Abstract
Glucocorticoids are crucial for stress-coping, resilience, and adaptation. However, if the stress hormones become dysregulated, the vulnerability to stress-related diseases is enhanced. In this brief review, we discuss the role of glucocorticoids in the pathogenesis of neurodegenerative disorders in both human and animal models, and focus in particular on amyotrophic lateral sclerosis (ALS). For this purpose, we used the Wobbler animal model, which mimics much of the pathology of ALS including a dysfunctional hypothalamic–pituitary–adrenal axis. We discuss recent studies that demonstrated that the pathological cascade characteristic for motoneuron degeneration of ALS is mimicked in the genetically selected Wobbler mouse and can be attenuated by treatment with the selective glucocorticoid receptor antagonist (GRA) CORT113176. In long-term treatment (3 weeks) GRA attenuated progression of the behavioral, inflammatory, excitatory, and cell-death-signaling pathways while increasing the survival signal of serine–threonine kinase (pAkt). The action mechanism of the GRA may be either by interfering with GR deactivation or by restoring the balance between pro- and anti-inflammatory signaling pathways driven by the complementary mineralocorticoid receptor (MR)- and GR-mediated actions of corticosterone. Accordingly, GR antagonism may have clinical relevance for the treatment of neurodegenerative diseases.
Highlights
The global rise of life expectancy is increasing the incidence of neurodegenerative diseases
CORT113176 was given to male and female Wobbler mice at the dose of 30 mg/kg for 3 weeks, at the end of which we analyzed whether the glial-derived pro-inflammatory mediators were curtailed. After this dose and period of treatment, we found that CORT113176 decreased astro and microgliosis, and downregulated the inflammatory mediator HMGB1 and its cognate receptor toll-like receptor 4 (TLR4) in immunoreactive cells showing a glial morphology
NFκB prime the NLRP3 inflammasome and increase the transcription of genes dependent on analyzed whether the glial-derived pro-inflammatory mediators were curtailed
Summary
The global rise of life expectancy is increasing the incidence of neurodegenerative diseases. Patients with metabolic syndrome show poor cognition, oxidative stress, and neuroinflammation, accompanied by hypercortisolemia, a highly reactive HPA axis, and dysregulation of the cortisol-producing enzyme HSD1 [26]. Depression is comorbid with neurodegeneration [28], and patients with depression, in particular if their depression is accompanied by psychotic symptoms, show resistance to glucocorticoid suppression of the HPA axis and high levels of circulating cortisol and ACTH [27,28]. Another example comes from patients with stroke, a circumstance leading to secondary neurodegeneration. The concomitant changes in the production, action, central regulation, and rhythm of glucocorticoids with changes of brain pathology have led to cortisol being proposed as a biomarker of human neurodegeneration [15]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
