11B-HSD1 inhibition rescues cognitive disturbances after chronic mild stress in mice: target engagement determination through TAPS assay

Abstract

With the increase in life expectancy, the study of age-related diseases and the development of different strategies to deal with them become mandatory. Cognitive and behavioural disturbances are growing public healthcare issue for the modern society, which is experiencing an increasingly common stressful lifestyle. Taking into consideration the convergence of aging, stress and neurodegenerative diseases, such as AD, there is impaired glucocorticoid (GC) signalling. Therefore, the study of GC-mediated stress response to chronic moderate stressful (CMS) situations, as account in the daily life, becomes of huge interest in order to design pharmacological strategies to prevent neurodegeneration. Several pieces of evidence link the inhibition of 11β-HSD1 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, an 11β-HSD1 inhibitor, could restore the deleterious effects of CMS on cognition and behavioural abilities, but also acts on molecular mechanisms that compromise healthy aging in SAMP8 mice.