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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.

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Deoxyglucose can prevent loss of live neurons induced by amyloid beta and disrupted neurons. (A) Deoxyglucose (DOG) prevented the neuronal loss induced by amyloid beta (Aβ; 250 nM for 96 hours). (B) DOG prevented the neuronal loss induced by adding disrupted neurons (30 μg protein for 96 hours – Trauma). Data presented as mean ± standard error of the mean for ≥ 3 independent experiments. Statistically significant differences between live neuron densities:*P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.
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Figure 3: Deoxyglucose can prevent loss of live neurons induced by amyloid beta and disrupted neurons. (A) Deoxyglucose (DOG) prevented the neuronal loss induced by amyloid beta (Aβ; 250 nM for 96 hours). (B) DOG prevented the neuronal loss induced by adding disrupted neurons (30 μg protein for 96 hours – Trauma). Data presented as mean ± standard error of the mean for ≥ 3 independent experiments. Statistically significant differences between live neuron densities:*P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

Mentions: We have previously reported that nanomolar levels of Aβ induce neuronal loss over 3 days in neuronal–glial co-cultures that is prevented if microglia are eliminated by LME [17,26]. We thus tested whether DOG could prevent this neuronal loss, and indeed found that 10 mM DOG prevented the neuronal loss induced by 250 nM Aβ (Figure 3A). Aβ-induced neuronal loss, when mediated by microglia, can thus be prevented by DOG, presumably by eliminating the microglia.


Deoxyglucose prevents neurodegeneration in culture by eliminating microglia.

Vilalta A, Brown GC - J Neuroinflammation (2014)

Deoxyglucose can prevent loss of live neurons induced by amyloid beta and disrupted neurons. (A) Deoxyglucose (DOG) prevented the neuronal loss induced by amyloid beta (Aβ; 250 nM for 96 hours). (B) DOG prevented the neuronal loss induced by adding disrupted neurons (30 μg protein for 96 hours – Trauma). Data presented as mean ± standard error of the mean for ≥ 3 independent experiments. Statistically significant differences between live neuron densities:*P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Deoxyglucose can prevent loss of live neurons induced by amyloid beta and disrupted neurons. (A) Deoxyglucose (DOG) prevented the neuronal loss induced by amyloid beta (Aβ; 250 nM for 96 hours). (B) DOG prevented the neuronal loss induced by adding disrupted neurons (30 μg protein for 96 hours – Trauma). Data presented as mean ± standard error of the mean for ≥ 3 independent experiments. Statistically significant differences between live neuron densities:*P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.
Mentions: We have previously reported that nanomolar levels of Aβ induce neuronal loss over 3 days in neuronal–glial co-cultures that is prevented if microglia are eliminated by LME [17,26]. We thus tested whether DOG could prevent this neuronal loss, and indeed found that 10 mM DOG prevented the neuronal loss induced by 250 nM Aβ (Figure 3A). Aβ-induced neuronal loss, when mediated by microglia, can thus be prevented by DOG, presumably by eliminating the microglia.

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