Perinatal glucocorticoid treatment and perspectives for antioxidat therapy

Abstract

Pre- and postnatal glucocorticoids are a life-saving therapy for prematurely born infants. However, glucocorticoids also trigger unwanted side effects. In part I we investigated the effects of antenatal glucocorticoids on hippocampal development. First in a mice model using a clinically relevant dose of antenatal dexamethasone. Dexamethasone treatment increased apoptosis in the hippocampus until birth.During the phase with increased apoptosis, proliferation was reduced. The number of proliferative cells was increased postnatally, but was decreased at adult stage. Thereafter, we investigated effects of antenatal glucocorticoid treatment on the human hippocampus. Included were preterms who died during or within 4 days after delivery. We detected a decreased neuronal density in the CA zones of the hippocampus of glucocorticoid treated neonates. Part II focuses on side effects of postnatal glucocorticoid treatment and how to reduce these effects. Accumulating evidence suggests that one pathway by which glucocorticoids may promote their deleterious effects is increasing oxidative stress and decreasing nitric oxide bioavailability. Therefore we combined postnatal dexamethasone treatment with antioxidant therapy (vitamins C and E) in a rat model and investigated effects on brain development at postnatal day 21. Dexamethasone increased indices of oxidative stress in the cortex and decreased brain volume and soma volumes of neurons in the CA 1 and the dentate gyrus of the hippocampus. Combined treatment restored some but not all indices of oxidative stress to control levels and improved brain volume and soma volumes of neurons in the hippocampus. However, vitamins alone also increased indices of oxidative stress in the cortex. In the following chapters, we tested dexamethasone combined with pravastatin using a comparable rat model. In addition to the effects of dexamethasone on brain development that we found in the dexamethasone and vitamins C and E study, dexamethasone treatment led to a fall in plasma NOx concentrations (nitrates and nitrites,well established indices of circulating NO bioavailability), impaired weight gain during treatment followed by accelerated weight gain thereafter, a decreased number of neurons in the cerebral cortex and increased density of GFAP positive cells in the cingulate white matter. Most of these effects were restored to control levels by giving combined dexamethasone and pravastatin treatment. As regards cardiovascular function; dexamethasone increased basal arterial pressure, decreased vascular reactivity and increased the rate pressure product indicating a higher myocardial workload. These effects were ameliorated by combined treatment with pravastatin. Pravastatin treatment alone decreased NOx concentrations, had no effect on brain development but led to a significant fall in vascular relaxation sensitivity. As changes in growth patterns may have consequences for long term health we compared in a retrospective cohort study growth patterns for weight, height and head circumference from birth to age four years, between prematurely born children postnatally treated with dexamethasone or hydrocortisone and a prematurely born reference group. Growth patterns of preterm born infants were affected by glucocorticoid-treatment, effects were observed mainly on growth velocities.