Identifying the cellular targets of drug action in the central nervous system following corticosteroid therapy

Hdl Handle:
http://hdl.handle.net/10034/606268
Title:
Identifying the cellular targets of drug action in the central nervous system following corticosteroid therapy
Authors:
Jenkins, Stuart I.; Pickard, Mark R.; Khong, Melinda; Smith, Heather L.; Mann, Carl L. A.; Emes, Richard D.; Chari, Divya M.
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.
Affiliation:
Keele University, University of Nottingham, University Hospital of North Staffordshire NHS Trust, United Kingdom
Citation:
Jenkins, S. I., Pickard, M. R., Khong, M., Smith, H. L., Mann, C. L. A., Emes, R. D., & Chari, D. M. (2014). Identifying the cellular targets of drug action in the central nervous system following corticosteroid therapy. ACS Chemical Neuroscience, 5(1), 51-63. http://dx.doi.org/10.1021/cn400167n
Publisher:
American Chemical Society
Journal:
ACS Chemical Neuroscience
Publication Date:
15-Jan-2014
URI:
http://hdl.handle.net/10034/606268
DOI:
10.1021/cn400167n
Type:
Article
Language:
en
Description:
This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Chemical Neuroscience, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/cn400167n
ISSN:
1948-7193
EISSN:
1948-7193
Sponsors:
British Neuro-pathological Society, North Staffordshire Medical Institute, and The University of Nottingham.
Appears in Collections:
Institute of Medicine

Full metadata record

DC FieldValue Language
dc.contributor.authorJenkins, Stuart I.en
dc.contributor.authorPickard, Mark R.en
dc.contributor.authorKhong, Melindaen
dc.contributor.authorSmith, Heather L.en
dc.contributor.authorMann, Carl L. A.en
dc.contributor.authorEmes, Richard D.en
dc.contributor.authorChari, Divya M.en
dc.date.accessioned2016-04-21T11:53:31Zen
dc.date.available2016-04-21T11:53:31Zen
dc.date.issued2014-01-15en
dc.identifier.citationJenkins, S. I., Pickard, M. R., Khong, M., Smith, H. L., Mann, C. L. A., Emes, R. D., & Chari, D. M. (2014). Identifying the cellular targets of drug action in the central nervous system following corticosteroid therapy. ACS Chemical Neuroscience, 5(1), 51-63. http://dx.doi.org/10.1021/cn400167nen
dc.identifier.issn1948-7193en
dc.identifier.doi10.1021/cn400167nen
dc.identifier.otherPMC3894723en
dc.identifier.urihttp://hdl.handle.net/10034/606268en
dc.descriptionThis document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Chemical Neuroscience, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/cn400167nen
dc.description.abstractCorticosteroid (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.en
dc.description.sponsorshipBritish Neuro-pathological Society, North Staffordshire Medical Institute, and The University of Nottingham.en
dc.language.isoenen
dc.publisherAmerican Chemical Societyen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectoligodendrocyteen
dc.subjectOlig1en
dc.subjectcorticosteroiden
dc.subjectglucocorticoid receptoren
dc.subjectmicrogliaen
dc.subjectmicroarrayen
dc.titleIdentifying the cellular targets of drug action in the central nervous system following corticosteroid therapyen
dc.typeArticleen
dc.identifier.eissn1948-7193en
dc.contributor.departmentKeele University, University of Nottingham, University Hospital of North Staffordshire NHS Trust, United Kingdomen
dc.identifier.journalACS Chemical Neuroscienceen
dc.date.accepted2013-10-22en
or.grant.openaccessYesen
rioxxterms.funderBritish Neuro-pathological Society, North Staffordshire Medical Institute and The University of Nottinghamen
rioxxterms.identifier.projectUnknownen
rioxxterms.versionAMen
rioxxterms.licenseref.startdate2016-04-21en
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