Postnatal glucocorticoid-induced hypomyelination, gliosis, and neurologic deficits are dose-dependent, preparation-specific, and reversible

Muhammad T K Zia, Govindaiah Vinukonda, Linnea R. Vose, Bala B R Bhimavarapu, Sanda Iacobas, Nishi K. Pandey, Ann Marie Beall, Preeti Dohare, Edmund F. LaGamma, Dumitru A. Iacobas, Praveen Ballabh

Research output: Contribution to journalArticle

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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 (0.5. mg/kg/day) or low (0.2. mg/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.

Original languageEnglish (US)
Pages (from-to)200-213
Number of pages14
JournalExperimental Neurology
Volume263
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

Fingerprint

Gliosis
Neurologic Manifestations
Glucocorticoids
Dexamethasone
Betamethasone
Myelin Basic Protein
Oligodendroglia
Premature Infants
Mifepristone
Glucocorticoid Receptors
Cerebral Palsy
Mitogen-Activated Protein Kinases
Astrocytes
Brain Injuries
Lung Diseases
Cell Cycle
Chronic Disease

Keywords

  • Astrocytes
  • Betamethasone
  • Dexamethasone
  • Glucocorticoids
  • Myelination
  • Oligodendrocytes

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience
  • Medicine(all)

Cite this

Postnatal glucocorticoid-induced hypomyelination, gliosis, and neurologic deficits are dose-dependent, preparation-specific, and reversible. / Zia, Muhammad T K; Vinukonda, Govindaiah; Vose, Linnea R.; Bhimavarapu, Bala B R; Iacobas, Sanda; Pandey, Nishi K.; Beall, Ann Marie; Dohare, Preeti; LaGamma, Edmund F.; Iacobas, Dumitru A.; Ballabh, Praveen.

In: Experimental Neurology, Vol. 263, 01.01.2015, p. 200-213.

Research output: Contribution to journalArticle

Zia, MTK, Vinukonda, G, Vose, LR, Bhimavarapu, BBR, Iacobas, S, Pandey, NK, Beall, AM, Dohare, P, LaGamma, EF, Iacobas, DA & Ballabh, P 2015, 'Postnatal glucocorticoid-induced hypomyelination, gliosis, and neurologic deficits are dose-dependent, preparation-specific, and reversible', Experimental Neurology, vol. 263, pp. 200-213. https://doi.org/10.1016/j.expneurol.2014.09.013
Zia, Muhammad T K ; Vinukonda, Govindaiah ; Vose, Linnea R. ; Bhimavarapu, Bala B R ; Iacobas, Sanda ; Pandey, Nishi K. ; Beall, Ann Marie ; Dohare, Preeti ; LaGamma, Edmund F. ; Iacobas, Dumitru A. ; Ballabh, Praveen. / Postnatal glucocorticoid-induced hypomyelination, gliosis, and neurologic deficits are dose-dependent, preparation-specific, and reversible. In: Experimental Neurology. 2015 ; Vol. 263. pp. 200-213.
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AU - Vose, Linnea R.

AU - Bhimavarapu, Bala B R

AU - Iacobas, Sanda

AU - Pandey, Nishi K.

AU - Beall, Ann Marie

AU - Dohare, Preeti

AU - LaGamma, Edmund F.

AU - Iacobas, Dumitru A.

AU - Ballabh, Praveen

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