Research reportEffects of hyperglycemia or hypoglycemia on brain cell membrane function and energy metabolism during the immediate reoxygenation–reperfusion period after acute transient global hypoxia–ischemia in the newborn piglet
Introduction
Perinatal hypoxic–ischemic brain injury remains a major cause of neonatal and infant mortality, and of permanent neurodevelopmental sequelae such as mental retardation, seizure disorders and cerebral palsy [25], [26]. Hyperglycemia or hypoglycemia is a frequent metabolic derangement among asphyxiated infants, and might have additive deleterious effects on the brain injury of perinatal asphyxia [3], [5], [13], [14], [23]. Thus, blood glucose concentration may be one of the variables affecting outcome of asphyxial insults. In our previous studies [3], [5], we demonstrated that neither hyperglycemia nor hypoglycemia was beneficial, and might even be harmful during hypoxic–ischemic brain injury in the newborn piglet. However, since it is practically impossible to institute some neuroprotective treatment during the primary asphyxial insult, it would be clinically more important to know the effects of blood glucose concentration after hypoxic–ischemic brain injury rather than during injury. Surprisingly, very few studies have been performed regarding the role of blood glucose concentration after hypoxic–ischemic brain damage in the neonatal animals, and the results are still contradictory [12], [13], [14], [15], [23]. Therefore, further studies will be necessary to clarify this.
This study was done to determine whether alterations in posthypoxic–ishcemic blood glucose concentrations could affect the severity of cerebral injury in the developing brain. We tested the hypothesis that hyperglycemia or hypoglycemia during the immediate reoxygenation-reperfusion period after acute transient global hypoxia–ishcemia interferes with recovery in brain cell membrane function and energy metabolism in the newborn piglet. We used the same hypoxic–ischemic model of newborn piglets previously described [3], [4], [5]. Hyperglycemia (blood glucose level 350 mg/dl) or hypoglycemia (blood glucose level 50 mg/dl) was instituted and maintained by modified glucose clamp technique with glucose or insulin infusion, respectively [3], [5], [19]. Changes in brain cell membrane structure, function and energy metabolism were determined by measuring lipid peroxidation products (conjugated dienes), Na+,K+-ATPase activity and concentrations of cerebral high-energy phosphate compounds in the cerebral cortex.
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Animal preparation
The experimental protocols described herein were reviewed and approved by the Institutional Animal Care and Use Committee of the Samsung Biomedical Research Center, Seoul, South Korea. This study also followed the institutional and National Institutes of Health guidelines for laboratory animal care.
Newborn piglets less than 3 days old and of mixed strain (Yorkshire, conventional breed, purchased from Paju farm, Paju, Kyonggi-Do, Korea) were used in this study. Animals inhaled ether for
Physiologic variables
The mean physiologic variables from the four experimental groups were summarized in Table 1. In NC group, there were no significant changes in the values of physiologic variables including heart rate, arterial blood gases and mean arterial blood pressure during the experiment. During hypoxia–ischemia, heart rate increased, and mean arterial blood pressure, arterial oxygen tension, base excess and pH decreased significantly in HC, HE and HO groups compared to the corresponding values in NC
Discussion
In this study, we investigated the role of blood glucose concentration after hypoxic–ischemic insult in the developing newborn brain. Our data demonstrated potentially detrimental effects of hyperglycemia, but not hypoglycemia, during the immediate reoxygenation–reperfusion period after acute transient global hypoxia–ischemia in the newborn piglet. Hyperglycemia hampered the recovery in brain ATP and phosphocreatine levels, and aggravated brain damage as indicated by reduced cerebral cortical
Acknowledgements
This study was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (HMP-00-B-21300-0204).
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