Title:Contribution of Glucocorticoids and Glucocorticoid Receptors to the Regulation of Neurodegenerative Processes
VOLUME: 12 ISSUE: 8
Author(s):Sheela Vyas and Layal Maatouk
Affiliation:CNRS UMR7224, 9 Quai St Bernard, F-75005, Paris France.
Keywords:Glucocorticoids, glucocorticoid receptors, hypothalamic-pituitary-adrenal axis, neurodegenerative diseases, stress.
Abstract:Isolation of glucocorticoids (GCs) from adrenal glands followed by synthesis led rapidly to their first clinical
application, about 70 years ago, for treatment of rheumatoid arthritis. To this day GCs are used in diseases that have an
inflammatory component. However, their use is carefully monitored because of harmful side effects. GCs are also
synonymous with stress and adaptation. In CNS, GC binds and activates high affinity mineralocorticoid receptor (MR)
and low affinity glucocorticoid receptor (GR). GR, whose expression is ubiquitous, is only activated when GC levels rise
as during circadian peak and in response to stress. Numerous recent studies have yielded important and new insights on
the mechanisms concerning pulsatile secretory pattern of GCs as well as various processes that tightly control their
synthesis via hypothalamic-pituitary-adrenal (HPA) axis involving regulated release of corticotropin-releasing hormone
(CRH) and adrenocorticotropic hormone (ACTH) from hypothalamus and pituitary, respectively. GR modulates neuronal
functions and viability through both genomic and non-genomic actions, and importantly its transcriptional regulatory
activity is tightly locked with GC secretory pattern. There is increasing evidence pointing to involvement of GC-GR in
neurodegenerative disorders. Patients with Alzheimer’s or Parkinson’s or Huntington’s disease show chronically high
cortisol levels suggesting changes occurring in controls of HPA axis. In experimental models of these diseases, chronic
stress or GC treatment was found to exacerbate both the clinical symptoms and neurodegenerative processes. However,
recent evidence also shows that GC-GR can exert neuroprotective effects. Thus, for any potential therapeutic strategies in
these neurodegenerative diseases we need to understand the precise modifications both in HPA axis and in GR activity
and find ways to harness their protective actions.
