Repeated prenatal corticosteroid administration delays myelination of the corpus callosum in fetal sheep

Abstract

Glucocorticoids regulate oligodendrocyte maturation and the myelin biosynthetic pathways. Synthetic glucocorticoids, the corticosteroids have been successfully used in clinical practice as a single course to enhance lung maturation and reduce mortality and morbidity in preterm infants with no long-term neurologic or cognitive side effects. However, a trend has arisen to use repeated courses despite an absence of safety data from clinical trials. We examined the effects of clinically appropriate, maternally administrated, repeated courses of corticosteroids on myelination of the corpus callosum using sheep as a large animal model. The corpus callosum is a major white matter tract that undergoes protracted myelination, underpins higher order cognitive processing and developmental damage to which is associated with, for example, cerebral palsy, mental retardation and attention deficit hyperactivity disorder. Pregnant ewes were given saline or betamethasone (0.5 mg/kg) at 104,111,118 and 124 days gestation, stages equivalent to the third trimester in humans. Lambs were delivered at 145 days (term), perfused and the corpus callosum examined light and electron microscopically. Total axon numbers were unaffected (P>0.05). However, myelination was significantly delayed. Myelinated axons were 5.7% in the experimental group and 9.2% in controls (P<0.05); conversely, unmyelinated axons were 88.3 and 83.7% (P<0.05). Myelinated axon diameter and myelin sheath thickness were also reduced (0.68 vs. 0.94 and 0.11 vs. 0.14 microm, P<0.05). Our data suggest that repeated prenatal corticosteroid administration delays myelination of the corpus callosum and that further safety data are needed to evaluate clinical practice.

Exposure to Prenatal Psychobiological Stress Exerts Programming Influences on the Mother and Her Fetus

“…Cortisol also affects myelination in the developing brain because glucocorticoid receptors are expressed in oligodendrocytes, the glia cells that manufacture myelin sheets in the CNS. Specifically, delayed myelination has been reported in the corpus callosum in association with prenatal exogenous glucocorticoid exposure [116], which is consistent with findings that prenatal stress exposure affects the size of the corpus callosum [117]. …”

Severe Early Life Stress Hampers Spatial Learning and Neurogenesis, but Improves Hippocampal Synaptic Plasticity and Emotional Learning under High-Stress Conditions in Adulthood

“…Glucocorticoids are necessary for normal brain maturation (Meyer, 1983;Weinstock, 2001;Welberg and Seckl, 2001) and dendritic integrity depends on continuous mineralocorticoid receptor activation (Wossink et al, 2001), but glucocorticoid overexposure during development can delay CNS maturation (Huang et al, 2001;Alfarez et al, 2009;Lucassen et al, 2009). Differences in postnatal corticosteroid levels, as described after MD (Oomen et al, 2009), may therefore contribute to the morphological alterations in adulthood.…”

15 Periventrikuläre Leukomalazie

“…Sowohl reife als auch unreife Oligodendrocyten exprimieren die Rezeptoren für Corticoide [Vielkind et al, 1990] [Dunlop et al, 1997;Huang et al, 2001]. Außerdem wurde die Expression der mRNA der Proteine MBP und PLP durch Gabe von Dexamethason in der frühen postnatalen Periode unterdrückt [Tsuneishi et al, 1991].…”

“…Auch Beeinträchtigungen der Myelinisierung bzw. der Expression Myelin-spezifischer mRNA wurde in einigen in vivo Studien beobachtet [Tsuneishi et al, 1991;Dunlop et al, 1997;Huang et al, 2001]. In diesen Versuchen wurden jedoch mehrfach sehr hohe Dosen an Corticosteroiden gegeben, wie sie in der Perinatalmedizin nicht zur Anwendung kommen würden.…”