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

International Journal of Molecular Sciences

Hazel Hunt¹  Joseph Belanoff¹  E.Ronald de Kloet²  Maria Meyer³  AlejandroF. De Nicola³  MariaClaudia Gonzalez Deniselle³  Michael Schumacher⁴  Rachida Guennoun⁴ 

[1] CORCEPT Therapeutics, 149 Commonwealth Dr, Menlo Park, CA 94025, USA;Division of Endocrinology, Dept. of Internal Medicine, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands;Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428 Buenos Aires, Argentina;U1195 Inserm and University Paris-Sud and University Paris Saclay 80 rue du Général Leclerc, 94276 Kremlin-Bicêtre, France;

关键词: wobbler mouse;    amyotrophic lateral sclerosis;    glucocorticoid receptor antagonist;    neurodegeneration;    neuroinflammation;   

DOI  :  10.3390/ijms21062137

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown