Comparison of the Effects of Cyclosporin a on the Metabolism of Perfused Rat Brain Slices during Normoxia and Hypoxia

The authors evaluated and compared the metabolic effects of cyclosporin A in the rat brain during normoxia and hypoxia/reperfusion. Ex vivo31P magnetic resonance spectroscopy experiments based on perfused rat brain slices showed that under normoxic conditions, 500 μg/L cyclosporin A significantly reduced mitochondrial energy metabolism (nucleotide triphosphate, 83 ± 9% of controls; phosphocreatine, 69 ± 9%) by inhibition of the Krebs cycle (glutamate, 77 ± 5%) and oxidative phosphorylation (NAD+, 65 ± 14%) associated with an increased generation of reactive oxygen species (285 ± 78% of control). However, the same cyclosporin A concentration (500 μg/L) was found to be the most efficient concentration to inhibit the hypoxia-induced mitochondrial release of Ca2+ in primary rat hippocampal cells with cytosolic Ca2+ concentrations not significantly different from normoxic controls. Addition of 500 μg/L cyclosporin A to the perfusion medium protected high-energy phosphate metabolism (nucleotide triphosphate, 11 ± 15% of control vs. 35 ± 9% with 500 μg/L cyclosporin A) and the intracellular pH (6.2 ± 0.1 control vs. 6.6 ± 0.1 with cyclosporin A) in rat brain slices during 30 minutes of hypoxia. Results indicate that cyclosporin A simultaneously decreases and protects cell glucose and energy metabolism. Whether the overall effect was a reduction or protection of cell energy metabolism depended on the concentrations of both oxygen and cyclosporin A in the buffer solution.

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Early Postischemic Dantrolene-Induced Amelioration of Poly(ADP-Ribose) Polymerase-Related Bioenergetic Failure in Neonatal Rat Brain Slices

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-199812000-00009 ◽

1998 ◽

Vol 18 (12) ◽

pp. 1346-1356 ◽

Cited By ~ 18

Author(s):

Robert C. Tasker ◽

Sati K. Sahota ◽

Finbar E. Cotter ◽

Stephen R. Williams

Keyword(s):

Ex Vivo ◽

Brain Slices ◽

High Energy ◽

Neonatal Rat ◽

Resonance Spectroscopy ◽

High Energy Phosphates ◽

Energy Depletion ◽

Neonatal Rat Brain ◽

Energy Failure ◽

Induced Amelioration

In the infant brain, ischemia-induced ionic and enzyme mechanisms may independently lead to cell death by energy depletion: resequestration of calcium mobilized from intracellular stores consumes ATP, and activated poly(ADP-ribose) polymerase (PARP) uses oxidized nicotinamide adenine dinucleotide to form polyADP-ribosyl nuclear proteins associated with DNA damage, Using 31P nuclear magnetic resonance spectroscopy, we have monitored intracellular pH and cellular energy metabolites in ex vivo neonatal rat cerebral cortex before, during, and after substrate and oxygen deprivation, In an insult that exhibited secondary energy failure and apoptosis we identified a relative 25% augmentation of high-energy phosphates at the end of recovery when the ryanodine-receptor antagonist, dantrolene, was introduced in the early (0- to 40-minute) but not late (40- to 120-minute) stage of recovery ( P < 0,05). In contrast to the absence of a late dantrolene-sensitive effect, inhibition of PARP with 3-methoxybenzamide was as effective ( P < 0.05) as early dantrolene, even when introduced after a 40-minute delay. The dantrolene and 3-methoxybenzamide effects on high-energy phosphates were not additive, rather the early dantrolene-sensitive effect nullified the potential 3-methoxybenzamide effect. Therefore, in this vascular-independent neonatal preparation, postischemic mobilization of calcium from intracellular stores is associated with PARP-related energy depletion. Inhibition of either of these processes confers improved postischemic bioenergetic recovery in the developing brain.

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In vivo Evidence for Cerebral Depletion in High-Energy Phosphates in Progressive Supranuclear Palsy

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2009.2 ◽

2009 ◽

Vol 29 (4) ◽

pp. 861-870 ◽

Cited By ~ 29

Author(s):

Maria Stamelou ◽

Ulrich Pilatus ◽

Alexander Reuss ◽

Jörg Magerkurth ◽

Karla M Eggert ◽

...

Keyword(s):

Energy Metabolism ◽

Basal Ganglia ◽

Progressive Supranuclear Palsy ◽

Inorganic Phosphate ◽

High Energy ◽

Resonance Spectroscopy ◽

High Energy Phosphates ◽

Mitochondrial Energy Metabolism ◽

Neuronal Marker

Indirect evidence from laboratory studies suggests that mitochondrial energy metabolism is impaired in progressive supranuclear palsy (PSP), but brain energy metabolism has not yet been studied directly in vivo in a comprehensive manner in patients. We have used combined phosphorus and proton magnetic resonance spectroscopy to measure adenosine-triphosphate (ATP), adenosine-diphosphate (ADP), phosphorylated creatine, unphosphorylated creatine, inorganic phosphate and lactate in the basal ganglia and the frontal and occipital lobes of clinically probable patients ( N= 21; PSP stages II to III) and healthy controls ( N= 9). In the basal ganglia, which are severely affected creatine in PSP patients, the concentrations of high-energy phosphates (= ATP + phosphorylated creatine) and inorganic phosphate, but not low-energy phosphates (=ADP+ unphosphorylated creatine), were decreased. The decrease probably does not reflect neuronal death, as the neuronal marker N-acetylaspartate was not yet significantly reduced in the early-stage patients examined. The frontal lobe, also prone to neurodegeneration in PSP, showed similar alterations, whereas the occipital lobe, typically unaffected, showed less pronounced alterations. The levels of lactate, a product of anaerobic glycolysis, were elevated in 35% of the patients. The observed changes in the levels of cerebral energy metabolites in PSP are consistent with a functionally relevant impairment of oxidative phosphorylation.

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Investigation of lithium distribution in the rat brain ex vivo using lithium-7 magnetic resonance spectroscopy and imaging at 17.2 T

NMR in Biomedicine ◽

10.1002/nbm.3770 ◽

2017 ◽

Vol 30 (11) ◽

pp. e3770 ◽

Cited By ~ 4

Author(s):

Jacques Stout ◽

Anne-Sophie Hanak ◽

Lucie Chevillard ◽

Boucif Djemaï ◽

Patricia Risède ◽

...

Keyword(s):

Magnetic Resonance ◽

Magnetic Resonance Spectroscopy ◽

Rat Brain ◽

Ex Vivo ◽

Resonance Spectroscopy

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Interferon-beta affects mitochondrial activity in CD4+lymphocytes: Implications for mechanism of action in multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458514561909 ◽

2014 ◽

Vol 21 (10) ◽

pp. 1262-1270 ◽

Cited By ~ 4

Author(s):

Aiden Haghikia ◽

Simon Faissner ◽

Derek Pappas ◽

Bartosz Pula ◽

Denis A Akkad ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

Energy Metabolism ◽

Mitochondrial Function ◽

Interferon Beta ◽

Mononuclear Cells ◽

Ex Vivo ◽

Mitochondrial Activity ◽

Mitochondrial Energy Metabolism ◽

The Impact

Background:Whereas cellular immune function depends on energy supply and mitochondrial function, little is known on the impact of immunotherapies on cellular energy metabolism.Objective:The objective of this paper is to assess the effects of interferon-beta (IFN-β) on mitochondrial function of CD4+T cells.Methods:Intracellular adenosine triphosphate (iATP) in phytohemagglutinin (PHA)-stimulated CD4+cells of multiple sclerosis (MS) patients treated with IFN-β and controls were analyzed in a luciferase-based assay. Mitochondrial-transmembrane potential (ΔΨm) in IFN-β-treated peripheral blood mononuclear cells (PBMCs) was investigated by flow cytometry. Expression of genes involved in mitochondrial oxidative phosphorylation (OXPHOS) in CD4+cells of IFN-β-treated individuals and correlations between genetic variants in the key metabolism regulator PGC-1α and IFN-β response in MS were analyzed.Results:IFN-β-treated MS patients exhibited a dose-dependent reduction of iATP levels in CD4+T cells compared to controls ( p < 0.001). Mitochondrial effects were reflected by depolarization of ΔΨm. Expression data revealed changes in the transcription of OXPHOS-genes. iATP levels in IFN-β-responders were reduced compared to non-responders ( p < 0.05), and the major T allele of the SNP rs7665116 of PGC-1α correlated with iATP-levels.Conclusion:Reduced iATP-synthesis ex vivo and differential expression of OXPHOS-genes in CD4+T cells point to unknown IFN-β effects on mitochondrial energy metabolism, adding to potential pleiotropic mechanisms of action.

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Metabolic Effects of Doxorubicin on the Rat Liver Assessed With Hyperpolarized MRI and Metabolomics

Frontiers in Physiology ◽

10.3389/fphys.2021.782745 ◽

2022 ◽

Vol 12 ◽

Author(s):

Kerstin N. Timm ◽

Vicky Ball ◽

Jack J. Miller ◽

Dragana Savic ◽

James A. West ◽

...

Keyword(s):

Oxidative Stress ◽

Carbohydrate Metabolism ◽

Liver Damage ◽

Functional Decline ◽

High Energy ◽

Metabolic Effects ◽

Resonance Spectroscopy ◽

Acid Uptake ◽

High Energy Phosphates ◽

Time Point

Doxorubicin (DOX) is a successful chemotherapeutic widely used for the treatment of a range of cancers. However, DOX can have serious side-effects, with cardiotoxicity and hepatotoxicity being the most common events. Oxidative stress and changes in metabolism and bioenergetics are thought to be at the core of these toxicities. We have previously shown in a clinically-relevant rat model that a low DOX dose of 2 mg kg–1 week–1 for 6 weeks does not lead to cardiac functional decline or changes in cardiac carbohydrate metabolism, assessed with hyperpolarized [1-13C]pyruvate magnetic resonance spectroscopy (MRS). We now set out to assess whether there are any signs of liver damage or altered liver metabolism using this subclinical model. We found no increase in plasma alanine aminotransferase (ALT) activity, a measure of liver damage, following DOX treatment in rats at any time point. We also saw no changes in liver carbohydrate metabolism, using hyperpolarized [1-13C]pyruvate MRS. However, using metabolomic analysis of liver metabolite extracts at the final time point, we found an increase in most acyl-carnitine species as well as increases in high energy phosphates, citrate and markers of oxidative stress. This may indicate early signs of steatohepatitis, with increased and decompensated fatty acid uptake and oxidation, leading to oxidative stress.

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Mechanisms of Energy Metabolism in Skeletal Muscle Mitochondria Following Radiation Exposure

Cells ◽

10.3390/cells8090950 ◽

2019 ◽

Vol 8 (9) ◽

pp. 950 ◽

Cited By ~ 2

Author(s):

Kim ◽

Lee ◽

Kim ◽

Keyword(s):

Skeletal Muscle ◽

Energy Metabolism ◽

Ionizing Radiation ◽

Radiation Exposure ◽

Biological Effects ◽

Mitochondrial Protein ◽

Metabolic Effects ◽

Acid Oxidation ◽

Mitochondrial Energy Metabolism ◽

Effects Of Radiation

An understanding of cellular processes that determine the response to ionizing radiation exposure is essential for improving radiotherapy and assessing risks to human health after accidental radiation exposure. Radiation exposure leads to many biological effects, but the mechanisms underlying the metabolic effects of radiation are not well known. Here, we investigated the effects of radiation exposure on the metabolic rate and mitochondrial bioenergetics in skeletal muscle. We show that ionizing radiation increased mitochondrial protein and mass and enhanced proton leak and mitochondrial maximal respiratory capacity, causing an increase in the fraction of mitochondrial respiration devoted to uncoupling reactions. Thus, mice and cells treated with radiation became energetically efficient and displayed increased fatty acid and amino acid oxidation metabolism through the citric acid cycle. Finally, we demonstrate that radiation-induced alterations in mitochondrial energy metabolism involved adenosine monophosphate-activated kinase signaling in skeletal muscle. Together, these results demonstrate that alterations in mitochondrial mass and function are important adaptive responses of skeletal muscle to radiation.

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Impaired mitochondrial energy metabolism and neuronal apoptotic cell death after chronic dichlorvos (OP) exposure in rat brain

NeuroToxicology ◽

10.1016/j.neuro.2007.08.001 ◽

2007 ◽

Vol 28 (6) ◽

pp. 1208-1219 ◽

Cited By ~ 119

Author(s):

P KAUR ◽

B RADOTRA ◽

R MINZ ◽

K GILL

Keyword(s):

Cell Death ◽

Energy Metabolism ◽

Rat Brain ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Mitochondrial Energy Metabolism

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In vivo brain phosphocreatine and ATP regulation in mice fed a creatine analog

AJP Cell Physiology ◽

10.1152/ajpcell.1997.272.5.c1567 ◽

1997 ◽

Vol 272 (5) ◽

pp. C1567-C1577 ◽

Cited By ~ 23

Author(s):

D. Holtzman ◽

R. Meyers ◽

E. O'Gorman ◽

I. Khait ◽

T. Wallimann ◽

...

Keyword(s):

Reaction Rate ◽

Ex Vivo ◽

Competitive Inhibitor ◽

High Energy ◽

Energy Deficit ◽

Resonance Spectroscopy ◽

Atp Metabolism ◽

Creatine Transport ◽

Atp Regulation

Mitochondrial and cytosolic creatine kinase (CK) isozymes are active in cells with high and variable ATP metabolic rates. beta-Guanidinopropionic acid (GPA), a competitive inhibitor of creatine transport, was used to study the hypothesis that the creatine-CK-phosphocreatine (PCr) system is important in regulating brain ATP metabolism. The CK-catalyzed reaction rate and reactant concentrations were measured in vivo with 31P nuclear magnetic resonance spectroscopy during energy deficit (hypoxia) or high-energy turnover (seizures) states in urethane-anesthetized mice fed GPA, creatine, or standard chow (controls). Brain phosphagen (i.e., cellular energy reserves) or PCr plus phosphorylated GPA (GPAP) concentrations were equal. The phosphagen-to-NTP ratio was lower than in controls. In vivo CK reaction rate decreased fourfold, whereas ex vivo CK activity that was biochemically measured was doubled. During seizures, CK-catalyzed fluxes increased only in GPA-fed mice. Phosphagen increased in GPA-fed mice, whereas PCr decreased in controls. Survival was higher and brain phosphagen and ATP losses were less for hypoxic GPA-fed mice than for controls. In contrast to mice fed GPA, hypoxic survival and CK reactant concentrations during hypoxia and seizures were the same in creatine-fed mice and controls. Thus GPA, GPAP, or adaptive changes in ATP metabolism stabilize brain ATP and enhance survival during hypoxia in mice.

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