Dexamethasone Prevents Hypoxic-Ischemic Brain Damage in the Neonatal Rat

Abstract

ABSTRACT. Glucocorticoid therapy is frequently used in perinatology and neonatology for its beneficial pulmonary effects. We investigated the influence of neonatal glucocorticoid administration on brain damage caused by a concurrent episode of cerebral hypoxia-ischemia. Various doses of dexamethasone in several treatment schedules were administered to 7-d-old rats that were also subjected to unilateral cerebral hypoxia-ischemia. In 79% of control rats, a large unilateral cerebral infarction occurred, whereas all rats pretreated with dexamethasone in doses At present, glucocorticoids are frequently used in perinatal medicine, both antenatally to prevent respiratory distress syndrome by inducing fetal production of pulmonary surfactant and postnatally to improve lung function in infants with bronchopulmonary dysplasia after mechanical ventilation (1-4). Both groups of infants are at risk of experiencing episodes of cerebral hypoxia-ischemia either during or after glucocorticoid administration, due to con~plications of prematurity and neonatal intensive care.Glucocorticoids have long been used for the treatment of various neurologic disorders in the adult. Several beneficial effects of steroid therapy have been demonstrated. Treatment with veIy high doses of glucocorticoids (3-6 n~g/kg dexamethasone or 15-30 mg/kg methylprednisolone) have both reduced pathologic damage induced by experimental spinal cord trauma (5, 6) and improved neurologic outcome after human spinal cord injury (7). Reductions in cerebral edema caused by tumors, Received August 28, 1990; accepted January 28, 1991 infarction, pneumothorax, or convulsions with glucocorticoid therapy have also been reported (8-12). However, until the present study, glucocorticoid therapy did not appear to be effective in reducing brain damage due to cerebral hypoxia-ischemia. Clinical (1 3-15) and experimental (1 6, 17) studies indicated that, in the adult, glucocorticoids are of no benefit or are detrimental (16,17) for the treatment of a focal ischemic stroke or global cerebral ischemia.In our study, we investigated the effect of glucocorticoid administration on the extent of brain damage produced in a perinatal model of cerebral hypoxia-ischemia in the rat (1 8-20). The results demonstrate that in the neonate, rather than exacerbating neuronal damage, glucocorticoid administration before an episode of hypoxia-ischemia actually protects the brain from injury. MATERIALS AND METHODSProduction of cerebral hypoxia-ischemia. Seven-d-old rats (Wistar or Sprague-Dawley) were anesthetized with halothane (4% for induction, 0.5-1% for maintenance) and the incision site was infiltrated with 2% lidocaine. The right carotid artery was isolated and ligated. A 3-h recovery period with the dam was followed by 3 h in 8% oxygen wit11 92% nitrogen in a plastic chamber inside a neonatal incubator with an air temperature of 37°C. This well-established model of pelinatal cerebral hypoxiaischemia reliably produces ipsilateral infarction of the striatum, thalamus, hippocampus, and overly...

Adverse Neurodevelopmental Effects of Dexamethasone Modeled in PC12 Cells: Identifying the Critical Stages and Concentration Thresholds for the Targeting of Cell Acquisition, Differentiation and Viability

“…In contrast, NGF by itself reduced viability, a finding in keeping with the rise in oxidative stress that attends early stages of differentiation (Katoh et al, 1997;Qiao et al, 2005). One possibility, then, is that DEX reduces oxidative stress in differentiating neural cells, an effect that could contribute to apparent protective actions of this treatment toward hypoxic-ischemic brain damage (Barks et al, 1991). On the other hand, a moderate degree of oxidative stress actually provides one of the normal ontogenetic signals that initiates differentiation and is also required to prevent apoptotic cell death (Ikeda et al, 2002;Katoh et al, 1997;McCollum et al, 2004).…”

Efficacious experimental stroke treatment with high-dose methylprednisolone.

“…However, other studies suggest that glucocorticosteroids can protect the brain without such changes in CBF. 29 ' 30 Dexamethasone administered at low doses to newborn rats 24 hours (but not 3 hours or immediately) before exposure to 3 hours of hypoxia (8% O 2 ) plus carotid artery occlusion protects the brain. This effect was seen only in newborns; adult treatment failed to show such benefits.…”

Increased Plasma Beta-Hydroxybutyrate, Preserved Cerebral Energy Metabolism, and Amelioration of Brain Damage During Neonatal Hypoxia Ischemia with Dexamethasone Pretreatment

“…Similar to Altman et al (2), when a single dose was administered 3 h or immediately before HI, there was no protective effect. A decrease in somatic growth and posthypoxic hyperglycemia with DEX administration was documented (3).…”

“…A single low dose of the synthetic glucocorticoid DEX, 6 to 24 h before HI, will prevent cerebral infarction in the neonatal rat (3,6). Although the neuroprotective mechanism remains unknown, possible suggested explanations include growth retardation, blood brain barrier permeability alteration, hyperglycemia, or increased glucose utilization.…”

“…Barks et al discovered that pretreatment with DEX 3 h or more before a hypoxic-ischemic insult was neuroprotective (3). DEX at 0.5 mg/kg/d for 3 d, before the insult, prevented brain damage associated with 3 h of cerebral HI in the 7-d-old rat pup (PND 7) (modified Levine preparation).…”