Limits...
Deoxyglucose prevents neurodegeneration in culture by eliminating microglia.

Vilalta A, Brown GC - J Neuroinflammation (2014)

Bottom Line: 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.We conclude that deoxyglucose causes microglial loss by ATP depletion, and this can protect neurons from neurodegeneration, except in conditions of hypoxia.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QW, UK. gcb3@cam.ac.uk.

ABSTRACT

Background: 2-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.

Methods: Deoxyglucose 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.

Results: Surprisingly, 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.

Conclusions: We 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.

Show MeSH

Related in: MedlinePlus

Microglial phagocytosis contributes to the loss of microglia induced by deoxyglucose. (A) Pure primary microglia were treated ± deoxyglucose (DOG; 10 mM) for 21 hours, and were then incubated with 5 μm carboxylate-modified latex microspheres for 2 hours, and the number of beads phagocytosed per cell quantified. (B) The phagocytosis inhibitor cytochalasin D (1 μM) decreased the loss of microglia measured 6 hours after the addition of DOG (10 mM) in glial cultures. Data presented as mean ± standard error of the mean for ≥ 3 independent experiments. *Total microglia: *P < 0.05, **P < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC3986974&req=5

Figure 7: Microglial phagocytosis contributes to the loss of microglia induced by deoxyglucose. (A) Pure primary microglia were treated ± deoxyglucose (DOG; 10 mM) for 21 hours, and were then incubated with 5 μm carboxylate-modified latex microspheres for 2 hours, and the number of beads phagocytosed per cell quantified. (B) The phagocytosis inhibitor cytochalasin D (1 μM) decreased the loss of microglia measured 6 hours after the addition of DOG (10 mM) in glial cultures. Data presented as mean ± standard error of the mean for ≥ 3 independent experiments. *Total microglia: *P < 0.05, **P < 0.01.

Mentions: As the loss of microglia could be due to phagocytosis by other microglia, we tested whether deoxyglucose could stimulate or inhibit microglial phagocytosis. Pure microglia were treated with 10 mM deoxyglucose for 21 hours and then 5 μm carboxylate-modified latex microspheres were added for 2 hours. We observed a very small increase in phagocytosis of microspheres with DOG treatment (Figure 7A).


Deoxyglucose prevents neurodegeneration in culture by eliminating microglia.

Vilalta A, Brown GC - J Neuroinflammation (2014)

Microglial phagocytosis contributes to the loss of microglia induced by deoxyglucose. (A) Pure primary microglia were treated ± deoxyglucose (DOG; 10 mM) for 21 hours, and were then incubated with 5 μm carboxylate-modified latex microspheres for 2 hours, and the number of beads phagocytosed per cell quantified. (B) The phagocytosis inhibitor cytochalasin D (1 μM) decreased the loss of microglia measured 6 hours after the addition of DOG (10 mM) in glial cultures. Data presented as mean ± standard error of the mean for ≥ 3 independent experiments. *Total microglia: *P < 0.05, **P < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3986974&req=5

Figure 7: Microglial phagocytosis contributes to the loss of microglia induced by deoxyglucose. (A) Pure primary microglia were treated ± deoxyglucose (DOG; 10 mM) for 21 hours, and were then incubated with 5 μm carboxylate-modified latex microspheres for 2 hours, and the number of beads phagocytosed per cell quantified. (B) The phagocytosis inhibitor cytochalasin D (1 μM) decreased the loss of microglia measured 6 hours after the addition of DOG (10 mM) in glial cultures. Data presented as mean ± standard error of the mean for ≥ 3 independent experiments. *Total microglia: *P < 0.05, **P < 0.01.
Mentions: As the loss of microglia could be due to phagocytosis by other microglia, we tested whether deoxyglucose could stimulate or inhibit microglial phagocytosis. Pure microglia were treated with 10 mM deoxyglucose for 21 hours and then 5 μm carboxylate-modified latex microspheres were added for 2 hours. We observed a very small increase in phagocytosis of microspheres with DOG treatment (Figure 7A).

Bottom Line: 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.We conclude that deoxyglucose causes microglial loss by ATP depletion, and this can protect neurons from neurodegeneration, except in conditions of hypoxia.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QW, UK. gcb3@cam.ac.uk.

ABSTRACT

Background: 2-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.

Methods: Deoxyglucose 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.

Results: Surprisingly, 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.

Conclusions: We 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.

Show MeSH
Related in: MedlinePlus