title: Acute effects of neonatal dexamethasone treatment on proliferation and astrocyte immunoreactivity in hippocampus and corpus callosum: towards a rescue strategy.
abstract: Dexamethasone (DEX), a synthetic glucocorticoid, has been used to treat respiratory distress syndrome in prematurely born infants. Despite the important short-term benefit on lung function, there is growing concern about the long-term outcome of this treatment, since follow-up studies of prematurely born infants have shown lasting adverse neurodevelopmental effects. Since the mechanism underlying these neurodevelopmental impairments is largely unknown, the aim of the present study was (i) to investigate the acute effects of neonatal DEX treatment on the developing brain; and (ii) to block specifically the effects of DEX on the brain by central administration of the glucocorticoid receptor (GR) antagonist mifepristone. Long Evans rat pups were injected subcutaneously with tapering doses of DEX or saline (SAL) on postnatal days (pnd) 1, 2 and 3. Separate groups received intracerebroventricular injections with mifepristone prior to DEX treatment. On pnd 4 and 10, pups were sacrificed and brains collected for analysis of cell proliferation (Ki-67) and astrogliosis (GFAP). We report that neonatal DEX treatment reduced hippocampal cell proliferation on pnd 4, an effect that was normalized by pnd 10. Although on pnd 4, GFAP expression was not affected, DEX treatment caused a significant reduction in the number and density of astrocytes in hippocampus and corpus callosum on pnd 10, which was normalized by mifepristone pre-treatment. These acute alterations in the neonate brain might underlie later functional impairments reported in DEX-treated animals and humans and further illustrate the impact of early GR activation on brain development.
authors.affiliation: Department of Medical Pharmacology, LACDR/LUMC, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands. s.e.f.claessens@gmail.com
authors.forename: Sanne E F
authors.initials: SE
authors.lastname: Claessens
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Belanoff
authors.forename: Sofia
authors.initials: S
authors.lastname: Kanatsou
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lucassen
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Champagne
authors.forename: E Ronald
authors.initials: ER
authors.lastname: de Kloet
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects*; D003337:Corpus Callosum / Q000166:cytology / Q000187:drug effects / Q000254:growth & development; D003907:Dexamethasone / Q000494:pharmacology*; D004333:Drug Administration Routes; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005938:Glucocorticoids / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000254:growth & development; D006727:Hormone Antagonists / Q000494:pharmacology; D019394:Ki-67 Antigen / Q000378:metabolism; D015735:Mifepristone / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans
chemical_list: D005904:Glial Fibrillary Acidic Protein; D005938:Glucocorticoids; D006727:Hormone Antagonists; D019394:Ki-67 Antigen; D015735:Mifepristone; D003907:Dexamethasone