransmitters and Neurodegeneration)
Impaired glucocorticoid (GC) signaling is a significant factor in aging, stress, and neurodegenerative diseases such as Alzheimer’s disease. Therefore, the study of GC-mediated stress responses to chronic moderately stressful situations, which occur in daily life, is of huge interest for the design of pharmacological strategies toward the prevention of neurodegeneration. To address this issue, SAMP8 mice were exposed to the chronic mild stress (CMS) paradigm for 4 weeks and treated with RL-118, an 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor. The inhibition of this enzyme is linked with a reduction in 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 reverse the deleterious effects of CMS on cognition and behavioral abilities and to evaluate the molecular mechanisms that compromise healthy aging in SAMP8 mice. First, we confirmed the target engagement between RL-118 and 11β-HSD1. Additionally, we showed that DNA methylation, hydroxymethylation, and histone phosphorylation were decreased by CMS induction, and increased by RL-118 treatment. In addition, CMS exposure caused the accumulation of reactive oxygen species (ROS)-induced damage and increased pro-oxidant enzymes—as well as pro-inflammatory mediators—through the NF-κB pathway and astrogliosis markers, such as GFAP. Of note, these modifications were reversed by 11β-HSD1 inhibition. Remarkably, although CMS altered mTORC1 signaling, autophagy was increased in the SAMP8 RL-118-treated mice. We also showed an increase in amyloidogenic processes and a decrease in synaptic plasticity and neuronal remodeling markers in mice under CMS, which were consequently modified by RL-118 treatment. In conclusion, 11β-HSD1 inhibition through RL-118 ameliorated the detrimental effects induced by CMS, including epigenetic and cognitive disturbances, indicating that GC-excess attenuation shows potential as a therapeutic strategy for age-related cognitive decline and AD. View Full-Text
Keywords: glucocorticoids; stress; target engagement; aging; epigenetics; oxidative stress; inflammation; neurodegeneration; cognition glucocorticoids; stress; target engagement; aging; epigenetics; oxidative stress; inflammation; neurodegeneration; cognition
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MDPI and ACS Style

Puigoriol-Illamola, D.; Companys-Alemany, J.; McGuire, K.; Homer, N.Z.M.; Leiva, R.; Vázquez, S.; Mole, D.J.; Griñán-Ferré, C.; Pallàs, M. Inhibition of 11β-HSD1 Ameliorates Cognition and Molecular Detrimental Changes after Chronic Mild Stress in SAMP8 Mice. Pharmaceuticals 2021, 14, 1040. https://doi.org/10.3390/ph14101040

AMA Style

Puigoriol-Illamola D, Companys-Alemany J, McGuire K, Homer NZM, Leiva R, Vázquez S, Mole DJ, Griñán-Ferré C, Pallàs M. Inhibition of 11β-HSD1 Ameliorates Cognition and Molecular Detrimental Changes after Chronic Mild Stress in SAMP8 Mice. Pharmaceuticals. 2021; 14(10):1040. https://doi.org/10.3390/ph14101040

Chicago/Turabian Style

Puigoriol-Illamola, Dolors, Júlia Companys-Alemany, Kris McGuire, Natalie Z. M. Homer, Rosana Leiva, Santiago Vázquez, Damian J. Mole, Christian Griñán-Ferré, and Mercè Pallàs. 2021. "Inhibition of 11β-HSD1 Ameliorates Cognition and Molecular Detrimental Changes after Chronic Mild Stress in SAMP8 Mice" Pharmaceuticals 14, no. 10: 1040. https://doi.org/10.3390/ph14101040

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