Use of fluorocitrate and fluoroacetate in the study of brain metabolism

Fonnum, Frode; Johnsen, Arnt; Hassel, Bjørnar

doi:10.1002/(sici)1098-1136(199709)21:1<106::aid-glia12>3.3.co;2-v

Cited by 56 publications

(98 citation statements)

References 17 publications

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“…The needle track was the only confirmation of the injection site. Third, the dose of FC used will result in a decrease in glutamine, which is an important precursor for γ-aminobutyric acid (GABA) and glutamate (Fonnum et al, 1997). This will alter the release of these neuro-transmitters and may alter neuronal function (Paulsen et al, 1987;Keyser & Pellmar, 1994).…”

Section: Discussionmentioning

confidence: 99%

“…FC is selectively taken up by glial cells and is a 'suicide' substrate for the enzyme aconitase. Therefore, it temporarily depresses glial function (Hassel et al, 1992;Berg-Johnsen et al, 1993;Swanson & Graham, 1994;Fonnum et al, 1997). The FC solution was prepared from its barium salt after precipitation of the barium with sodium sulphate, as described by Paulsen et al (1987).…”

Section: α-Aa and Fc Treatmentmentioning

confidence: 99%

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Astrocytic regulation of the recovery of extracellular potassium after seizures in vivo

Xiong

Stringer

1999

Eur J of Neuroscience

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Glial cells are believed to play a major role in the regulation of the extracellular potassium concentration ([K+]o), particularly when the [K+]o is increased. Using ion-selective electrodes, we compared the [K+]o changes in the dentate gyrus of urethane-anaesthetized adult rats in the presence of reactive astrocytes and after reduction of glial function. The regulation of [K+]o in the dentate gyrus was determined by measuring the ceiling level of [K+]o and the half-time of recovery of [K+]o during and after seizures produced by 20 Hz trains of stimulation to the angular bundle. Reactive astrocytes were induced by repeated seizures and their presence was confirmed by a qualitative increase in glial fibrillary acidic protein (GFAP) and vimentin immunoreactivity. To inhibit glial function, fluorocitrate (FC), a reversible metabolic inhibitor, or alpha-aminoadipate (alpha-AA), an irreversible toxin, was injected into the dentate gyrus region, and the regulation of [K+]o was monitored for 8 h or 2 days later, respectively. After alpha-aminoadipate, loss of astrocytes in the dentate gyrus was demonstrated by loss of staining for GFAP. In the presence of reactive astrocytes there was no significant change in the peak [K+]o during seizures or the half-time of recovery of [K+]o after seizures compared to control animals. alpha-Aminoadipate significantly slowed the rate of recovery of [K+]o, but did not change the ceiling [K+]o. Fluorocitrate reversibly decreased the ceiling [K+]o, but also slowed the rate of recovery of [K+]o. Overall our results suggest that normal glial function is required for the recovery of elevated [K+]o after seizures in vivo.

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Section: Discussionmentioning

confidence: 99%

Section: α-Aa and Fc Treatmentmentioning

confidence: 99%

Astrocytic regulation of the recovery of extracellular potassium after seizures in vivo

Xiong

Stringer

1999

Eur J of Neuroscience

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“…Intriguingly, electrophysiological analyses have shown that the spontaneous activity of GnRH neurons in these animals is decreased and that this deficiency is mimicked by the bath application of either fluoroacetate, an inhibitor of astrocyte metabolism (Fonnum et al, 1997; Henneberger et al, 2010), or the COX blocker indomethacin, to slices of the preoptic region from wild-type animals (Clasadonte et al, 2011). The fact that GnRH neuronal activity in all these conditions can be rescued by exogenous PGE 2 (Clasadonte et al, 2011) strongly suggests that glial PGE 2 is an important component of the homeostatic mechanism controlling GnRH neuronal excitability.…”

Section: Introductionmentioning

confidence: 99%

Gliotransmission by Prostaglandin E2: A Prerequisite for GnRH Neuronal Function?

Clasadonte¹,

Sharif²,

Baroncini³

et al. 2011

Front. Endocrin.

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Over the past four decades it has become clear that prostaglandin E2 (PGE2), a phospholipid-derived signaling molecule, plays a fundamental role in modulating the gonadotropin-releasing hormone (GnRH) neuroendocrine system and in shaping the hypothalamus. In this review, after a brief historical overview, we highlight studies revealing that PGE2 released by glial cells such as astrocytes and tanycytes is intimately involved in the active control of GnRH neuronal activity and neurosecretion. Recent evidence suggests that hypothalamic astrocytes surrounding GnRH neuronal cell bodies may respond to neuronal activity with an activation of the erbB receptor tyrosine kinase signaling, triggering the release of PGE2 as a chemical transmitter from the glia themselves, and, in turn, leading to the feedback regulation of GnRH neuronal activity. At the GnRH neurohemal junction, in the median eminence of the hypothalamus, PGE2 is released by tanycytes in response to cell–cell signaling initiated by glial cells and vascular endothelial cells. Upon its release, PGE2 causes the retraction of the tanycyte end-feet enwrapping the GnRH nerve terminals, enabling them to approach the adjacent pericapillary space and thus likely facilitating neurohormone diffusion from these nerve terminals into the pituitary portal blood. In view of these new insights, we suggest that synaptically associated astrocytes and perijunctional tanycytes are integral modulatory elements of GnRH neuronal function at the cell soma/dendrite and nerve terminal levels, respectively.

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“…These results formed the basis of the assumption that glia plays the most important role in the stimulation-induced signal change. In view of the pleomorphic effects furosemide exerts at such high concentrations used in the above experiments (Gutschmidt et al, 1999), we have chosen a different approach by employing antidromic stimulation and application of FAC as a tool to selectively block glial cells (Fonnum et al, 1997). The substance significantly decreased slope and the maximum amplitude of the intrinsic optical signal, without affecting most electrophysiological parameters.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, there is evidence that the substance in concentrations used exerts non-specific and pleomorphic effects, including reduced neuronal excitability, interference with glial volume regulation mechanisms and pronounced changes in extracellular pH (Gutschmidt et al, 1999). In the current experiments we have tried to circumvent some of those methodological limitations by selectively blocking glial function with fluoroacetate (FAC) (Fonnum et al, 1997). Finally, on a subcellular level changes in size of mitochondria also appear to contribute to the generation of the intrinsic optical signal change during neuronal activation.…”

Section: Introductionmentioning

confidence: 99%

Processes and components participating in the generation of intrinsic optical signal changes in vitro

Buchheim

Wessel

Siegmund

et al. 2005

Eur J of Neuroscience

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Imaging of intrinsic optical signals has become an important tool in the neurosciences. To better understand processes underlying changes in intrinsic optical signals, we studied electrical stimulation at varying strengths in hippocampal slices of adult Wistar rats. Following serial stimulation we observed an increase in light transmittance in all tested slices. During antidromic stimulation at minimum stimulation strength the increase in light transmittance was 75 +/- 8% (P < 0.05), and during orthodromic minimum stimulation 19.6 +/- 5.6% (P < 0.001) in the stratum pyramidale of the CA1-region. During orthodromic stimulation no significant difference between submaximum, maximum and supramaximum stimulation was found, indicating saturation. In contrast, submaximum antidromic stimulation yielded 56.2 +/- 12% (P < 0.05) of maximum stimulation strength, indicating recruitment. In a further set of experiments serial stimulation was carried out under glial blockade with fluoroacetate (FAC) or blockage of mitochondrial function. Amplitude and slope of the intrinsic optical signal significantly decreased in the presence of FAC (amplitude: 36 +/- 6%, P < 0.01; slope: 37 +/- 11% as compared with baseline conditions, P < 0.05). This suggests a glial participation in signal generation. Rotenone, an inhibitor of mitochondrial complex I, yielded decreased amplitudes of the intrinsic optical signal (27 +/- 7% after 40 min, P < 0.01). Our data indicate that the intrinsic optical signal change reflects type and strength of neuronal activation and point to glia and mitochondria as important participants in signal generation.

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Use of fluorocitrate and fluoroacetate in the study of brain metabolism

Cited by 56 publications

References 17 publications

Astrocytic regulation of the recovery of extracellular potassium after seizures in vivo

Astrocytic regulation of the recovery of extracellular potassium after seizures in vivo

Gliotransmission by Prostaglandin E2: A Prerequisite for GnRH Neuronal Function?

Processes and components participating in the generation of intrinsic optical signal changes in vitro

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