Glucocorticoid receptor antagonist CORT113176 attenuates motor and neuropathological symptoms of Huntington's disease in R6/2 mice.

Autor: Gentenaar M; Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands. Electronic address: m.gentenaar@lumc.nl., Meulmeester FL; Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands., van der Burg XR; Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands., Hoekstra AT; Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands; Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands., Hunt H; Corcept Therapeutics, Menlo Park, CA, USA., Kroon J; Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands; Corcept Therapeutics, Menlo Park, CA, USA., van Roon-Mom WMC; Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands., Meijer OC; Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands.
Jazyk: angličtina
Zdroj: Experimental neurology [Exp Neurol] 2024 Apr; Vol. 374, pp. 114675. Date of Electronic Publication: 2024 Jan 10.
DOI: 10.1016/j.expneurol.2024.114675
Abstrakt: Huntington's Disease (HD) is a progressive neurodegenerative disease caused by a mutation in the huntingtin gene. The mutation leads to a toxic gain of function of the mutant huntingtin (mHtt) protein resulting in cellular malfunction, aberrant huntingtin aggregation and eventually neuronal cell death. Patients with HD show impaired motor functions and cognitive decline. Elevated levels of glucocorticoids have been found in HD patients and in HD mouse models, and there is a positive correlation between increased glucocorticoid levels and the progression of HD. Therefore, antagonism of the glucocorticoid receptor (GR) may be an interesting strategy for the treatment of HD. In this study, we evaluated the efficacy of the selective GR antagonist CORT113176 in the commonly used R6/2 mouse model. In male mice, CORT113176 treatment significantly delayed the loss of grip strength, the development of hindlimb clasping, gait abnormalities, and the occurrence of epileptic seizures. CORT113176 treatment delayed loss of DARPP-32 immunoreactivity in the dorsolateral striatum. It also restored HD-related parameters including astrocyte markers in both the dorsolateral striatum and the hippocampus, and microglia markers in the hippocampus. This suggests that CORT113176 has both cell-type and brain region-specific effects. CORT113176 delayed the formation of mHtt aggregates in the striatum and the hippocampus. In female mice, we did not observe major effects of CORT113176 treatment on HD-related symptoms, with the exception of the anti-epileptic effects. We conclude that CORT113176 effectively delays several key symptoms related to the HD phenotype in male R6/2 mice and believe that GR antagonism may be a possible treatment option.
Competing Interests: Declaration of competing interest Hazel Hunt is an employee and Jan Kroon is seconded at Corcept Therapeutics, the pharmaceutical company that designs and develops CORT113176. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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