Activity‐dependent regulation of energy metabolism by astrocytes: An update

Pellerin, Luc; Bouzier‐Sore, Anne‐Karine; Aubert, Agnès; Serres, Sébastien; Merle, M.; Costalat, Robert; Magistretti, Pierre J.

doi:10.1002/glia.20528

Cited by 704 publications

(541 citation statements)

References 115 publications

(183 reference statements)

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“…Astrocytes also produce neurotrophic factors that promote neuronal survival and provide neurons with precursors for glutathione biosyn-thesis, which is necessary to combat oxidative stress (Dringen, 2000;Drukarch et al, 1997;Makarov et al, 2002). Moreover, astrocytes release lactate, which is then used by neighboring neurons as fuel for aerobic energy metabolism (Dienel and Hertz, 2001) particularly following cerebral ischemia (Schurr, 2002;Pellerin et al, 2007). Therefore, the death or dysfunction of astrocytes in acute brain injury may compromise neuronal metabolism and survival, thereby contributing to neurologic impairment (Chen and Swanson, 2003;O'Malley et al, 1992;Takeshima et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

Hyperoxia promotes astrocyte cell death after oxygen and glucose deprivation

Danilov

Fiskum

2008

Glia

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Astrocyte dysfunction and death accompany cerebral ischemia/reperfusion and possibly compromise neuronal survival. Animal studies indicate that neuronal death, neurologic injury, and oxidative molecular modifications are worse in animals exposed to hyperoxic compared to normoxic ventilation during reperfusion after global cerebral ischemia. It is unknown, however, whether ambient O 2 affects brain cell survival using in vitro ischemia paradigms where mechanisms of injury to specific cell types can be more thoroughly investigated. This study tested the hypothesis that compared with the supraphysiological level of 20% O 2 normally used in cell culture, lower, more physiological O 2 levels protect astrocytes from death following oxygen and glucose deprivation. Primary rat cortical astrocytes were cultured under either 7 or 20% O 2 , exposed to O 2 , and glucose deprivation for 4 h, and then exposed to normal medium under either 7 or 20% O 2 . Cell death and 3-nitrotyrosine and 8-hydroxy-2-deoxyguanosine immunoreactivities were assessed at different periods of reoxygenation. Astrocytes exposed to low levels of O 2 during reoxygenation undergo less death and exhibit lower levels of protein nitration and nucleic acid oxidation when compared with those under high levels of O 2 during reoxygenation. These results support the hypothesis that the 20% O 2 normally used in cell culture exacerbates astrocyte death and oxidative stress in an in vitro ischemia/reperfusion model compared to levels that more closely approximate those that exist in vivo.

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Section: Discussionmentioning

confidence: 99%

Hyperoxia promotes astrocyte cell death after oxygen and glucose deprivation

Danilov

Fiskum

2008

Glia

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“…Different models, modeling principles, and model assumptions underlie discordant conclusions related to the roles of lactate and glucose in brain activation derived from computerbased simulation studies. Interested readers are referred to studies by Aubert et al (2005Aubert et al ( , 2007 …”

Section: Metabolic Modeling and Simulation Studiesmentioning

confidence: 99%

Brain Lactate Metabolism: The Discoveries and the Controversies

Dienel

2011

J Cereb Blood Flow Metab

422

434

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Potential roles for lactate in the energetics of brain activation have changed radically during the past three decades, shifting from waste product to supplemental fuel and signaling molecule. Current models for lactate transport and metabolism involving cellular responses to excitatory neurotransmission are highly debated, owing, in part, to discordant results obtained in different experimental systems and conditions. Major conclusions drawn from tabular data summarizing results obtained in many laboratories are as follows: Glutamate-stimulated glycolysis is not an inherent property of all astrocyte cultures. Synaptosomes from the adult brain and many preparations of cultured neurons have high capacities to increase glucose transport, glycolysis, and glucose-supported respiration, and pathway rates are stimulated by glutamate and compounds that enhance metabolic demand. Lactate accumulation in activated tissue is a minor fraction of glucose metabolized and does not reflect pathway fluxes. Brain activation in subjects with low plasma lactate causes outward, brain-toblood lactate gradients, and lactate is quickly released in substantial amounts. Lactate utilization by the adult brain increases during lactate infusions and strenuous exercise that markedly increase blood lactate levels. Lactate can be an 'opportunistic', glucose-sparing substrate when present in high amounts, but most evidence supports glucose as the major fuel for normal, activated brain. Keywords: astrocyte; brain activation; glucose; lactate shuttling; metabolism; neuron Glucose is the major fuel for the brain, and its metabolism by different pathways has important functions related to energetics, neurotransmission, oxidation-reduction (redox) reactions, and biosynthesis of essential brain components (Figure 1). For many decades, lactate production in the brain was viewed as a consequence of inadequate oxygen delivery, disruption of oxidative metabolism, or mismatch between glycolytic and oxidative rates (Siesjö, 1978), but more recently, the conceptual role of lactate metabolism and function in the normal brain have undergone major changes, shifting from developmental fuel and glycolytic waste product to include its use as a supplemental fuel and signaling molecule. Starting in the 1970s to 1980s studies carried out in different laboratories with diverse experimental interests related to brain function brought attention to upregulation of glycolysis, lactate production, lactate release into the blood, the possibility of lactate shuttling among cell types within the brain, lactate fueling adult brain during exercise, and roles of lactate in the regulation of blood flow; some of these topics are controversial and highly debated. The experimental paradigm and physiologic status of subjects are critical for interpretation of data, and this review first presents a brief historical overview of studies related to brain lactate transport and metabolism, then compares sets of data to provide a perspective and context within which the consistency of simi...

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“…LDH is found in both neurons and astrocytes, as isoenzymes LDH1 and LDH5 respectively. It is traditionally believed lactate is an end product of anaerobic glycolysis however there is increasing evidence suggesting lactate is a principal product of glycolysis (even in the presence of oxygen) and also a secondary fuel for the tricarboxylic acid cycle since lactate demonstrated to be an important cerebral oxidative energy substrate (for review see Pellerin et al, 2007 andSchurr, 2006). (Bröer et al, 1999).…”

Section: Lactate Metabolism In the Brainmentioning

confidence: 99%

“…Since the astrocyte-neuron lactate shuttle hypothesis (ANLSH) was proposed by Pellerin and Magistretti (1994), many studies have documented and supported this hypothesis in which lactate synthesized within astrocytes is released (shuttled) into the interstitial space and used as a supplementary fuel (in addition to glucose) for neurons (for review see Pellerin et al, 2007). The bulk of ANLSH has been developed based on in vitro studies but has also been supported with in vivo studies ( Hyder et al, 2006 andSerres et al, 2005).…”

Section: Lactate As An Energy Sourcementioning

confidence: 99%

“…Upon glutamate activation, glucose transport and utilization increases in astrocytes ( Loaiza et al, 2003 andPellerin andMagistretti, 2004) but decreases in neurons (Porras et al, 2004) even though energy demands increase. This favours lactate oxidation in neurons (Pellerin et al, 2007). Astrocytes can afford to produce lactate from pyruvate since glutamate taken up by high affinity transporters in the astrocytes may also be used to fuel the tricarboxylic acid cycle and oxidative metabolism (Hertz, 2004).…”

Section: Lactate As An Energy Sourcementioning

confidence: 99%

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Increase brain lactate in hepatic encephalopathy: Cause or consequence?

Rose

2010

Neurochemistry International

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Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome which develops as a result of liver failure or disease. Increased concentrations of brain lactate (microdialysate, cerebrospinal fluid, tissue) are commonly measured in patients with HE induced by either acute or chronic liver failure. Whether an increase in brain lactate is a cause or a consequence of HE remains undetermined. A rise in cerebral lactate may occur due to (1) blood-borne lactate (hyperlactataemia) crossing the blood-brain barrier, (2) increased glycolysis due to energy failure or impairment and (3) increased lactate production/release or decreased lactate utilization/uptake. This review explores the different reasons for lactate accumulation in the brain during liver failure and describes the possible roles of lactate in the pathogenesis of HE.

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Activity‐dependent regulation of energy metabolism by astrocytes: An update

Cited by 704 publications

References 115 publications

Hyperoxia promotes astrocyte cell death after oxygen and glucose deprivation

Hyperoxia promotes astrocyte cell death after oxygen and glucose deprivation

Brain Lactate Metabolism: The Discoveries and the Controversies

Increase brain lactate in hepatic encephalopathy: Cause or consequence?

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