Background
Dexamethasone (DEX) can cause severe neuropsychiatric effects. 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. Assessment of MR functionality may be feasible using putative human MR target genes, based on differential expression that we previously detected in forebrain specific MR knockout (fbMRKO) mice.
Objective and hypotheses
The aim of the study was to investigate the expression and functionality of MR and GR in the brain of a DEX-treated patient and aged matched controls. It was hypothesized that MR target gene expression as identified in fbMRKO mice 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 who died under high DEX treatment was obtained from the VUmc biobank. Matched pediatric brain tissue of subjects not treated with glucocorticoids was used to assess expression and functionality of MR and GR with q-PCR for target genes and immunofluorescence for nuclear receptor localization.
Results
In DEX-treated tissue MR target genes were expressed at low levels compared to unaffected controls. Expression of the classical, shared MR/GR target genes was low compared to unaffected controls, except for FKBP5. Strikingly, immunofluorescence showed nuclear staining for MR and GR, suggesting activation of both receptors to an extent that allows nuclear translocation.
Conclusion
Overall, in human pediatric hippocampal tissue treated with chronic DEX low MR target gene expression was observed. DEX does seem to be able to cause nuclear translocation of MR, but did not induce expression of MR target genes. Currently, an RCT is set up to investigate the MR refill concept: adding cortisol to DEX to restore MR activity and reduce side effects.