Postnatal glucocorticoid-induced hypomyelination, gliosis, and neurologic deficits are dose-dependent, preparation-specific, and reversible
| Autor: | Bala B.R. Bhimavarapu, Muhammad T. Zia, Ann Marie Beall, Preeti Dohare, Govindaiah Vinukonda, Nishi Kant Pandey, Dumitru A. Iacobas, Edmund F. LaGamma, Sanda Iacobas, Linnea R. Vose, Praveen Ballabh |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
medicine.medical_specialty
Blotting Western Real-Time Polymerase Chain Reaction Betamethasone Article Dexamethasone Receptors Glucocorticoid Developmental Neuroscience Internal medicine In Situ Nick-End Labeling medicine Animals Gliosis Glucocorticoids Myelin Sheath Dose-Response Relationship Drug biology business.industry Brain Mifepristone medicine.disease Immunohistochemistry Oligodendrocyte Myelin basic protein Astrogliosis Disease Models Animal medicine.anatomical_structure Endocrinology Animals Newborn Neurology biology.protein Rabbits medicine.symptom business Glucocorticoid medicine.drug |
| Zdroj: | Experimental Neurology. 263:200-213 |
| ISSN: | 0014-4886 |
| DOI: | 10.1016/j.expneurol.2014.09.013 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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