Abstract
Background2-Deoxy-d-glucose is an inhibitor of glycolysis, which is protective in animal models of brain pathology, but the mechanisms of this protection are unclear. We examined whether, when and how deoxyglucose protects neurons in co-culture with astrocytes and microglia. Microglia are brain macrophages, which can damage neurons in inflammatory conditions.MethodsDeoxyglucose was added to primary cultures of microglia and astrocytes from rat cortex, or neurons and glia from rat cerebellum, or the BV-2 microglial cell line, and cell death and cell functions were evaluated.ResultsSurprisingly, addition of deoxyglucose induced microglial loss and prevented spontaneous neuronal loss in long-term cultures of neurons and glia, while elimination of microglia by l-leucine-methyl ester prevented the deoxyglucose-induced neuroprotection. Deoxyglucose also prevented neuronal loss induced by addition of amyloid beta or disrupted neurons (culture models of Alzheimer’s disease and brain trauma respectively). However, deoxyglucose greatly increased the neuronal death induced by hypoxia. Addition of deoxyglucose to pure microglia induced necrosis and loss, preceded by rapid ATP depletion and followed by phagocytosis of the microglia. Deoxyglucose did not kill astrocytes or neurons.ConclusionsWe conclude that deoxyglucose causes microglial loss by ATP depletion, and this can protect neurons from neurodegeneration, except in conditions of hypoxia. Deoxyglucose may thus be beneficial in brain pathologies mediated by microglia, including brain trauma, but not where hypoxia is involved.
Highlights
Addition of deoxyglucose induced microglial loss and prevented spontaneous neuronal loss in long-term cultures of neurons and glia, while elimination of microglia by L-leucine-methyl ester prevented the deoxyglucose-induced neuroprotection
Deoxyglucose prevents neuronal loss mediated by microglia To test whether DOG was neurotoxic or neuroprotective, we added 10 mM DOG to primary co-cultures of neurons and glia from rat cerebellum for 96 hours, and observed that there was an apparent increase in the density of live neurons compared with the untreated condition (Figure 1A,D)
The density of live microglia substantially decreased over 96 hours of DOG treatment (Figure 1B) but there was no effect on astrocytes (Figure 1C)
Summary
Addition of deoxyglucose induced microglial loss and prevented spontaneous neuronal loss in long-term cultures of neurons and glia, while elimination of microglia by L-leucine-methyl ester prevented the deoxyglucose-induced neuroprotection. Deoxyglucose prevented neuronal loss induced by addition of amyloid beta or disrupted neurons (culture models of Alzheimer’s disease and brain trauma respectively). Deoxyglucose greatly increased the neuronal death induced by hypoxia. Addition of deoxyglucose to pure microglia induced necrosis and loss, preceded by rapid ATP depletion and followed by phagocytosis of the microglia. Deoxyglucose did not kill astrocytes or neurons
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