Isoflurane increases the uptake of glutamate in synaptosomes from rat cerebral cortex

Larsen, Marthe; Hegstad, Elisabeth; Berg-Johnsen, Jon; Langmoen, Iver A.

doi:10.1093/bja/78.1.55

Cited by 46 publications

(20 citation statements)

References 33 publications

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“…This process is enhanced by volatile anesthetics such as isoflurane (Larsen et al, 1997;Zuo, 2001;Huang and Zuo, 2003) and halothane (Miyazaki et al, 1997). Blockage of glutamate uptake leads to an increased demand of anesthesia (Cechova and Zuo, 2006), which is used to counteract increasing excitatory signaling.…”

Section: Discussionmentioning

confidence: 99%

“…One reason for this impairment may be the action of isoflurane on an enhancement of glutamate uptake by specific glial GLT1/EAAT2 transporters (Larsen et al, 1997;Zuo, 2001) and the consequent reduction of excitatory neuronal inputs to inhibitory interneurons. The idea behind this reasoning is that a reduction in excitation would result in a diminished inhibitory drive.…”

Section: Pharmacological Correlates Of Inhibition During Bsmentioning

confidence: 99%

“…Isoflurane appears to target several membrane proteins: glycine and GABA A receptors Nishikawa et al, 2002), as well as two-pore-domain K ϩ channels (Franks and Lieb, 1988;Patel et al, 1999). In addition, isoflurane has been shown to stimulate the activity of the GLT1/EAAT2 glial glutamate transporter (Larsen et al, 1997;Zuo, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Cortical Inhibition during Burst Suppression Induced with Isoflurane Anesthesia

Ferron¹,

Kroeger²,

Chever³

et al. 2009

J. Neurosci.

125

126

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Isoflurane is a widely used anesthetic which safely and reversibly induces deep coma and associated burst suppression (BS) electroencephalographic patterns. Here we investigate possible underlying causes for the state of cortical hyperexcitability which was recently shown to be one of the characteristics of BS. Our hypothesis was that cortical inhibition is diminished during isoflurane-induced BS. Experiments were performed in vivo using intracellular recordings of cortical neurons to assess their responsiveness to stimulations of connected thalamic nuclei. We demonstrate that during BS EPSPs were diminished by 44%, whereas inhibitory potentials were completely suppressed. This finding was supported by additional results indicating that a decrease in neuronal input resistance normally found during inhibitory responses under low isoflurane conditions was abolished in the BS condition. Moreover, removal of inhibition occasionally revealed excitatory components which were absent during recordings before the induction of BS. We also show that the absence of inhibition during BS is not caused by a blockage of GABA receptors, since iontophoretically applied GABA shows receptor availability. Moreover, the concentration of extracellular chloride was increased during BS, as would be expected after reduced flow of chloride through GABA A receptors. Also inhibitory responses were reinstated by selective blockage of glial glutamate transporters with dihydrokainate. These results suggest that the lack of inhibition during BS is caused by reduced excitation, probably resulting from increased glial uptake of glutamate stimulated by isoflurane, which creates a diminished activation of cortical interneurons. Thus cortical hyperexcitability during BS is favored by suppressed inhibition.

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Section: Discussionmentioning

confidence: 99%

Section: Pharmacological Correlates Of Inhibition During Bsmentioning

confidence: 99%

See 1 more Smart Citation

Cortical Inhibition during Burst Suppression Induced with Isoflurane Anesthesia

Ferron¹,

Kroeger²,

Chever³

et al. 2009

J. Neurosci.

125

126

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“…Larsen et al (1997) showed that isoflurane increased glutamate uptake in synaptosomes prepared from rat cerebral cortex. However, using a similar experimental model, Nicol et al (1995) failed to demonstrate any increases in glutamate uptake by isoflurane.…”

Section: Discussionmentioning

confidence: 99%

Isoflurane Induces a Protein Kinase C α-Dependent Increase in Cell-Surface Protein Level and Activity of Glutamate Transporter Type 3

Huang¹,

Zuo²

2005

Mol Pharmacol

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Glutamate transporters regulate extracellular concentrations of glutamate, an excitatory neurotransmitter in the central nervous system. We have shown that the commonly used anesthetic isoflurane increased the activity of glutamate transporter type 3 (excitatory amino acid transporter 3, EAAT3) possibly via a protein kinase C (PKC)-dependent pathway. In this study, we showed that isoflurane induced a time-and concentrationdependent redistribution of EAAT3 to the cell membrane in C6 glioma cells. This redistribution was inhibited by staurosporine, a pan PKC inhibitor, or by 12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo(3,4-c)-carbazole (Gö 6976) at a concentration that selectively inhibits conventional PKC isozymes (PKC␣, -␤, and -␥). This isoflurane-induced EAAT3 redistribution was also blocked when the expression of PKC␣ but not PKC␤ proteins was down-regulated by the respective antisense oligonucleotides. The isoflurane-induced increase of glutamate uptake by EAAT3 was abolished by the down-regulation of PKC␣ expression. Immunoprecipitation with an anti-EAAT3 antibody pulled down more PKC␣ in cells exposed to isoflurane than in control cells. Isoflurane also increased the phosphorylated EAAT3 and the redistribution of PKC␣ to the particulate fraction of cells. Consistent with the results in C6 cells, isoflurane also increased EAAT3 cell-surface expression and enhanced the association of PKC␣ with EAAT3 in rat hippocampal synaptosomes. Our results suggest that the isoflurane-induced increase in EAAT3 activity requires an increased amount of EAAT3 protein in the plasma membrane. These effects are PKC␣-dependent and may rely on the formation of an EAAT3-PKC␣ complex. Together, these results suggest an important mechanism for the regulation of glutamate transporter functions and expand our understanding of isoflurane pharmacology at cellular and molecular levels.Glutamate transporters (also called excitatory amino acid transporters, EAAT) are important in regulating extracellular concentrations of glutamate (Danbolt, 2001), a major excitatory neurotransmitter in the mammalian central nervous system (CNS). By transporting glutamate from extracellular to intracellular space under physiological conditions, EAATs prevent extracellular glutamate accumulation and regulate glutamate neurotransmission. Five EAATs have been identified: EAAT1 to EAAT5 (Danbolt, 2001). In rats, EAAT1 and EAAT2 are found in glial cells, and EAAT3 and EAAT4 are mainly expressed in neurons, whereas EAAT5 is located in neurons and glial cells of retina (Rothstein et al., 1994;Lehre et al., 1995;Arriza et al., 1997). The transporting functions of all five EAATs are sodium-dependent. They use the transmembrane gradient of Na ϩ , K ϩ , and H ϩ as a driving force to uptake glutamate (Billups et al., 1998;Danbolt, 2001).Studies on regional distribution of EAATs have shown that EAAT3 is widely distributed in forebrain, hippocampus, and cerebellum and that EAAT4 is largely restricted to the molecular cell layer ...

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“…The in¯uence of the general anaesthetics on this process, however, is not fully understood. Recent studies (Larsen et al, 1997;Miyazaki et al, 1997) suggest that volatile anaesthetics at clinical concentrations can potentiate glutamate uptake into synaptosomes and astrocytes.…”

Section: Introductionmentioning

confidence: 99%

Concentration‐dependent isoflurane effects on depolarization‐evoked glutamate and GABA outflows from mouse brain slices

Liachenko

Tang

Somogyi

et al. 1999

British J Pharmacology

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1 The synaptic concentrations of glutamate and g-aminobutyric acid (GABA) are modulated by their release and re-uptake. The e ects of general anaesthetics on these two processes remain unclear. This study evaluates the e ects of iso¯urane, a clinically important anaesthetic, on glutamate and GABA release and re-uptake in superfused mouse cerebrocortical slices. 2 Experiments consisted of two 1.5-min exposures to 40 mM KCl in 30 min intervals. During the second exposure, di erent concentrations of iso¯urane with and without 0.3 mM L-transpyrrolidine-2,4-dicarboxylic acid (PDC, a competitive inhibitor of glutamate uptake transporter) or 1 mM nipecotic acid (a competitive inhibitor of GABA uptake transporter) were introduced. The ratios of the second to ®rst KCl-evoked increases in glutamate and GABA were used to determine the iso¯urane concentration-response curves.3 The results can be described as a sum of two independent processes, corresponding to the inhibitions of release and re-uptake, respectively. The EC 50 values for the inhibitions of release and re-uptake were 295+16 and 805+43 mM for glutamate, and 229+13 and 520+25 mM for GABA, respectively. Addition of PDC did not signi®cantly a ect glutamate release but shifted the re-uptake curve to the left (EC 50 =315+20 mM). Nipecotic acid completely blocked GABA uptake, rendering iso¯urane inhibition of GABA re-uptake undetectable. 4 Our data suggest that iso¯urane inhibits both the release and re-uptake of neurotransmitters and that the inhibitions occur at di erent EC 50 's. For GABA, both EC 50 's are within the clinical concentration range. The net anaesthetic e ect on extracellular concentrations of neurotransmitters, particularly GABA, depends on the competition between inhibition of release and that of re-uptake.

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Isoflurane increases the uptake of glutamate in synaptosomes from rat cerebral cortex

Cited by 46 publications

References 33 publications

Cortical Inhibition during Burst Suppression Induced with Isoflurane Anesthesia

Cortical Inhibition during Burst Suppression Induced with Isoflurane Anesthesia

Isoflurane Induces a Protein Kinase C α-Dependent Increase in Cell-Surface Protein Level and Activity of Glutamate Transporter Type 3

Concentration‐dependent isoflurane effects on depolarization‐evoked glutamate and GABA outflows from mouse brain slices

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