title: Postnatal glucocorticoid-induced hypomyelination, gliosis, and neurologic deficits are dose-dependent, preparation-specific, and reversible.
abstract: Postnatal glucocorticoids (GCs) are widely used in the prevention of chronic lung disease in premature infants. Their pharmacologic use is associated with neurodevelopmental delay and cerebral palsy. However, the effect of GC dose and preparation (dexamethasone versus betamethasone) on short and long-term neurological outcomes remains undetermined, and the mechanisms of GC-induced brain injury are unclear. We hypothesized that postnatal GC would induce hypomyelination and motor impairment in a preparation- and dose-specific manner, and that GC receptor (GR) inhibition might restore myelination and neurological function in GC-treated animals. Additionally, GC-induced hypomyelination and neurological deficit might be transient. To test our hypotheses, we treated prematurely delivered rabbit pups with high (0.5mg/kg/day) or low (0.2mg/kg/day) doses of dexamethasone or betamethasone. Myelin basic protein (MBP), oligodendrocyte proliferation and maturation, astrocytes, transcriptomic profile, and neurobehavioral functions were evaluated. We found that high-dose GC treatment, but not low-dose, reduced MBP expression and impaired motor function at postnatal day 14. High-dose dexamethasone induced astrogliosis, betamethasone did not. Mifepristone, a GR antagonist, reversed dexamethasone-induced myelination, but not astrogliosis. Both GCs inhibited oligodendrocyte proliferation and maturation. Moreover, high-dose dexamethasone altered genes associated with myelination, cell-cycle, GR, and mitogen-activated protein kinase. Importantly, GC-induced hypomyelination, gliosis, and motor-deficit, observed at day 14, completely recovered by day 21. Hence, high-dose, but not low-dose, postnatal GC causes reversible reductions in myelination and motor functions. GC treatment induces hypomyelination by GR-dependent genomic mechanisms, but astrogliosis by non-genomic mechanisms. GC-induced motor impairment and neurodevelopmental delay might be transient and recover spontaneously in premature infants.
authors.affiliation: Department of Pediatrics, Regional Neonatal Center, Maria Fareri Children's Hospital at Westchester Medical Center-New York Medical College, Valhalla, NY, USA; Department of Pediatrics, Hudson Valley Hospital, Cortlandt Manor, NY, USA.
authors.forename: Muhammad T K
authors.initials: MT
authors.lastname: Zia
authors.affiliation: Department of Pediatrics, Regional Neonatal Center, Maria Fareri Children's Hospital at Westchester Medical Center-New York Medical College, Valhalla, NY, USA; Department of Cell Biology and Anatomy, Regional Neonatal Center, Maria Fareri Children's Hospital at Westchester Medical Center-New York Medical College, Valhalla, NY, USA.
authors.forename: Govindaiah
authors.initials: G
authors.lastname: Vinukonda
authors.affiliation: Department of Pediatrics, Regional Neonatal Center, Maria Fareri Children's Hospital at Westchester Medical Center-New York Medical College, Valhalla, NY, USA.
authors.forename: Linnea R
authors.initials: LR
authors.lastname: Vose
authors.affiliation: Department of Pediatrics, Regional Neonatal Center, Maria Fareri Children's Hospital at Westchester Medical Center-New York Medical College, Valhalla, NY, USA.
authors.forename: Bala B R
authors.initials: BB
authors.lastname: Bhimavarapu
authors.affiliation: Department of Pathology, Regional Neonatal Center, Maria Fareri Children's Hospital at Westchester Medical Center-New York Medical College, Valhalla, NY, USA.
authors.forename: Sanda
authors.initials: S
authors.lastname: Iacobas
authors.affiliation: Department of Cell Biology and Anatomy, Regional Neonatal Center, Maria Fareri Children's Hospital at Westchester Medical Center-New York Medical College, Valhalla, NY, USA.
authors.forename: Nishi K
authors.initials: NK
authors.lastname: Pandey
authors.affiliation: Department of Pharmacy, Hudson Valley Hospital, Cortlandt Manor, NY, USA.
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Beall
authors.affiliation: Department of Pediatrics, Regional Neonatal Center, Maria Fareri Children's Hospital at Westchester Medical Center-New York Medical College, Valhalla, NY, USA; Department of Cell Biology and Anatomy, Regional Neonatal Center, Maria Fareri Children's Hospital at Westchester Medical Center-New York Medical College, Valhalla, NY, USA.
authors.forename: Preeti
authors.initials: P
authors.lastname: Dohare
authors.affiliation: Department of Pediatrics, Regional Neonatal Center, Maria Fareri Children's Hospital at Westchester Medical Center-New York Medical College, Valhalla, NY, USA; Department of Molecular Biology and Biochemistry, Regional Neonatal Center, Maria Fareri Children's Hospital at Westchester Medical Center-New York Medical College, Valhalla, NY, USA.
authors.forename: Edmund F
authors.initials: EF
authors.lastname: LaGamma
authors.affiliation: Department of Pathology, Regional Neonatal Center, Maria Fareri Children's Hospital at Westchester Medical Center-New York Medical College, Valhalla, NY, USA.
authors.forename: Dumitru A
authors.initials: DA
authors.lastname: Iacobas
authors.affiliation: Department of Pediatrics, Regional Neonatal Center, Maria Fareri Children's Hospital at Westchester Medical Center-New York Medical College, Valhalla, NY, USA; Department of Cell Biology and Anatomy, Regional Neonatal Center, Maria Fareri Children's Hospital at Westchester Medical Center-New York Medical College, Valhalla, NY, USA. Electronic address: Pballabh@msn.com.
authors.forename: Praveen
authors.initials: P
authors.lastname: Ballabh
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001623:Betamethasone / Q000008:administration & dosage / Q000009:adverse effects; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D003907:Dexamethasone / Q000008:administration & dosage / Q000009:adverse effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005911:Gliosis / Q000139:chemically induced / Q000473:pathology; D005938:Glucocorticoids / Q000008:administration & dosage / Q000009:adverse effects*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D009186:Myelin Sheath / Q000187:drug effects* / Q000473:pathology; D011817:Rabbits; D060888:Real-Time Polymerase Chain Reaction; D011965:Receptors, Glucocorticoid / Q000378:metabolism
chemical_list: D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D001623:Betamethasone
keywords: Astrocytes; Betamethasone; Dexamethasone; Glucocorticoids; Myelination; Oligodendrocytes