Lactate: The Ultimate Cerebral Oxidative Energy Substrate?

Schurr, Avital

doi:10.1038/sj.jcbfm.9600174

Cited by 268 publications

(258 citation statements)

References 75 publications

(111 reference statements)

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“…To our great interest, not all the metabolic variations occur consistently in the four brain regions in this study. For instance, lactate, as one major end product of both aerobic and anaerobic glycolysis [41], was found significantly decreased only in cerebral cortex and thalamus with sensory and motor functions. Such abnormal alteration might indicate that energy metabolism in cortex and thalamus was an outcome of long-time fatigue of CUMS-treated rats in our study.…”

Section: Discussionmentioning

confidence: 98%

Metabolic profiling reveals disorder of amino acid metabolism in four brain regions from a rat model of chronic unpredictable mild stress

et al. 2008

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Chronic stress is closely linked to clinical depression, which could be assessed by a chronic unpredictable mild stress (CUMS) animal model. We present here a GC/MS-based metabolic profiling approach to investigate neurochemical changes in the cerebral cortex, hippocampus, thalamus, and remaining brain tissues. Multi-criteria assessment for multivariate statistics could identify differential metabolites between the CUMS-model rats versus the healthy controls. This study demonstrates that the significantly perturbed metabolites mainly involving amino acids play an indispensable role in regulating neural activity in the brain. Therefore, results obtained from such metabolic profiling strategy potentially provide a unique perspective on molecular mechanisms of chronic stress.

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Section: Discussionmentioning

confidence: 98%

Metabolic profiling reveals disorder of amino acid metabolism in four brain regions from a rat model of chronic unpredictable mild stress

et al. 2008

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“…Very similar time frames of extracellular lactate were seen in the muscle, an organ that should inspire us, 'brainy investigators' to think (Schurr, 2006). In this organ, the cellular export of lactate during exercise or after stimulation of the muscle starts to rise after approximately 30 secs to 1 min (e.g., De Boer et al, 1991).…”

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confidence: 84%

Is Brain Lactate Metabolized Immediately after Neuronal Activity through the Oxidative Pathway?

Korf

2006

J Cereb Blood Flow Metab

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In the central nervous system, lactate is formed under both aerobic and anaerobic conditions. The question is whether the generated lactate after neural excitation by glutamate is immediately metabolized. It has been hypothesized that lactate is formed after glutamate uptake in the glia, then released into the intercellular compartment and subsequently used by neurones (the so-called astrocyte-neuron lactate shuttle; Pellerin and Magistretti, 1994). In two recent reports (Schurr, 2006;Aubert et al, 2005), the question was addressed whether lactate could serve as a substrate for oxidative metabolism during nerve cell activation under aerobic conditions in vivo. Aubert et al (2005) designed a mathematical model to show that the time course of extracellular changes of lactate levels during enhanced neural activity could be interpreted as aerobic metabolism. Schurr (2006) summarized the arguments favouring the idea that in the functioning brain, lactate is the major end product of both aerobic and anaerobic glycolysis and that lactate subsequently serves as an oxidative substrate. For both reports, the results shown by Hu and Wilson (1997) are crucial. In that study, the perforant pathway of the rat was simulated for 5 secs once or repeatedly and the time course of extracellular lactate, oxygen, and glucose in the dentate gyrus of the rat brain was measured with rapidly responding biosensors. A single stimulation showed an initial decrease of all the analytes, followed by transient increases. After repeated stimulations, extracellular lactate was substantially increased, with a concomitant decrease of glucose and little, if any change of oxygen. This study and several others (e.g., De Bruin et al, 1990;Kuhr et al, 1988;Van der Kuil and Korf, 1991;Krugers et al, 1992) show that lactate is formed under conditions of enhanced neural activity which is-at least in part-associated with lower extracellular glucose. The time course of hippocampus lactate after a single stimulation (lasting 5 secs; Hu and Wilson, 1997) and detected with the biosensors is very similar to that seen with continuous flow analysis of microdialysates in rats, subjected to a single electroconvulsive stimulus with an intact entorhinalhippocampal glutamatergic pathway (Krugers et al, 1992). Modelling shows that such a time course can best be described by a very rapid (nearly immediate) increase of intracellular lactate that is subsequently released into the extracellular compartment via a carrier-mediated process (Kuhr et al, 1988).To appreciate the results of in vivo studies, a few cautionary remarks should be made. It should be realized that a lactate level is the net result of appearance and disappearance, which is a composite of the rates of lactate influx and efflux across the blood brain barrier, lactate influx and efflux across the membranes of brain cells, lactate formation from glucose and glycogen, lactate oxidation in any brain cells, diffusion to and from the site of the sensor, and also the size of extracellular space in brain and blood ...

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“…However, the assumption that brain lactate accumulation signifies brain hypoxia in PD is inconsistent with current knowledge of the role of lactate in brain metabolism. 36,41 The current study tests this idea experimentally, by examining whether elevated brain lactate responses occur in PD patients when hypoxia can be excluded as a mechanism. If elevated brain lactate responses in PD do not signify hypoxia, then there is no evidence that episodes of brain hypoxia occur in PD.…”

Section: Introductionmentioning

confidence: 97%

“…35,36 Although its exact role as a metabolic fuel is not yet fully understood, studies have shown that lactate is the end product of glycogenolysis in astroglia, 37,38 that accumulation of lactate in brain parenchyma is a normal occurrence during neural activation under fully aerobic conditions 39,40 and that lactate is a significant substrate for neuronal oxidative metabolism. 36,41 The hypoxia model of PD interprets the exaggerated brain lactate responses to alkalosis as confirmation that alkalosisinduced vasoconstriction has caused hypoxia in the PD patients. The inference that elevated brain lactate responses observed in PD are due to hypoxia is critical to this model, as this is the only experimental evidence that episodes of brain hypoxia occur in PD.…”

Section: Introductionmentioning

confidence: 99%

Elevated brain lactate responses to neural activation in panic disorder: a dynamic 1H-MRS study

et al. 2008

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Converging evidence suggests that patients with panic disorder have a metabolic disturbance that may influence the regulation of arousal systems and confer vulnerability to 'spontaneous' panic attacks. The consistent finding of elevated brain lactate responses to various metabolic challenges in panic disorder appears to support this model, although the mechanism of this effect is not understood. Several mechanisms have been proposed to account for elevated brain lactate responses in panic disorder, including (1) brain hypoxia due to excessive cerebral vasoconstriction, and (2) a metabolic disturbance affecting lactate metabolism. Recent studies have shown that neural activation (for example, sensory stimulation) causes local lactate accumulation in the presence of increased oxygen availability. The current study used proton magnetic resonance spectroscopic measures of visual cortex lactate changes during visual stimulation in 15 untreated patients with panic disorder and 15 matched volunteers to critically test these two proposed mechanisms of elevated brain lactate responses in panic disorder. Visual cortex lactate/N-acetylaspartate increased during visual stimulation in both groups. The increase was significantly greater in the panic patients than in the comparison group. There were no group differences in end-tidal pCO 2 . The finding that visual stimulation leads to significantly greater visual cortex lactate responses in panic patients is not predicted by the hypoxia model. These results suggest that a metabolic disturbance affecting the production or clearance of lactate is the cause of the elevated brain lactate responses consistently observed in panic disorder and provide further support for metabolic models of vulnerability to this illness.

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Lactate: The Ultimate Cerebral Oxidative Energy Substrate?

Cited by 268 publications

References 75 publications

Metabolic profiling reveals disorder of amino acid metabolism in four brain regions from a rat model of chronic unpredictable mild stress

Metabolic profiling reveals disorder of amino acid metabolism in four brain regions from a rat model of chronic unpredictable mild stress

Is Brain Lactate Metabolized Immediately after Neuronal Activity through the Oxidative Pathway?

Elevated brain lactate responses to neural activation in panic disorder: a dynamic 1H-MRS study

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