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 (0.5 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.

The Gene Master Regulators (GMR) Approach Provides Legitimate Targets for Personalized, Time-Sensitive Cancer Gene Therapy

“…Such genes have the expression so strongly correlated with that of many other genes that their forced alteration triggers unbearable perturbations of major functional pathways. In tens of previous papers on a large variety of cells and tissues from humans [21,22] and animal (e.g., mouse [10,11,29,38], rat [13,30,39], rabbit [56], dog, chicken embryo [12]) models of human diseases, we proved that major functional pathways remodel in disease, with certain genes being promoted to command positions. We know that a gene is critical for a particular phenotype when its expression is strongly controlled by the homeostatic mechanisms, making it resistant to the small environmental fluctuations and thus very stably expressed across biological replicas.…”

Pharmacological approaches to intervention in hypomyelinating and demyelinating white matter pathology

“…However, the use of immunosuppressant steroids dexamethasone, or mineralocorticoids have been reported to show side effects as well as impaired neurodevelopment (Halliday et al, 2003). Animal studies have shown that glucocorticoids, especially repeated administration of dexamethasone, adversely affect myelination of the developing brain (Zia et al, 2014). Despite mixed reports of improvement in myelination in models of lipopolysaccharide-induced perinatal brain injury (Pang et al, 2012) it is now widely accepted that the risks of cerebellar and WM damage by glucocorticoids during critical periods of brain development may outweigh its benefits on immunosuppression.…”

Neuroprotective effect of ACTH on collagenase-induced peri-intraventricular hemorrhage in newborn male rats

“…However, repeated antenatal glucocorticoid courses can cause adverse effects on fetal growth and cerebral cortical maturation 7 without further reducing the incidence of PIVH 44 . Postnatal glucocorticoids (dexamethasone or betamethasone) cause a preparation- and dose-dependent reversible reduction in oligodendrocyte proliferation and maturation, reduction in myelination, induced astrogliosis, and impaired motor functions evaluated on postnatal days 14 and 21 in rabbit pups 45 , see also 46 . Here, morphological data indicate that ACTH 1-24 microinjected 12 h after collagenase in PN 2 alleviated the impact of PIVH in rats.…”