In vivo effects of adenosine A2 receptor agonist and antagonist on neuronal and astrocytic intermediary metabolism studied with ex vivo13C MR spectroscopy

Hammer, Janniche; Qu, Hong; Håberg, Asta; Sonnewald, Ursula

doi:10.1046/j.1471-4159.2001.00622.x

Cited by 21 publications

(7 citation statements)

References 45 publications

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“…In the extracellular space ATP can be converted to adenosine by the dephosphorylating action of the ectonucleotidase anchored at the plasma membrane (Joseph et al, 2003). Adenosine can activate adenosine receptors and therefore modulate neuronal activity by triggering K + efflux (e.g., Newman, 2003), as well as intermediary metabolism (Haberg et al, 2000; Hammer et al, 2001; Duarte et al, 2016) and blood flow (Blood et al, 2003; Iliff et al, 2003; Gordon et al, 2008). D-serine that can be released from astrocytes was also shown to modulate electrical neurotransmission by acting at the glycine binding site of NMDA receptor (Stevens et al, 2003).…”

Section: Functions Of Astrocytes In the Brainmentioning

confidence: 99%

How Energy Metabolism Supports Cerebral Function: Insights from 13C Magnetic Resonance Studies In vivo

2017

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Cerebral function is associated with exceptionally high metabolic activity, and requires continuous supply of oxygen and nutrients from the blood stream. Since the mid-twentieth century the idea that brain energy metabolism is coupled to neuronal activity has emerged, and a number of studies supported this hypothesis. Moreover, brain energy metabolism was demonstrated to be compartmentalized in neurons and astrocytes, and astrocytic glycolysis was proposed to serve the energetic demands of glutamatergic activity. Shedding light on the role of astrocytes in brain metabolism, the earlier picture of astrocytes being restricted to a scaffold-associated function in the brain is now out of date. With the development and optimization of non-invasive techniques, such as nuclear magnetic resonance spectroscopy (MRS), several groups have worked on assessing cerebral metabolism in vivo. In this context, 1H MRS has allowed the measurements of energy metabolism-related compounds, whose concentrations can vary under different brain activation states. 1H-[13C] MRS, i.e., indirect detection of signals from 13C-coupled 1H, together with infusion of 13C-enriched glucose has provided insights into the coupling between neurotransmission and glucose oxidation. Although these techniques tackle the coupling between neuronal activity and metabolism, they lack chemical specificity and fail in providing information on neuronal and glial metabolic pathways underlying those processes. Currently, the improvement of detection modalities (i.e., direct detection of 13C isotopomers), the progress in building adequate mathematical models along with the increase in magnetic field strength now available render possible detailed compartmentalized metabolic flux characterization. In particular, direct 13C MRS offers more detailed dataset acquisitions and provides information on metabolic interactions between neurons and astrocytes, and their role in supporting neurotransmission. Here, we review state-of-the-art MR methods to study brain function and metabolism in vivo, and their contribution to the current understanding of how astrocytic energy metabolism supports glutamatergic activity and cerebral function. In this context, recent data suggests that astrocytic metabolism has been underestimated. Namely, the rate of oxidative metabolism in astrocytes is about half of that in neurons, and it can increase as much as the rate of neuronal metabolism in response to sensory stimulation.

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Section: Functions Of Astrocytes In the Brainmentioning

confidence: 99%

How Energy Metabolism Supports Cerebral Function: Insights from 13C Magnetic Resonance Studies In vivo

2017

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“…Since adenosine is a by-product of adenosine monophosphate resulting from acetate metabolism, it was suggested that its production should increase in the brain following acetate administration as previously found in both liver and heart (Kiviluoma et al 1989;Campisi et al 1997). However it was recently shown that no adenosine could be detected after cerebral acetate metabolism (Haberg et al 2000;Hammer et al 2001). Potential short-term effects of acetate infusion on brain metabolism remain to be investigated in more detail.…”

Section: Physiological Effects Of Acetatementioning

confidence: 99%

Acetate transport and utilization in the rat brain

Deelchand

Shestov

Koski

et al. 2009

Journal of Neurochemistry

108

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Abbreviations used: BBB, blood-brain barrier; CMR ace , cerebral metabolic rate of acetate; NAA, N-acetyl-aspartate; PC, pyruvate carboxylase; TCA, tricarboxylic acid. AbstractAcetate, a glial-specific substrate, is an attractive alternative to glucose for the study of neuronal-glial interactions. The present study investigates the kinetics of acetate uptake and utilization in the rat brain in vivo during infusion of [2-13 C]acetate using NMR spectroscopy. When plasma acetate concentration was increased, the rate of brain acetate utilization (CMR ace ) increased progressively and reached close to saturation for plasma acetate concentration > 2-3 mM, whereas brain acetate concentration continued to increase. The Michaelis-Menten constant for brain acetate utilization (K util M = 0.01 ± 0.14 mM) was much smaller than for acetate transport through the blood-brain barrier (BBB) (K t M = 4.18 ± 0.83 mM). The maximum transport capacity of acetate through the BBB (V t max = 0.96 ± 0.18 lmol/g/min) was nearly twofold higher than the maximum rate of brain acetate utilization (V util max = 0.50 ± 0.08 lmol/g/min). We conclude that, under our experimental conditions, brain acetate utilization is saturated when plasma acetate concentrations increase above 2-3 mM. At such high plasma acetate concentration, the rate-limiting step for glial acetate metabolism is not the BBB, but occurs after entry of acetate into the brain.

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“…1). Apart from these predominant synaptic effects, it has also been reported that A 2A R can impact on neuronal metabolism [92] but the functional relevance of this finding remains to be explored. Finally, A 2A R are also located in astrocytes and microglia cells [68,93], where they control the uptake of glutamate [94] and the expression of cytokines [68,93].…”

Section: B Adenosine a 2a Receptor Neuromodulation Systemmentioning

confidence: 99%

Role of The Purinergic Neuromodulation System in Epilepsy

Tomé¹,

Silva²,

Cunha³

2010

TONEURJ

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Adenosine has long been considered an endogenous anti-epileptic compound. This concept was based on the widespread distribution of adenosine A 1 receptors (A 1 R), which are mostly located in excitatory synapses; here, A 1 R inhibit glutamate release, decrease glutamatergic responsiveness and hyperpolarise neurons. However, the combined observation that synaptic A 1 R undergo desensitisation in chronic noxious situations whereas the activation of A 1 R still prevents seizure activity suggests that the A 1 R anti-epileptic action may involve non-synaptic mechanisms. Two alternative mechanisms can be considered to explain the ability of A 1 R to control seizure activity and resulting neurodegeneration: 1) the possible role of A 1 R-mediated control of metabolism; 2) the A 1 R-mediated preconditioning involving a coordinated control of neuron-glia communication. However, purinergic modulation of seizure activity is likely to involve other systems apart from A 1 R. Thus, the blockade of adenosine A 2A receptors (A 2A R), which density increases in animal models of epilepsy, can attenuate seizure activity and prevent seizure-induced neurodegeneration. Furthermore, ATP, which is the main source of the endogenous adenosine activating A 2A R, also act as a general danger signal and may also directly control seizure activity through P 2 receptors (P 2 R). Therefore, the purinergic control of epilepsy may actually involve different parallel signalling arms, some beneficial and others deleterious, probably acting at different sites (in epileptic foci and in their neighbourhood) and at different times. It is likely that combined targeting of different purinergic receptors may be the most efficacious way to control seizure activity, its spreading and the resulting neurodegeneration.

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In vivo effects of adenosine A₂ receptor agonist and antagonist on neuronal and astrocytic intermediary metabolism studied with ex vivo¹³C MR spectroscopy

Cited by 21 publications

References 45 publications

How Energy Metabolism Supports Cerebral Function: Insights from 13C Magnetic Resonance Studies In vivo

How Energy Metabolism Supports Cerebral Function: Insights from 13C Magnetic Resonance Studies In vivo

Acetate transport and utilization in the rat brain

Role of The Purinergic Neuromodulation System in Epilepsy

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