Reduction in N-methyl-D-aspartate Receptor-mediated Cell Death in Hippocampal Neurons by Glucose Reduction Preconditioning

Background: Repeated episodes of reduced glucose availability can precondition the brain against damage caused by severe hypoglycemia. Because N-methyl-D-aspartate (NMDA) receptor activation may contribute to neuronal loss in the hippocampus following glucose deprivation, we tested the hypothesis that preconditioning with reduced glucose decreased NMDA receptor-mediated cell death in hippocampal neurons. Methods: Hippocampal slice cultures from 7-day old rats were used to study glucose reduction preconditioning and N-methyl-D-aspartate receptor (NMDAR)-mediated cell death. Preconditioning involved reductions in glucose to the following levels: 0.1 mM, 0.5, or 1.0 mM for 30 minutes, 60 minutes, or 90 minutes on 3 consecutive days. Cell death following 1-hour total glucose deprivation was measured with a vital dye technique (SYTOX fluorescence). As an index of NMDAR activity, cell death following application of 1 mM NMDA, was also measured. Results: A preconditioning protocol of 30 minutes of 0.1 mM glucose per day for 3 days reduced cell death following 1-hour total glucose by 65% to 70%, depending on cellular region. No reduction in NMDAR-mediated cell death was seen following any of the preconditioning treatments. However, when NMDAR-mediated cell death was assessed following preconditioning combined with subsequent total glucose deprivation, cell death was reduced in the cultures that had been preconditioned with 0.1 mM glucose for 30 minutes×3 days. Conclusions: We found that that glucose reduction preconditioning protects hippocampal neurons against severe glucose deprivation-induced neuronal damage. This preconditioning was not associated with reductions in NMDAR-mediated cell death except when the preconditioning was combined with an additional exposure to a period of total glucose deprivation.

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