Characteristics of monocarboxylates as energy substrates other than glucose in rat brain slices and the effect of selective glial poisoning — a 31P NMR study

Yoshioka, Keitaro; Nisimaru, Naoko; Yanai, Soroku; Shimoda, Hiroshi; Yamada, Keiko

doi:10.1016/s0168-0102(99)00124-8

Cited by 25 publications

(16 citation statements)

References 41 publications

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“…The concentration gradients among these different compartments suggest a net flux of pyruvate from astrocytes to extracellular pool, then to neurons. In agreement with this, other reports show that astrocytes release pyruvate (Pellerin and Magistretti, 1994) and that neurons can use pyruvate for their function recovery or survival (Selak et al, 1985;Matsumoto et al, 1994;Yoshioka et al, 2000). Given the evidence above, it is suggested that the extracellular pool of pyruvate is contributed mainly by astrocytes rather than neurons.…”

Section: Discussionsupporting

confidence: 64%

Pyruvate Released by Astrocytes Protects Neurons from Copper-Catalyzed Cysteine Neurotoxicity

2001

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We have found previously that astrocytes can provide cysteine to neurons. However, cysteine has been reported to be neurotoxic although it plays a pivotal role in regulating intracellular levels of glutathione, the major cellular antioxidant. Here, we show that cysteine toxicity is a result of hydroxyl radicals generated during cysteine autoxidation. Transition metal ions are candidates to catalyze this process. Copper substantially accelerates the autoxidation rate of cysteine even at submicromolar levels, whereas iron and other transition metal ions, including manganese, chromium, and zinc, are less efficient. The autoxidation rate of cysteine in rat CSF is equal to that observed in the presence of ϳ0.2 M copper. In tissue culture tests, we found that cysteine toxicity depends highly on its autoxidation rate and on the total amount of cysteine being oxidized, suggesting that the toxicity can be attributed to the free radicals produced from cysteine autoxidation, but not to cysteine itself.We have also explored the in vivo mechanisms that protect against cysteine toxicity. Catalase and pyruvate were each found to inhibit the production of hydroxyl radicals generated by cysteine autoxidation. In tissue culture, they both protected primary neurons against cysteine toxicity catalyzed by copper. This protection is attributed to their ability to react with hydrogen peroxide, preventing the formation of hydroxyl radicals. Pyruvate, but not catalase or glutathione peroxidase, was detected in astrocyte-conditioned medium and CSF. Our data therefore suggest that astrocytes can prevent cysteine toxicity by releasing pyruvate.

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Section: Discussionsupporting

confidence: 64%

Pyruvate Released by Astrocytes Protects Neurons from Copper-Catalyzed Cysteine Neurotoxicity

2001

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“…Our results indicate that neurons use monocarboxylate as a main energetic substrate to sustain synaptic function during repeated hypoglycemia. We and others have reported that replacement of exogenous glucose with lactate, pyruvate, or ␤-hydroxybutyrate fails to maintain synaptic function (14,15,19,20,30,31). However, monocarboxylate (lactate or pyruvate) was able to maintain synaptic activity during secondary hypoglycemia (Figs.…”

Section: Diabetes Vol 51 February 2002mentioning

confidence: 91%

Synaptic Adaptation to Repeated Hypoglycemia Depends on the Utilization of Monocarboxylates in Guinea Pig Hippocampal Slices

et al. 2002

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This report provides in vitro evidence that synaptic activity becomes resistant to repeated hypoglycemia, i.e., hypoglycemic synaptic adaptation occurs. Synaptic function was estimated by the amplitude of the postsynaptic population spike (PS) recorded in the granule cell layer of guinea pig hippocampal slices. ATP, phosphocreatine (PCr), glycogen, and glucose concentrations were measured to investigate energy metabolism homeostasis. Glucose deprivation produced a complete elimination of the PS amplitude, with a 50% inhibition by 10.6 min, and a ϳ15% reduction in ATP and PCr concentrations. Low-glucose (0.5-1 mmol/l) medium gradually depressed the PS. After recovery from glucose depletion, repeated glucose deprivation produced a slowly developing depression of PS, with a 50% inhibition by 36.5 min. However, ATP and PCr concentrations were maintained. Incubation in secondary low-glucose medium maintained PS amplitude. Hippocampal glycogen and glucose concentrations promptly decreased during repeated glucose deprivation, indicating that glycogenolysis does not fuel synaptic adaptation to repeated hypoglycemia. Synaptic function during repeated glucose depletion was reversibly depressed by addition of ␣-cyano-4-hydroxycinnamic acid or 3-isobutyl-1-methylxanthine, inhibitors of the monocarboxylate transporter. Replacement of extracellular glucose with Na-lactate or Na-pyruvate sustained synaptic transmission after transient glucose depletion. These results indicate that synaptic utilization of monocarboxylates sustains hypoglycemic synaptic adaptation. Diabetes 51:430 -438, 2002 P rospective studies of diabetes and its complications clearly demonstrate that glycemic control prevents or delays several long-term complications of the disease. However, attempts to achieve near-normal blood glucose levels increase the risk of hypoglycemia, the most common and serious iatrogenic morbidity in patients with diabetes. Because glucose is the principal metabolic fuel of the brain, acute hypoglycemia can cause profound but reversible autonomic and neuroglycopenic symptoms (1). Hypoglycemia induces counterregulatory hormonal responses, which produce sympathetic symptoms. Neurobehavioral deficits associated with insulin-induced hypoglycemia frequently arise on tasks that require sustained attention, rapid decision making, analysis of complex visual stimuli, mental flexibility, and memory of recently learned information (1,2).The main defense against severe hypoglycemia is the subjective recognition of the onset of falling glucose levels. Some diabetic patients lose this symptomatic awareness and show reduced neuroendocrine responses to hypoglycemia, which is defined as hypoglycemia unawareness. In response to repeated hypoglycemia, the glucose threshold at which the brain detects hypoglycemia and triggers neurohumoral responses is shifted downward in nondiabetic individuals and in patients with diabetes (3-5). Glucose-sensing areas of the brain, presumably including the ventromedial hypothalamus, are responsible for the detection...

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“…11 As lactate enters the TCA cycle by conversion into pyruvate with subsequent oxidative decarboxylation of pyruvate to acetyl-CoA, pyruvate is an oxidizable substrate as well. 12 Oxygen Supply O 2 reaches the respiratory chain by diffusion through a number of different membranes. Hence, the O 2 concentration sensed by complex IV of the respiratory chain is much lower than the O 2 concentration in the extracellular space.…”

Section: Substrate Supplymentioning

confidence: 99%

Physiology-Based Kinetic Modeling of Neuronal Energy Metabolism Unravels the Molecular Basis of NAD(P)H Fluorescence Transients

Berndt

Kann

Holzhütter

2015

J Cereb Blood Flow Metab

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Imaging of the cellular fluorescence of the reduced form of nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) is one of the few metabolic readouts that enable noninvasive and time-resolved monitoring of the functional status of mitochondria in neuronal tissues. Stimulation-induced transient changes in NAD(P)H fluorescence intensity frequently display a biphasic characteristic that is influenced by various molecular processes, e.g., intracellular calcium dynamics, tricarboxylic acid cycle activity, the malate-aspartate shuttle, the glycerol-3-phosphate shuttle, oxygen supply or adenosine triphosphate (ATP) demand. To evaluate the relative impact of these processes, we developed and validated a detailed physiologic mathematical model of the energy metabolism of neuronal cells and used the model to simulate metabolic changes of single cells and tissue slices under different settings of stimulus-induced activity and varying nutritional supply of glucose, pyruvate or lactate. Notably, all experimentally determined NAD(P)H responses could be reproduced with one and the same generic cellular model. Our computations reveal that (1) cells with quite different metabolic status may generate almost identical NAD(P)H responses and (2) cells of the same type may quite differently contribute to aggregate NAD(P)H responses recorded in brain slices, depending on the spatial location within the tissue. Our computational approach reconciles different and sometimes even controversial experimental findings and improves our mechanistic understanding of the metabolic changes underlying live-cell NAD(P)H fluorescence transients.

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Characteristics of monocarboxylates as energy substrates other than glucose in rat brain slices and the effect of selective glial poisoning — a 31P NMR study

Cited by 25 publications

References 41 publications

Pyruvate Released by Astrocytes Protects Neurons from Copper-Catalyzed Cysteine Neurotoxicity

Pyruvate Released by Astrocytes Protects Neurons from Copper-Catalyzed Cysteine Neurotoxicity

Synaptic Adaptation to Repeated Hypoglycemia Depends on the Utilization of Monocarboxylates in Guinea Pig Hippocampal Slices

Physiology-Based Kinetic Modeling of Neuronal Energy Metabolism Unravels the Molecular Basis of NAD(P)H Fluorescence Transients

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