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

Abstract

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.

Using a 3-D multicellular simulation of spinal cord injury with live cell imaging to study the neural immune barrier to nanoparticle uptake

“…Clearly, the use of immunosuppressive or immunomodulatory therapies to reduce microglial activity could constitute one such clinically relevant approach. In this regard, the corticosteroid DEX is commonly prescribed as an immunosuppressive therapy following injuries to the CNS [40,41] and acts by inhibiting microglial proliferation [42], reducing their migratory capabilities [43] and potentially increasing microglial apoptosis [44,45]. In keeping with this role of DEX in vivo, we observed a significant reduction in the numbers of microglia in slice lesion sites.…”

Protracted abstinence from chronic ethanol exposure alters the structure of neurons and expression of oligodendrocytes and myelin in the medial prefrontal cortex

“…Notably, recent studies in the hippocampus indicate that exposure to the glucocorticoid stress hormone, corticosterone, induces a transcriptional program that promotes an increase in oligodendrogenesis, which intern enhances levels of myelin (Chetty et al, 2014). In addition, there is emerging evidence that oligodendrocyte progenitor cells express glucocorticoid receptors, and corticosteroids regulate myelin expression in the central nervous system via regulation of the differentiation of oligodendrocyte progenitor cells (Chari, 2014; Jenkins et al, 2014). Therefore, the increases in myelin expression during protracted abstinence could be associated with changes in corticosterone or GR itself.…”

Transcriptional signatures of steroid hormones in the striatal neurons and astrocytes

“…Slezak et al [18] compared the responses of astrocytes and neurons to dexamethasone. Jenkins et al [19] compared the responses of oligodendrocytes, astrocytes and microglia to the same steroid. The transcriptional responses of these cell types to dexamethasone were diverse.…”