Selective agonists of the glucocorticoid receptor (SEGRA) as an alternative to glucocorticoids: a pilot study of their effects on normal mouse brain tissue in the context of an acute peripheral inflammatory model in vivo.

BACKGROUND

Glucocorticoids (GCs) are used to treat multiple pathologies; however, their prolonged use leads to numerous adverse effects. Non-steroidal selective agonists of the glucocorticoid receptor (SEGRAs) have the potential to be a worthy substitute for dexamethasone (DXM). The aim of this study was to compare the effects of SEGRAs and DXM on the cell composition and extracellular matrix of normal brain tissue, with a focus on the acute short-term effects of these drugs.

METHODS

C57Bl/6 mice (n = 28) received an intraperitoneal injection of SEGRA (CpdA or CpdA-03) or DXM after carrageenan-induced paw edema. After 7.5 h, brain tissue was analyzed for neurons and astrocytes by IHC and Western blotting (anti-NF and anti-GFAP, respectively). Expression of proteoglycan (PG) core proteins and heparan sulfate (HS) metabolism-involved genes was determined by RT-PCR. The glycosaminoglycan (GAG) content was determined by dot blot and Alcian blue staining.

RESULTS

All studied drugs possessed similar anti-edema activity but differed in their effects on brain tissue. Unlike DXM, SEGRAs had no effect on neurofilament (NF) content in the mouse brain. Regarding astrocytes, although all drugs increased astrocyte number and outgrowth, only DXM and CpdA, but not CpdA-03, induced the appearance of a minor (44kDa) GFAP isoform associated with neurocognitive impairment. Neither DXM nor CpdA-03 affected the expression of genes coding PG core proteins and HS biosynthetic enzymes, and only CpdA upregulated the expression of syndecan-3, neurocan, aggrecan, and biglycan (2.5- to 3.5-fold). At the same time, all drugs decreased the content of total (1.5- to 2.8-fold) and sulfated (2- to 3-fold) GAGs, with the least effect observed for CpdA-03.

CONCLUSION

Between the two studied SEGRAs, CpdA shows more pronounced effects on the cellular and extracellular components of normal mouse brain tissue compared with DXM. CpdA-03 demonstrated the least effect on brain tissue and may be promising for further development as a less toxic replacement for glucocorticoids.