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Hypoxic injury to developing glial cells: protective effect of high glucose
D J Callahan1, M J Engle, J J Volpe
1Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110.
Insights
Hypoxic injury to developing glial cells, a cause of brain damage in premature infants, can be prevented by increasing glucose availability. Higher glucose levels protect these cells from hypoxia by enhancing glycolysis and lactate production.
Area of Science:
- Neuroscience
- Cell Biology
- Neonatal Research
Background:
- Hypoxic injury to differentiating glial cells is key in periventricular leukomalacia development.
- Periventricular leukomalacia is a major hypoxic-ischemic brain lesion in premature infants.
Purpose of the Study:
- To investigate the effects of hypoxia on differentiating glial cells, particularly astrocytes.
- To determine if glucose availability influences glial cell resistance to hypoxic injury.
Main Methods:
- Primary cultures of newborn rat brain cells, predominantly differentiating astroglia, were used.
- Cellular injury was quantified by measuring lactate dehydrogenase efflux.
- Glucose concentration in the culture medium was manipulated (5.6 mM vs. 15 mM).
Main Results:
- Differentiating astrocytes showed initial resistance to hypoxia, but severe injury occurred by 24 hours.
- Supplementing the medium with 15 mM glucose completely prevented hypoxic injury over 24 hours.
- High glucose protection correlated with increased glycolysis, glucose consumption, and lactate production.
Conclusions:
- Increased glucose availability, through enhanced glycolysis, protects differentiating glial cells from hypoxic injury.
- This suggests that augmenting glucose supply could be a strategy to prevent or mitigate hypoxic brain injury in premature infants.
Abstract:
Hypoxic injury to differentiating glial cells is a critical event in the development of periventricular leukomalacia, the major hypoxic-ischemic lesion of the premature infant. This study has addressed the effects of hypoxia on differentiating glial cells, primarily astrocytes. Primary cultures of dissociated newborn rat brain, which are composed predominantly of differentiating astroglia, were used. Efflux of lactate dehydrogenase, an enzyme enriched in astroglia, was used to quantitate cellular injury. Three major findings are reported. First, differentiating astrocytes were resistant to hypoxic injury for many hours, although by 24 h of hypoxia severe cellular injury (lactate dehydrogenase efflux of 86% of total and morphologic changes) was obvious. Second, increase of glucose in the culture medium from the approximately physiological concentration of 5.6 to 15 mM had a marked protective effect versus hypoxia, i.e. lactate dehydrogenase efflux was totally prevented during 24 h of hypoxia in 15 mM glucose. Third, the protective effect of high glucose appeared to be related to increased utilization by glycolysis, because there was a direct correlation between the resistance to hypoxic cellular injury and the amount of lactate generated and of glucose consumed by the cells. Thus, the cells with the lowest lactate dehydrogenase efflux (and highest glucose supplementations) had medium lactate concentrations as high as 32-36 mM. These concentrations of lactate are approximately double the reported threshold concentration of lactate considered to produce cellular necrosis in in vivo models of hypoxic injury, primarily in mature animals. The data raise the possibility that hypoxic injury to differentiating glia can be prevented or ameliorated by increase in glucose availability.