In vivo detection of intermediate metabolic products of [1‐13C]ethanol in the brain using 13C MRS

Xiang, Yun; Shen, Jun

doi:10.1002/nbm.1653

Cited by 13 publications

(17 citation statements)

References 52 publications

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“…However, contribution of direct oxidation of ethanol in brain is reported to be significantly lower than oxidation of acetate that is derived from ethanol metabolism in liver . In accordance with these ideas, 13 C labeling of cerebral amino acids from [2- 13 C]ethanol was demonstrated recently in the rat brain (Xiang and Shen 2011). Very recently, cerebral amino acids labeling has been measured in awake rats during an intravenous infusion of [2-13 C]ethanol.…”

Section: Contribution Of Ethanol To Energy Metabolismmentioning

confidence: 58%

Differential effects of ethanol on regional glutamatergic and GABAergic neurotransmitter pathways in mouse brain

Tiwari

Veeraiah

Subramaniam

et al. 2013

Journal of Neurochemistry

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This study investigates the effects of ethanol on neuronal and astroglial metabolism using 1 H- Although several behavioral, electrophysiological studies have been performed in rats and humans to understand the effects of acute ethanol exposure on cerebral function, there is scarcity of quantitative data pertaining to ethanol effects on metabolic demand at the level of glutamatergic (excitatory) and GABAergic (inhibitory) neurotransmission. Received November 16, 2012; revised manuscript received October 21, 2013; accepted October 22, 2013. Address correspondence and reprint requests to Dr Anant B. Patel, NMR Microimaging and Spectroscopy, CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Habsiguda, Hyderabad, India. E-mail: abpatel@ccmb.res.in Abbreviations used: GS, glutamine synthetase; OAA, oxaloacetate; PC, pyruvate carboxylase; Suc, succinate; V cyc(GABA-Gln) , GABAglutamine cycling flux; V cyc(Glu-Gln) , glutamate-glutamine cycling flux; V GAD , glutamate decarboxylase flux; V GS , glutamine synthetase flux; V pc , pyruvate carboxylase flux; V shunt , flux of GABA shunt; V tca(A) , Astroglial TCA cycle flux; V tca(GABA) , GABAergic TCA cycle flux; V tca(Glu) , glutamatergic TCA cycle flux; V x , exchange rate between a-ketoglutarate and glutamate; a-KG, a-ketoglutarate.

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Section: Contribution Of Ethanol To Energy Metabolismmentioning

confidence: 58%

Differential effects of ethanol on regional glutamatergic and GABAergic neurotransmitter pathways in mouse brain

Tiwari

Veeraiah

Subramaniam

et al. 2013

Journal of Neurochemistry

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“…14 C-and 11 C-13 C-labeled Etoh have been used to study the fate of Etoh in the brain (10,(52)(53)(54). One difficulty has been that isotopically labeled Etoh quickly becomes labeled Ac, whose intracerebral oxidation could not be distinguished from that of Etoh.…”

Section: Discussionmentioning

confidence: 99%

Oxidation of ethanol in the rat brain and effects associated with chronic ethanol exposure

Wang

Jiang³

et al. 2013

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

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It has been reported that chronic and acute alcohol exposure decreases cerebral glucose metabolism and increases acetate oxidation. However, it remains unknown how much ethanol the living brain can oxidize directly and whether such a process would be affected by alcohol exposure. The questions have implications for reward, oxidative damage, and long-term adaptation to drinking. One group of adult male Sprague-Dawley rats was treated with ethanol vapor and the other given room air. After 3 wk the rats received i.v. [2-13 C]ethanol and [1, 2-13 C 2 ]acetate for 2 h, and then the brain was fixed, removed, and divided into neocortex and subcortical tissues for measurement of 13 C isotopic labeling of glutamate and glutamine by magnetic resonance spectroscopy. Ethanol oxidation was seen to occur both in the cortex and the subcortex. In ethanol-naïve rats, cortical oxidation of ethanol occurred at rates of 0.017 ± 0.002 μmol/min/g in astroglia and 0.014 ± 0.003 μmol/min/g in neurons, and chronic alcohol exposure increased the astroglial ethanol oxidation to 0.028 ± 0.002 μmol/min/g (P = 0.001) with an insignificant effect on neuronal ethanol oxidation. Compared with published rates of overall oxidative metabolism in astroglia and neurons, ethanol provided 12.3 ± 1.4% of cortical astroglial oxidation in ethanol-naïve rats and 20.2 ± 1.5% in ethanol-treated rats. For cortical astroglia and neurons combined, the ethanol oxidation for naïve and treated rats was 3.2 ± 0.3% and 3.8 ± 0.2% of total oxidation, respectively. 13C labeling from subcortical oxidation of ethanol was similar to that seen in cortex but was not affected by chronic ethanol exposure.T he liver is the major organ for the oxidation of ethanol (Etoh) (1, 2), followed by the stomach and other organs. Acetate (Ac) generated from Etoh by the liver is consumed by the brain (3, 4), where it replaces a significant portion of cerebral glucose metabolism in humans and animals (5-8), either decreasing glucose consumption directly or compensating for glucose consumption decreased by some other effect. However, the brain may also oxidize Etoh (9-14), and that capacity is important with respect to several perspectives. The first step of Etoh oxidation generates acetaldehyde (AA), which is toxic, reactive, and potentially carcinogenic. AA is aversive systemically, as has been observed from the unpleasant effects of disulfuram, an inhibitor of AA dehydrogenase, but it has been shown to be rewarding in parts of the brain (12,15,16) especially in the posterior ventral tegmental area (17-19) by activating dopamine neurons (20)(21)(22). The liver maintains circulating levels of AA at levels of 20-155 μM (23, 24), and AA has been reported not to penetrate the blood-brain barrier or to penetrate very slowly (23,25). Thus, if the brain can oxidize Etoh, then intracerebral AA may mediate behavioral, neurochemical, and toxic effects of Etoh in the brain, possibly playing a role in the development of alcohol dependence (6,16,26).AA is difficult to measure in living systems. The ...

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“…The question as to whether this is caused by substitution of glucose as a fuel source by ethanol has been dealt with by the finding that ethanol is not significantly metabolized in the brain (Mukherji et al . ; Xiang and Shen ) although uptake varies regionally (Li et al . ).…”

Section: Discussionmentioning

confidence: 99%

Ethanol, not detectably metabolized in brain, significantly reduces brain metabolism, probably via action at specific GABA(A) receptors and has measureable metabolic effects at very low concentrations

Rae

Davidson

Maher

et al. 2013

Journal of Neurochemistry

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Ethanol is a known neuromodulatory agent with reported actions at a range of neurotransmitter receptors. Here, we used an indirect approach, measuring the effect of alcohol on metabolism of [3-13C]pyruvate in the adult Guinea pig brain cortical tissue slice and comparing the outcomes to those from a library of ligands active in the GABAergic system as well as studying the metabolic fate of [1,2-13C]ethanol. Ethanol (10, 30 and 60 mM) significantly reduced metabolic flux into all measured isotopomers and reduced all metabolic pool sizes. The metabolic profiles of these three concentrations of ethanol were similar and clustered with that of the α4β3δ positive allosteric modulator DS2 (4-Chloro-N-[2-(2-thienyl)imidazo[1,2a]-pyridin-3-yl]benzamide). Ethanol at a very low concentration (0.1 mM) produced a metabolic profile which clustered with those from inhibitors of GABA uptake, and ligands showing affinity for α5, and to a lesser extent, α1-containing GABA(A)R. There was no measureable metabolism of [1,2-13C]ethanol with no significant incorporation of 13C from [1,2-13C]ethanol into any measured metabolite above natural abundance, although there were measurable effects on total metabolite sizes similar to those seen with unlabeled ethanol. The reduction in metabolism seen in the presence of ethanol is therefore likely to be due to its actions at neurotransmitter receptors, particularly α4β3δ receptors, and not because ethanol is substituting as a substrate or because of the effects of ethanol catabolites acetaldehyde or acetate. We suggest that the stimulatory effects of very low concentrations of ethanol are due to release of GABA via GAT1 and the subsequent interaction of this GABA with local α5-containing, and to a lesser extent, α1-containing GABA(A)R.

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In vivo detection of intermediate metabolic products of [1‐¹³C]ethanol in the brain using ¹³C MRS

Cited by 13 publications

References 52 publications

Differential effects of ethanol on regional glutamatergic and GABAergic neurotransmitter pathways in mouse brain

Differential effects of ethanol on regional glutamatergic and GABAergic neurotransmitter pathways in mouse brain

Oxidation of ethanol in the rat brain and effects associated with chronic ethanol exposure

Ethanol, not detectably metabolized in brain, significantly reduces brain metabolism, probably via action at specific GABA(A) receptors and has measureable metabolic effects at very low concentrations

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