Dexamethasone (DXM) is commonly used in the management of glioma patients to treat intracranial edema but patients often suffer from its side effects. The molecular mechanisms of these side effects are poorly studied. DXM seems to affect extracellular matrix (ECM) especially proteoglycans (PGs) known to be a major component of the ECM in brain tissue. The aim of our study was to investigate if the effects of DXM on brain tissue PGs depend on the treatment regimen or DXM dose.
Effects of different doses and regimens of DXM treatment on the brain ECM were studied using RT-PCR and IHC in the ex vivo model of organotypic brain tissue culture and in vivo experimental animal model. The ex vivo organotypic culture model was chosen instead of in vitro cell culture model as it represents the real 3D structure of the tissue and can be used to study ECM.
The most expressed PGs in rat brain tissue were syndecan-1, glypican-1, decorin, biglycan and lumican. DXM treatment of organotypic hippocampus culture ex vivo led to dose-dependent suppression of brevican, perlecan and biglycan expression and increase in expression of glypican-1, NG2 and versican. In the in vivo experiments, PGs demonstrated age-specific and brain zone-specific expression patterns in normal brain of Wistar rats. The effects of DXM on cortex and hippocampus of the experimental animals were dose- and regimen-dependent. Low-dose DXM treatment led to significant decrease in expression of most PGs in cortex but 3-fold increase in syndecan-1, perlecan and brevican expression in hippocampus. Treatment with high-dose DXM resulted in 2-6-fold increase in most of PGs expression in both brain zones. Long-term treatment led to the most dramatic changes in PGs expression on both mRNA and protein levels, completely changing their expression pattern.
Taken together, obtained data demonstrate an importance of DXM doses/regimens during antiglioma therapy. Long-term treatment and high doses of DXM lead to the most dramatic alteration of PGs composition in brain ECM creating a favorable niche for tumor growth and relapses.
Clinical trial identification
Legal entity responsible for the study
Institute of Molecular Biology and Biophysics
Russian Science Foundation (RSF grant 16-15-10243).
All authors have declared no conflicts of interest.