Glucocorticoid receptor modulators

Abstract

The glucocorticoid hormone cortisol acts throughout the body to support circadian processes and adaptation to stress. The glucocorticoid receptor is the target of cortisol and of synthetic glucocorticoids, which are used widely in the clinic. Both agonism and antagonism of the glucocorticoid receptor may be beneficial in disease, but given the wide expression of the receptor and involvement in various processes, beneficial effects are often accompanied by unwanted side effects. Selective glucocorticoid receptor modulators are ligands that induce a receptor conformation that allows activation of only a subset of downstream signaling pathways. Such molecules thereby combine agonistic and antagonistic properties. Here we discuss the mechanisms underlying selective receptor modulation and their promise in treating diseases in several organ systems where cortisol signaling plays a role.

Glucocorticoid receptors signaling impairment potentiates amyloid‐β oligomers‐induced pathology in an acute model of Alzheimer’s disease

“…3,4 The HPA axis, highly involved in the stress response, triggers the adrenal cortex to release GC. 11 In an acute pathomimetic model of AD obtained after a single intracerebroventricular (icv) injection of an oligomeric solution of Aβ (oAβ [25][26][27][28][29][30][31][32][33][34][35], [12][13][14] we demonstrated a strong, long-lasting activation of the HPA axis, associated with a modification of GR and MR expression in brain regions involved in the control of GC secretion (hippocampus, amygdala, and hypothalamus), 15 supporting its involvement in the etiology of AD. 5 GC are necessary for normal cellular activity and fundamental for many CNS functions, including learning and memory.…”

“…These steroid hormones readily cross the BBB and bind to low-affinity glucocorticoid receptors (GR) and high-affinity mineralocorticoid receptors (MR). 9,[16][17][18][19] We also observed that an antagonist and selective modulators of the GR could potently counteract the effects of oAβ [25][26][27][28][29][30][31][32][33][34][35] injection in the hippocampus, arguing strongly for a therapeutic potential of modulating GR activity. 6 While MR are localized mainly in the hippocampus, GR are more ubiquitous and are particularly found in several structures of the limbic system (prefrontal cortex [PFC], hippocampus, and amygdala), which are strongly involved in cognitive and psychological functions but also are important components of the neural circuitry modulating HPA axis activity.…”

“…CORT113176 (10 mg/kg b.w. One group has not undergone surgery (control rats, white column), a second group received an icv injection of scrambled Aβ 25-35 peptide (negative control-10 µg/rat-orange column) and a third group received an icv injection of oAβ [25][26][27][28][29][30][31][32][33][34][35] peptide (Aβ-0 µg/rat-red column). The short-term memory or anxiety state of different groups of rats were tested (day 14) in a T-maze or in an elevated plus maze test (EPM), respectively.…”

“…36 Interest in this undecapeptide, which itself shows a β-sheet structure, 12,36 has grown over the last decade, mainly because it induces neurite atrophy, neuronal cell death, synaptic loss, as well as synaptic plasticity and memory deficits in a similar way to Aβ 1-40 and Aβ 1-42 , 37 but with better solubility and efficiency. Since soluble Aβ oligomers correlate better with the progression of the disease, 40 Aβ 25-35 and scrambled peptides were aggregated by in vitro incubation at 37°C (4 days) to obtain a solution mainly composed (more than 95%) of a mixture of soluble oligomer species (oAβ [25][26][27][28][29][30][31][32][33][34][35], as previously characterized. Since soluble Aβ oligomers correlate better with the progression of the disease, 40 Aβ 25-35 and scrambled peptides were aggregated by in vitro incubation at 37°C (4 days) to obtain a solution mainly composed (more than 95%) of a mixture of soluble oligomer species (oAβ [25][26][27][28][29][30][31][32][33][34][35], as previously characterized.…”

“…Rats were sacrificed by decapitation 15 days after oAβ [25][26][27][28][29][30][31][32][33][34][35] injection and brains were rapidly removed, PFC dissected out, weighted, frozen in liquid nitrogen, and stored at −80°C until assayed. After thawing, PFC were sonicated (VibraCell; Sonics & Materials, Newtown, CT, USA) for 20 seconds in a lysis buffer.…”