Brain uptake and metabolism of [1-11C]octanoate in rats: Pharmacokinetic basis for its application as a radiopharmaceutical for studying brain fatty acid metabolism

Kuge, Yuji; Yajima, Kazuyoshi; Kawashima, Hidefumi; Yamazaki, Hiroyoshi; Hashimoto, Naoto; Miyake, Yoshihiro

doi:10.1007/bf03165040

Cited by 39 publications

(30 citation statements)

References 15 publications

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“…Measurements of radioactivity levels after infusion with both [1-11 C]-and [1-14 C] octanoate have shown that octanoate can readily cross the blood-brain barrier. 8 Further studies have shown that with infusion of [1-14 C]-or [1- 13 C] octanoate at 15% to 25% of caloric requirements, the labeled carbon appears predominantly in glutamine as compared with glutamate. As glutamine is predominantly found in astrocytes, this suggests that medium-chain fatty acids are primarily metabolized by astrocytes.…”

Section: Introductionmentioning

confidence: 99%

Alterations of Hippocampal Glucose Metabolism by Even versus Uneven Medium Chain Triglycerides

McDonald

Tan

Hodson

et al. 2013

J Cereb Blood Flow Metab

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Medium chain triglycerides (MCTs) are used to treat neurologic disorders with metabolic impairments, including childhood epilepsy and early Alzheimer's disease. However, the metabolic effects of MCTs in the brain are still unclear. Here, we studied the effects of feeding even and uneven MCTs on brain glucose metabolism in the mouse. Adult mice were fed 35% (calories) of trioctanoin or triheptanoin (the triglycerides of octanoate or heptanoate, respectively) or a matching control diet for 3 weeks. Enzymatic assays and targeted metabolomics by liquid chromatography tandem mass spectrometry were used to quantify metabolites in extracts from the hippocampal formations (HFs). Both oils increased the levels of b-hydroxybutyrate, but no other significant metabolic alterations were observed after triheptanoin feeding. The levels of glucose 6-phosphate and fructose 6-phosphate were increased in the HF of mice fed trioctanoin, whereas levels of metabolites further downstream in the glycolytic pathway and the pentose phosphate pathway were reduced. This indicates that trioctanoin reduces glucose utilization because of a decrease in phosphofructokinase activity. Trioctanoin and triheptanoin showed similar anticonvulsant effects in the 6 Hz seizure model, but it remains unknown to what extent the anticonvulsant mechanism(s) are shared. In conclusion, triheptanoin unlike trioctanoin appears to not alter glucose metabolism in the healthy brain.

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Section: Introductionmentioning

confidence: 99%

Alterations of Hippocampal Glucose Metabolism by Even versus Uneven Medium Chain Triglycerides

McDonald

Tan

Hodson

et al. 2013

J Cereb Blood Flow Metab

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“…24,25 We have developed a fullyautomated apparatus for the preparation of the [1-11 C]carboxylic acids and used it for routinely supplying [1-11 C]octanoic acid to PET studies. 26 In the manipulation of radioactivity, it is most important to minimize the operator's exposure to radiation.…”

Section: Introductionmentioning

confidence: 99%

Kinetic Study on the Reaction of Heptylmagnesium Bromide with Carbon Dioxide Using Non-Carrier-Added C-11 Labeled Carbon Dioxide

et al. 1996

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We studied the chemical kinetics of the Grignard reaction between heptylmagnesium bromide and carbon dioxide with a new experimental method utilizing positron emitter C-11 labeled CO 2 . A series of experiments was carried out in the presence of a large excess of heptylmagnesium bromide (C 7 H 15 MgBr ) ca. 1.0 × 10 -4 mol) relative to carbon dioxide (CO 2 ) ca. 1.2 × 10 -8 mol). An empirical scheme was assumed based on the results obtained in experiments at the reaction temperature of 20°C. Differential equations were determined by the scheme. It was possible to calculate rate constant values at each temperature of the reaction (at 10, 20, and 30°C) by fitting the equations to experimental measurements. We obtained the value 1.76 × 10 4 J/mol as the activation energy of the main reaction between C 7 H 15 MgBr and CO 2 from the Arrhenius plot (r 2 ) 0.9986) of the rate constants. The reaction simulated with the equations and the activation energy value were in good agreement with the ones obtained experimentally. The obtained value for the activation energy of the main reaction would be applicable to the more common type of Grignard carboxylation with a large excess of CO 2 .

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“…It was conjectured that the selection of glucose, the predominant substrate for brain energy metabolism, over fatty acids for energy metabolism in the brain may be evolutionarily beneficial to avoid the disadvantages of β-oxidation (Schonfeld and Reiser, 2013). While fatty acids are used by the brain as well (Ebert et al , 2003; Kuge et al , 1995; Panov et al , 2014), neurons have low level rate-setting fatty acid catabolism enzymes and are generally not thought to rely on fatty acid β-oxidation for bioenergetics (Cahoy et al , 2008; Lee and Wolfgang, 2012) (Schonfeld and Reiser, 2013). …”

Section: Brain Energy Metabolismmentioning

confidence: 99%

Alternative mitochondrial electron transfer for the treatment of neurodegenerative diseases and cancers: Methylene blue connects the dots

Yang

Sumien

et al. 2017

Progress in Neurobiology

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Brain has exceptional high requirement for energy metabolism with glucose as the exclusive energy source. Decrease of brain energy metabolism and glucose uptake has been found in patients of Alzheimer’s, Parkinson’s and other neurodegenerative diseases, providing a clear link between neurodegenerative disorders and energy metabolism. On the other hand, cancers, including glioblastoma, have increased glucose uptake and rely on aerobic glycolysis for energy metabolism. The switch of high efficient oxidative phosphorylation to low efficient aerobic glycolysis pathway (Warburg effect) provides macromolecule for biosynthesis and proliferation. Current research indicate that methylene blue, a century old drug, can receive electron from NADH in the presence of complex I and donates it to cytochrome C, providing an alternative electron transfer pathway. Methylene blue increases oxygen consumption, decrease glycolysis, and increases glucose uptake in vitro. Methylene blue enhances glucose uptake and regional cerebral blood flow in rats upon acute treatment. In addition, methylene blue provides protective effect in neuron and astrocyte against various insults in vitro and in rodent models of Alzheimer’s, Parkinson’s, and Huntington’s disease. In glioblastoma cells, methylene blue reverses Warburg effect by enhancing mitochondrial oxidative phosphorylation, arrests glioma cell cycle at s-phase, and inhibits glioma cell proliferation. Accordingly, methylene blue activates AMP-activated protein kinase, inhibits downstream acetyl-coA carboxylase and cyclin-dependent kinases. In summary, there is accumulating evidence providing a proof of concept that enhancement of mitochondrial oxidative phosphorylation via alternative mitochondrial electron transfer may offer protective action against neurodegenerative diseases and inhibit cancers proliferation.

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Brain uptake and metabolism of [1-11C]octanoate in rats: Pharmacokinetic basis for its application as a radiopharmaceutical for studying brain fatty acid metabolism

Cited by 39 publications

References 15 publications

Alterations of Hippocampal Glucose Metabolism by Even versus Uneven Medium Chain Triglycerides

Alterations of Hippocampal Glucose Metabolism by Even versus Uneven Medium Chain Triglycerides

Kinetic Study on the Reaction of Heptylmagnesium Bromide with Carbon Dioxide Using Non-Carrier-Added C-11 Labeled Carbon Dioxide

Alternative mitochondrial electron transfer for the treatment of neurodegenerative diseases and cancers: Methylene blue connects the dots

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