Pyruvate improves cerebral metabolism  during hemorrhagic shock

Mongan, Paul D.; Capacchione, John F.; Fontana, John L.; West, Shanda; Bünger, Rolf

doi:10.1152/ajpheart.2001.281.2.h854

Cited by 50 publications

(58 citation statements)

References 48 publications

(61 reference statements)

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“…Pyruvate is a molecule central to delivering energy to the body cells, and the metabolism is under control of a range of different physiological conditions (20)(21)(22). Despite this control, it is possible to create metabolic images of 13 C-lacate and 13 C-alanine within a minute after injection of supraphysiological levels of 13 C-pyruvate.…”

Section: Resultsmentioning

confidence: 99%

Real-time metabolic imaging

Golman¹,

Zandt²,

Thaning³

2006

Proc. Natl. Acad. Sci. U.S.A.

626

847

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The endogenous substance pyruvate is of major importance to maintain energy homeostasis in the cells and provides a window to several important metabolic processes essential to cell survival. Cell viability is therefore reflected in the metabolism of pyruvate. NMR spectroscopy has until now been the only noninvasive method to gain insight into the fate of pyruvate in the body, but the low NMR sensitivity even at high field strength has only allowed information about steady-state conditions. The medically relevant information about the distribution, localization, and metabolic rate of the substance during the first minute after the injection has not been obtainable. Use of a hyperpolarization technique has enabled 10 -15% polarization of 13 C1 in up to a 0.3 M pyruvate solution. i.v. injection of the solution into rats and pigs allows imaging of the distribution of pyruvate and mapping of its major metabolites lactate and alanine within a time frame of Ϸ10 s. Real-time molecular imaging with MRI has become a reality.13 C ͉ dynamic nuclear polarization ͉ hyperpolarized ͉ MRI ͉ spectroscopy T he technique for increase in signal-to-noise ratio of Ͼ10,000 times in liquid-state NMR and the use of this technique for molecular imaging with endogenous substances generated through the process of dynamic nuclear polarization (DNP) has been reported (1, 2). In both these studies, 13 C-enriched urea was used as an example of an endogenous substance that could be polarized to a high degree (37% for 13 C and 8% for 15 N) and used for high-resolution imaging of the cardiovascular system in rats.It was suggested that the signal enhancement could be used not only for visualizing the cardiovascular system but also for improved perfusion measurements and that it may allow realtime metabolic mapping of other endogenous substances such as alanine, glutamine, and acetate. Such studies should be possible if the relaxation time of the 13 C-labeled site in the hyperpolarized molecule is long enough and the metabolic products retain sufficient fraction of the nonequilibrium polarization. The possibilities for doing perfusion studies using 13 C labeled hyperpolarized substances have recently been reviewed by Månsson et al. (3), but the application of visualizing metabolic processes by using hyperpolarized substances have not yet been described.To reveal information about the metabolic status of the tissue, magnetic resonance (MR) spectroscopy has been used, employing nuclei like 1 H, 13 C, 31 P, and 19 F (4, 5). The main application areas have been brain, muscle, and prostate tissue. Information on fluxes through metabolic pathways is less straightforward to obtain though. Traditionally, 13 C NMR spectroscopy in combination with 13 C-labeled (enriched) substrates has been used to visualize the label applied, its metabolic intermediates, and͞or its end products during steady-state conditions. In certain cases the metabolic rates can be indirectly estimated by using mathematical modeling (6), for example, in determining the flux through the...

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Section: Resultsmentioning

confidence: 99%

Real-time metabolic imaging

Golman¹,

Zandt²,

Thaning³

2006

Proc. Natl. Acad. Sci. U.S.A.

626

847

View full text Add to dashboard Cite

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“…Finally, the model provides a means to explore new therapeutic strategies and pharmacology. It has been reported in animal studies that pyruvate may prolong neural survival during ischemic infarctions (48,49). Pyruvate is known to stabilize oxidative metabolism by increasing ATP production during hypoxic events.…”

Section: Discussionmentioning

confidence: 99%

A neurophysiological–metabolic model for burst suppression

Ching

Purdon

Vijayan

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

254

326

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Burst suppression is an electroencepholagram (EEG) pattern in which high-voltage activity alternates with isoelectric quiescence. It is characteristic of an inactivated brain and is commonly observed at deep levels of general anesthesia, hypothermia, and in pathological conditions such as coma and early infantile encephalopathy. We propose a unifying mechanism for burst suppression that accounts for all of these conditions. By constructing a biophysical computational model, we show how the prevailing features of burst suppression may arise through the interaction between neuronal dynamics and brain metabolism. In each condition, the model suggests that a decrease in cerebral metabolic rate, coupled with the stabilizing properties of ATP-gated potassium channels, leads to the characteristic epochs of suppression. Consequently, the model makes a number of specific predictions of experimental and clinical relevance.B urst suppression-an electroencephalogram (EEG) pattern in which high voltage activity (burst) and flatline (suppression) periods alternate systematically but quasiperiodically (almost periodic but with variations in inter-and intra-burst duration) (1)-is a state of profound brain inactivation. It is frequently observed in deep general anesthesia (2). It is also observed in a range of pathological conditions including hypothermia (3-5), hypoxic-ischemic trauma/coma (6), and the so-called Ohtahara syndrome (7,8), a type of early infantile encephalopathy. These etiologies indicate that the burst suppression pattern represents a low-order dynamic mechanism that persists in the absence of higher-level brain activity. Indeed, the fact that many different conditions produce similar brain activity suggests that there may be a common pathway to the state of brain inactivation and may indicate fundamental properties of the brain's arousal circuits (2).The basic features of the burst suppression phenomenon have been established through a variety of EEG studies that are reviewed in ref. 9. The two most notable of these features are the spatial homogeneity of bursts and the quasi-periodic nature of the suppression. Later research has been directed at describing the phenomenon in vivo and in the specific context of general anesthesia. In particular, the early work of Steriade et al. (10) helped establish the neural correlates of burst suppression, including the differential participation of cortical and subcortical cell types. More recent studies (11,12) have suggested that burst suppression is associated with enhanced excitability in cortical networks. These studies implicate extracellular calcium as a correlate for the switches between burst and suppression.Despite the findings of these studies, a unifying mechanism for burst suppression-one that explains its prevailing features and also accounts for its range of etiologies-has not been proposed. Indeed, the existing characterizations of burst suppression in pathological situations are highly limited. Computational models offer a means of synthesizing the availabl...

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“…The inability to correctly utilize pyruvate and its intracellular accumulation is considered damaging to the neuronal cell in HS. [30][31][32] The accumulating pyruvate would also inhibit the entire upstream pathway of glycolysis by a feedback mechanism. Given the slight increase in citrate synthase activity in LEH group as compared with the HS group, there is some indication of improvement in mitochondrial metabolism by LEH infusion.…”

Section: Discussionmentioning

confidence: 99%

The Brain Metabolic Activity after Resuscitation with Liposome-Encapsulated Hemoglobin in a Rat Model of Hypovolemic Shock

Rao

Hedrick

Yadav

et al. 2015

J Cereb Blood Flow Metab

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We examined the effect of resuscitation with liposome-encapsulated hemoglobin (LEH) on cerebral bioenergetics in a rat model of 45% hypovolemia. The rats were resuscitated with isovolemic LEH or saline after 15 minutes of shock and followed up to 6 hours. Untreated hypovolemic rats received no fluid. The cerebral uptake of F-18-fluorodeoxyglucose (FDG) was measured by PET, and at 6 hours, the brain was collected for various assays. Hypovolemia decreased cellular adenosine triphosphate (ATP), phosphocreatine, nicotinamide adenine dinucleotide (NAD)/NADH ratio, citrate synthase activity, glucose-6-phosphate, and nerve growth factor (NGF), even when FDG uptake remained unchanged. The FDG uptake was reduced by saline, but not by LEH infusion. The reduced FDG uptake in saline group was associated with a decrease in hexokinase I expression. The LEH infusion effectively restored ATP content, NAD/NADH ratio, and NGF expression, and reduced the hypovolemia-induced accumulation of pyruvate and ubiquitinated proteins; in comparison, saline was significantly less effective. The LEH infusion was associated with low pH and high anion gap, indicating anionic gap acidosis. The results suggest that hypovolemic shock perturbs glucose metabolism at the level of pyruvate utilization, resulting in deranged cerebral energy stores. The correction of volume and oxygen deficits by LEH recovers the cerebral metabolism and creates a prosurvival phenotype.

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Pyruvate improves cerebral metabolism during hemorrhagic shock

Cited by 50 publications

References 48 publications

Real-time metabolic imaging

Real-time metabolic imaging

A neurophysiological–metabolic model for burst suppression

The Brain Metabolic Activity after Resuscitation with Liposome-Encapsulated Hemoglobin in a Rat Model of Hypovolemic Shock

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