Effects of Dexamethasone in Hypoxic-Ischemic Brain Injury in the Neonatal Rat

Altman, Denis I.; Young, Richard S.; Yagel, Susan K.

doi:10.1159/000242058

Cited by 53 publications

(19 citation statements)

References 16 publications

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“…They also found that a single dose of 0.1 mg/kg given 24 h before the insult prevented cerebral infarction. 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).…”

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confidence: 58%

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

et al. 2000

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Dexamethasone (DEX) pretreatment has been shown to be neuroprotective in a neonatal rat model of hypoxia ischemia (HI). The exact mechanism of this neuroprotection is still unknown. This study used 31 P nuclear magnetic resonance spectroscopy to monitor energy metabolism during a 3-h episode of HI in 7-d-old rat pups in one of two groups. The first group was pretreated with 0.1 mL saline (i.p.) and the second group was treated with 0.1 mL of 0.1mg/kg DEX (i.p.) 22 h before HI. Animals pretreated with DEX had elevated nucleoside triphosphate and phosphocreatine levels during HI when compared with controls. Salinetreated animals had significant decreases in nucleoside triphosphate and phosphocreatine and increases in inorganic phosphate over this same period. 31 P nuclear magnetic resonance data unequivocally demonstrate preservation of energy metabolism during HI in neonatal rats pretreated with DEX. Animals pretreated with DEX had little or no brain damage following 3 h of HI when compared with matched controls, which experienced severe neuronal loss and cortical infarction. These same pretreated animals had an increase in blood beta-hydroxybutyrate levels before ischemia, suggesting an increase in ketone bodies, which is the neonate's primary energy source. Elevation of ketone bodies appears to be one of the mechanisms by which DEX pretreatment provides neuroprotection during HI in the neonatal rat. Abbreviations DEX, dexamethasone HI, hypoxia ischemia NTP, nucleoside triphosphate NMR, nuclear magnetic resonance NMRS, nuclear magnetic resonance spectroscopy BHB, beta-hydroxybutyrate D-␤-HBA, D-␤-hydroxybutyrate dehydrogenase Dexamethasone (DEX) is a synthetic glucocorticoid. A National Institutes of Health consensus committee has recommended its use for women who are believed to deliver prematurely (1). Administered antenatally (before birth), DEX can relieve or ameliorate symptoms associated with respiratory distress syndrome and intraventricular hemorrhage and thus reduce mortality. Research was recommended to guide clinical care on the "effects of antenatal corticosteroids on hypoxic-ischemic insults."The first study to document the effects of DEX on neonatal animals was performed using the modified Levine preparation in neonatal rat by Altman et al. (2). They s.c. injected rat pups with either saline, 4 mg/kg DEX, or 40 mg/kg DEX immediately before hypoxia ischemia (HI). Neither dose of DEX ameliorated brain edema, lactacidemia, or hypoglycemia. In addition, there was no preservation of high-energy metabolites and there was an increase in mortality associated with the highest dose. These negative results made other investigators reluctant to pursue DEX as an effective neuroprotective agent.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 Received August 8, 1998; accepted November 11, 1999

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supporting

confidence: 58%

“…The first study to document the effects of DEX on neonatal animals was performed using the modified Levine preparation in neonatal rat by Altman et al (2). They s.c. injected rat pups with either saline, 4 mg/kg DEX, or 40 mg/kg DEX immediately before hypoxia ischemia (HI).…”

mentioning

confidence: 99%

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

et al. 2000

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“…In this regard, common carotid artery ligation key enzymes of glycolysis (phosphofmctofinase, hexofinase, and and superimposed hypoxia in the immature rat lower blood flow pyruvate dehydrogenase), whose activities increase slowly with not only to the cerebral hemisphere ipsilateral to the arterial advancing maturity (48,49). Third, the model to produce hybut to the brainstem (27), and occasiOnall~ i s poxic~~schemic brain damage used in the present study represents chemic neuronal alterations are seen within specific brainstem a model of incomplete ischemia, whereby substrate delivery to regions as well (28). In adult rats, the combination of forebrain the vulnerable regons of brain is but not completely ischemia and insulin-induced hypoglycemia leads to brainstem damage, whereas normoglycemic animals rendered similarly is-disrupted (26).…”

Section: Discussionmentioning

confidence: 97%

Effect of Insulin-Induced and Fasting Hypoglycemia on Perinatal Hypoxic-Ischemic Brain Damage

et al. 1992

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“…This model requires permanent unilateral carotid artery occlusion and temporary systemic hypoxemia to produce focal cerebral infarction and impaired brain development (10) and is feasible in neonatal (PND 7) rats. This model has produced many seminal findings related to hypoxic-ischemic damage in the developing brain related to both mechanism (including: (22,23) and treatment (including: (24)(25)(26), leading to a significant advancement in the understanding of neonatal hypoxia-ischemia. Parallel studies examining mechanisms and treatment in age-appropriate models of pediatric hypoxia-ischemia; however, are lacking.…”

Section: Discussionmentioning

confidence: 99%

Experimental model of pediatric asphyxial cardiopulmonary arrest in rats

Fink

Alexander

Marco

et al. 2004

Pediatric Critical Care Medicine

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Objective-Develop a clinically relevant model of pediatric asphyxial cardiopulmonary arrest in rats. Design-Prospective interventional study. Setting-University research laboratory.Subjects-Post-natal day (PND) 16-18 rats.Interventions-Anesthetized rats were endotracheally intubated and mechanically ventilated, and vascular catheters were inserted. Vecuronium was administered and the ventilator was disconnected from the rats for 8 min, whereupon rats were resuscitated with epinephrine, sodium bicarbonate, and chest compressions until spontaneous circulation returned. Shams underwent all procedures except asphyxia.Measurements and Main Results-Asphyxial arrest typically occurred by 1 min after the ventilator was disconnected. Return of spontaneous circulation typically occurred <30 sec after resuscitation. An isoelectric electroencephalograph was observed for 30 min after asphyxia and rats remained comatose for 12-24 h. Survival rate in rats after asphyxia was 75%. Motor function measured using beam balance and inclined plane tests was impaired on d 1 and 2, but recovered by d 3, in rats after asphyxia vs. sham injury (n=9/group; P<0.05). Spatial memory acquisition measured using the Morris-water maze on d 7-14 and 28-35 was also impaired in rats after asphyxia vs. sham injury (total latency 379±28 vs. 501±40 sec, respectfully; n=9/group; P<0.05). CA1 hippocampal neuron survival after asphyxia was 39-43% (n=9/group; P<0.001 vs. sham). DNA fragmentation was detected in CA1 hippocampal neurons bilaterally in separate rats on d 3-7 after asphyxia (n=3-4/group). Neurodegeneration detected using Fluorojade-B was seen in bilateral CA1 hippocampi and layer III cortical neurons 3-7 d after asphyxia, with persistent neurodegeneration in CA1 hippocampus detected up to 5 wks after asphyxia. Evidence of DNA or cellular injury was not detected in sham rats.

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Effects of Dexamethasone in Hypoxic-Ischemic Brain Injury in the Neonatal Rat

Cited by 53 publications

References 16 publications

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

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

Effect of Insulin-Induced and Fasting Hypoglycemia on Perinatal Hypoxic-Ischemic Brain Damage

Experimental model of pediatric asphyxial cardiopulmonary arrest in rats

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