Insights into the Therapeutic Potential of Glucocorticoid Receptor Modulators for Neurodegenerative Diseases

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.

Chronic Glucocorticoids Consumption Triggers and Worsens Experimental Alzheimer’s Disease-Like Pathology by Detrimental Immune Modulations

“…It also highlights the therapeutic potential of new GR modulators, called sGRm, which are in capacity to re-establish GR functioning and signaling pathways and subsequent HPA axis physiological activity. These compounds represent a really attractive therapeutic approach in all stress-related disorders, pathologies displaying GC overproduction, or pathology needing an anti-inflammatory treatment [4,19,[100][101][102][103].…”

Neuroprotective Efficacy of the Glucocorticoid Receptor Modulator PT150 in the Rotenone Mouse Model of Parkinson’s Disease

“…Although largely anti-inflammatory effects of GR modulation have been described, it must be noted that GCs do not have solely immunosuppressive actions. GR agonism can sometimes increase pro-inflammatory responses in the brain, though these inflammatory actions have, thus far, been described primarily in the hippocampus [46]. The ubiquitous expression of GRs within parenchymal cells of the CNS also means there is the potential for undesired effects in some cell populations, such that therapeutics that solely act as GR agonists or antagonists may prove ineffective or problematic.…”

“…The ubiquitous expression of GRs within parenchymal cells of the CNS also means there is the potential for undesired effects in some cell populations, such that therapeutics that solely act as GR agonists or antagonists may prove ineffective or problematic. This is demonstrated by other models of PD, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity, where inactivating astrocytic GRs exacerbated DAn loss [21, 46]. Because PT150 is thought to allosterically modulate GR by binding to the co-activator domain of the receptor and thereby inhibit pro-inflammatory transcription, it may function as a better inhibitor of neuroinflammation [25].…”

Early Hormone Administration and Antibiotic Treatment is Key to Managing Cutaneous Anthrax

“…Bacillus anthracis is a Gram-positive bacterium whose exotoxins increase the permeability of capillary walls, causing local edema [1]. Glucocorticoids (GCS) are steroid hormones secreted by the adrenal cortex [25]. At high doses, they can produce strong pharmacological effects.…”