Identifying the Cellular Targets of Drug Action in the Central Nervous System Following Corticosteroid Therapy

Corticosteroid
(CS) therapy is used widely in the treatment of a range of pathologies,
but can delay production of myelin, the insulating sheath around central
nervous system nerve fibers. The cellular targets of CS action are
not fully understood, that is, “direct” action on cells
involved in myelin genesis [oligodendrocytes and their progenitors
the oligodendrocyte precursor cells (OPCs)] versus “indirect”
action on other neural cells. We evaluated the effects of the widely
used CS dexamethasone (DEX) on purified OPCs and oligodendrocytes,
employing complementary histological and transcriptional analyses.
Histological assessments showed no DEX effects on OPC proliferation
or oligodendrocyte genesis/maturation (key processes underpinning
myelin genesis). Immunostaining and RT-PCR analyses show that both
cell types express glucocorticoid receptor (GR; the target for DEX
action), ruling out receptor expression as a causal factor in the
lack of DEX-responsiveness. GRs function as ligand-activated transcription
factors, so we simultaneously analyzed DEX-induced transcriptional
responses using microarray analyses; these substantiated the histological
findings, with limited gene expression changes in DEX-treated OPCs
and oligodendrocytes. With identical treatment, microglial cells showed
profound and global changes post-DEX addition; an
unexpected finding was the identification of the transcription factor Olig1, a master regulator of myelination, as a DEX responsive
gene in microglia. Our data indicate that CS-induced myelination delays
are unlikely to be due to direct drug action on OPCs or oligodendrocytes,
and may occur secondary to alterations in other neural cells, such
as the immune component. To the best of our knowledge, this is the
first comparative molecular and cellular analysis of CS effects in
glial cells, to investigate the targets of this major class of anti-inflammatory
drugs as a basis for myelination deficits.