Inhibition of 11β-HSD1, a key enzyme in the stress management, improves cognition by RL-118 drug treatment

Abstract

In recent years, stress and stress-coping mechanisms constitute a growing public healthcare issue concerning modern society. Experiencing stress engenders a great complex mechanism named stress response, which consists of a rapid release of catecholamines by the sympathetic nervous system, followed by a slower response in which hormones, mainly glucocorticoids (GCs), are synthesized and released to the bloodstream. Once the stressful stimulus is perceived, the hypothalamus secretes the corticotropin-releasing hormone (CRH), which acts on the pituitary gland, activating the release of adrenocorticotropic hormone (ACTH) that binds to the adrenal glands, promoting GC secretion and conforming the hypothalamus-hypophysis-adrenal (HPA) axis. Under normal conditions, GC secretion follows a robust circadian oscillation with a peak around the onset of the active period of the day, i.e., about 1 hour before arising [1]. This basal level of GC secretion is important in exerting tonic effects upon metabolic, immune and neuronal pathways, involving gluconeogenesis stimulation, protein degradation and lipolysis increase, priming of neural regions involved in sensory processing, attention and adaptive responding, as well as accounting for immunosuppressive and anti-inflammatory actions [2]. However, when stressful exposure is prolonged, the HPA axis deregulates and GC secretion is exacerbated. This excessive GC concentration leads to several metabolic, neurological and behavioral alterations, notably cognitive impairment and affective dysfunctions. GC activity is regulated by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme, which inhibition has been proved to restore metabolic and behavioral alterations, as well as enhance cognitive abilities. In fact, cortisol, the main active GC in humans, has been postulated as a potential biomarker for neurodegenerative disorders [3], like Alzheimer's disease (AD) in which aging is the major risk factor. Although it is completely assumed that stress directly influences the frailty phenotype in aged people, there are strikingly few measures to restrain stressful lifestyles in order to reduce the progression of pathological towards successful aging. Therefore, the study of stress effects on cognition and its relationship with aging is of the utmost importance to unveil what challenged we might have to cope with as a society in a not so far future.