Glycogen is mobilized during the disposal of peroxides by cultured astroglial cells from rat brain

Rahman, Basim; Kußmaul, Lothar; Hamprecht, Bernd; Dringen, Ralf

doi:10.1016/s0304-3940(00)01369-0

Cited by 47 publications

(45 citation statements)

References 19 publications

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“…Previous studies have demonstrated that, in contrast to neurons, astrocytes are resistant to oxidative stress and in particular to face hydrogen peroxide toxicity (Dringen, 2000). This property is mainly due to the very efficient glutathione detoxifying system present in astrocytes compared with neurons which is also coupled to their capacity to increase NADPH production through activation of PPP from extracellular glucose or from glycogen mobilization (Ben Yoseph et al, 1994, 1996Dringen, 2000;Rahman et al, 2000;Sun et al, 2006). Results presented here are consistent with these observations.…”

Section: Discussionsupporting

confidence: 91%

Modulation of astrocytic metabolic phenotype by proinflammatory cytokines

Gavillet

Allaman

Magistretti

2008

Glia

122

118

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Astrocytes play an important role in nervous system homeostasis. In particular, they contribute to the regulation of local energy metabolism and to oxidative stress defence. In previous experiments, we showed that long-term treatment with interleukin 1alpha (IL-1alpha) or tumor necrosis factor-alpha (TNFalpha) alone increases glucose utilization in primary culture of mouse astrocytes. In our study, we report that a combination of IL-1beta and TNFalpha exerts a synergistic effect on glucose utilization and markedly modifies the metabolic phenotype of astrocytes. Thus, IL-1beta+TNFalpha treated astrocytes show a marked decrease in glycogen levels, a slight but not significant decrease in lactate release as well as a massive increase in both the pentose phosphate pathway and TCA cycle activities. Glutamate-stimulated glucose utilization and lactate release, a typical feature of astrocyte energy metabolism, are altered after pretreatment with IL-1beta+TNFalpha. As far as mechanisms for oxidative stress defence are concerned, we observed that treatment with IL-1beta+TNFalpha decreases cellular glutathione content and increases glutathione release into the extracellular space while stimulating superoxide anion and nitric oxide production as well as H(2)O(2) release. Interestingly, stimulation of glucose utilization by IL-1beta+TNFalpha is not affected by the antioxidant N-acetyl-L-cysteine, suggesting that cellular stress does not account for this effect. Finally, the effects of cytokines on glucose utilization appear to involve multiple signaling cascades including the phosphoinositide 3-kinase and mitogen-activated protein kinases. Taken together these results establish that a proinflammatory environment such as observed in several neuropathological conditions including Alzheimer's disease, markedly modifies the metabolic phenotype of astrocytes.

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Section: Discussionsupporting

confidence: 91%

Modulation of astrocytic metabolic phenotype by proinflammatory cytokines

Gavillet

Allaman

Magistretti

2008

Glia

122

118

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“…Moreover, glycogen may sustain the net synthesis of glutamine from glycogen (Gibbs et al, 2008) via stimulation of the anaplerotic pyruvate carboxylation pathway in astrocytes, as well as the generation in the pentose phosphate pathway of the NADPH needed for the detoxification of reactive oxygen species (Murin et al, 2009, and references therein). The latter point applies both to neurons, which can divert a larger fraction of glucose to pentose phosphate pathway during activation, and to astrocytes, as involvement of glycogen for disposal of peroxides was directly demonstrated in astrocytic preparations (Rahman et al, 2000). On the other hand, our results suggest that part of the functional significance of brain glycogen is identified in the energetic benefit for neurons (i.e., supporting neuronal glycolysis to proceed).…”

Section: Discussionsupporting

confidence: 50%

Glycogenolysis in Astrocytes Supports Blood-Borne Glucose Channeling Not Glycogen-Derived Lactate Shuttling to Neurons: Evidence from Mathematical Modeling

DiNuzzo

Mangia

Maraviglia

et al. 2010

J Cereb Blood Flow Metab

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In this article, we examined theoretically the role of human cerebral glycogen in buffering the metabolic requirement of a 360-second brain stimulation, expanding our previous modeling study of neurometabolic coupling. We found that glycogen synthesis and degradation affects the relative amount of glucose taken up by neurons versus astrocytes. Under conditions of 175:115 mmol/L (B1.5:1) neuronal versus astrocytic activation-induced Na + influx ratio, B12% of astrocytic glycogen is mobilized. This results in the rapid increase of intracellular glucose-6-phosphate level on stimulation and nearly 40% mean decrease of glucose flow through hexokinase (HK) in astrocytes via product inhibition. The suppression of astrocytic glucose phosphorylation, in turn, favors the channeling of glucose from interstitium to nearby activated neurons, without a critical effect on the concurrent intercellular lactate trafficking. Under conditions of increased neuronal versus astrocytic activation-induced Na + influx ratio to 190:65 mmol/L (B3:1), glycogen is not significantly degraded and blood glucose is primarily taken up by neurons. These results support a role for astrocytic glycogen in preserving extracellular glucose for neuronal utilization, rather than providing lactate to neurons as is commonly accepted by the current 'thinking paradigm'. This might be critical in subcellular domains during functional conditions associated with fast energetic demands.

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“…Nevertheless, astrocytes do not show signs of overt oxidative stress in our conditions, since neither an increase in the intracellular oxidized form of GSH, a change in the total intracellular GSH content, nor a loss of cellular viability could be observed. In contrast, these observations argue in favor of a cellular response mounted against pro-oxidative stimuli to provide sufficient NADPHreducing equivalents (Ben Yoseph et al, 1994;Rahman et al, 2000). Interestingly, we have recently described a similar mechanism following proinflammatory cytokines treatment of astrocytes (Gavillet et al, 2008).…”

Section: Discussionmentioning

confidence: 93%

Amyloid-β Aggregates Cause Alterations of Astrocytic Metabolic Phenotype: Impact on Neuronal Viability

Allaman

Gavillet²,

Bélanger³

et al. 2010

J. Neurosci.

248

212

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Amyloid-␤(A␤)peptidesplayakeyroleinthepathogenesisofAlzheimer'sdiseaseandexertvarioustoxiceffectsonneurons;however,relatively littleisknownabouttheirinfluenceonglialcells.Astrocytesplayapivotalroleinbrainhomeostasis,contributingtotheregulationoflocalenergy metabolism and oxidative stress defense, two aspects of importance for neuronal viability and function. In the present study, we explored the effects of A␤ peptides on glucose metabolism in cultured astrocytes. Following A␤ 25-35 exposure, we observed an increase in glucose uptake and its various metabolic fates, i.e., glycolysis (coupled to lactate release), tricarboxylic acid cycle, pentose phosphate pathway, and incorporation into glycogen. A␤ increased hydrogen peroxide production as well as glutathione release into the extracellular space without affecting intracellular glutathione content. A causal link between the effects of A␤ on glucose metabolism and its aggregation and internalization into astrocytes through binding to members of the class A scavenger receptor family could be demonstrated. Using astrocyte-neuron cocultures, we observed that the overall modifications of astrocyte metabolism induced by A␤ impair neuronal viability. The effects of the A␤ 25-35 fragment were reproduced by A␤ 1-42 but not by A␤ 1-40 . Finally, the phosphoinositide 3-kinase (PI3-kinase) pathway appears to be crucial in these events since both the changes in glucose utilization and the decrease in neuronal viability are prevented by LY294002, a PI3-kinase inhibitor. This set of observations indicates that A␤ aggregation and internalization into astrocytes profoundly alter their metabolic phenotype with deleterious consequences for neuronal viability.

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Glycogen is mobilized during the disposal of peroxides by cultured astroglial cells from rat brain

Cited by 47 publications

References 19 publications

Modulation of astrocytic metabolic phenotype by proinflammatory cytokines

Modulation of astrocytic metabolic phenotype by proinflammatory cytokines

Glycogenolysis in Astrocytes Supports Blood-Borne Glucose Channeling Not Glycogen-Derived Lactate Shuttling to Neurons: Evidence from Mathematical Modeling

Amyloid-β Aggregates Cause Alterations of Astrocytic Metabolic Phenotype: Impact on Neuronal Viability

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