Background
Dexamethasone (DEX) is a commonly used drug, but can cause severe neuropsychiatric effects, like depression, delirium and mania. As DEX is a glucocorticoid receptor (GR) agonist, it suppresses the production of cortisol and thereby depletes the mineralocorticoid receptor (MR) of its ligand, rendering MR inactive. Next to the strongly stimulated GR, the reduced MR activity by DEX might be the cause of the neuropsychiatric effects.

Objective and hypotheses
The aim of this study was to investigate the expression and functionality of GR and MR in the brain of a DEX-treated patient and unaffected controls. It was hypothesized that MR target gene expression in the DEX-treated patient is reduced, because of the absence of cortisol, whereas GR target gene expression was expected to be high.

Methods
Frozen and paraffin embedded hippocampal tissue from an 8-year-old brain tumor patient treated with DEX was obtained from the VUmc biobank. Paraffin embedded hippocampal tissue from 2 unaffected controls was obtained from the Department of Pathology of the LUMC. Frozen hippocampal tissue from 8 unaffected controls was obtained from the NIH NeuroBioBank at the University of Maryland, Baltimore, MD. Expression and functionality of GR and MR was analyzed with q-PCR, immunohistochemistry and immunofluorescence.

Results
In DEX-treated tissue q-PCR analyses showed low expression of MR target genes, whereas expression of classical GR target genes was high. Despite the low MR target gene expression, immunohistochemistry and immunofluorescence analyses showed nuclear staining for both GR and MR, suggesting activation of both receptors to an extent that allow nuclear translocation.

Conclusion
In human pediatric hippocampal tissue treated with DEX, low MR target gene expression is seen. DEX does seem to be able to cause nuclear translocation of MR, but does not induce expression of MR target genes. Currently, an RCT is set up to investigate the MR refill concept: adding hydrocortisone to DEX to restore MR activity and thereby reducing the adverse neuropsychological effects.