Publications by authors named "Stephan Kratzer"

18 Publications

  • Page 1 of 1

The influence of age on EEG-based anaesthesia indices.

J Clin Anesth 2021 Oct 8;73:110325. Epub 2021 May 8.

Department of Anesthesiology and Intensive Care Medicine, Technical University of Munich, School of Medicine, Munich, Germany. Electronic address:

Study Objective: In the upcoming years there will be a growing number of elderly patients requiring general anaesthesia. As age is an independent risk factor for postoperative delirium (POD) the incidence of POD will increase concordantly. One approach to reduce the risk of POD would be to avoid excessively high doses of anaesthetics by using neuromonitoring to guide anaesthesia titration. Therefore, we evaluated the influence of patient's age on various electroencephalogram (EEG)-based anaesthesia indices.

Design And Patients: We conducted an analysis of previously published data by replaying single electrode EEG episodes of maintenance of general anaesthesia from 180 patients (18-90 years; ASA I-IV) into the five different commercially available monitoring systems and evaluated their indices. We included the State/Response Entropy, Narcotrend, qCON/qNOX, bispectral index (BIS), and Treaton MGA-06. For a non-commercial comparison, we extracted the spectral edge frequency (SEF) from the BIS. To evaluate the influence of the age we generated linear regression models. We also assessed the correlation between the various indices.

Main Results: During anaesthetic maintenance the values of the SEF, State/Response Entropy, qCON/qNOX and BIS all significantly increased (0.05 Hz/0.19-0.26 index points per year) with the patient's age (p < 0.001); whereas the Narcotrend did not change significantly with age (0.06 index points per year; p = 0.28). The index values of the Treaton device significantly decreased with age (-0.09 index points per year; p < 0.001). These findings were independent of the administered dose of anaesthetics.

Conclusions: Almost all current neuromonitoring devices are influenced by age, with the potential to result in inappropriately high dosage of anaesthetics. Therefore, anaesthesiologists should be aware of this phenomenon, and the next generation of monitors should correct for these changes.
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http://dx.doi.org/10.1016/j.jclinane.2021.110325DOI Listing
October 2021

Attenuation of Native Hyperpolarization-Activated, Cyclic Nucleotide-Gated Channel Function by the Volatile Anesthetic Sevoflurane in Mouse Thalamocortical Relay Neurons.

Front Cell Neurosci 2020 21;14:606687. Epub 2021 Jan 21.

Department of Anesthesiology and Intensive Care Medicine, Technical University of Munich School of Medicine, Munich, Germany.

As thalamocortical relay neurons are ascribed a crucial role in signal propagation and information processing, they have attracted considerable attention as potential targets for anesthetic modulation. In this study, we analyzed the effects of different concentrations of sevoflurane on the excitability of thalamocortical relay neurons and hyperpolarization-activated, cyclic-nucleotide gated (HCN) channels, which play a decisive role in regulating membrane properties and rhythmic oscillatory activity. The effects of sevoflurane on single-cell excitability and native HCN channels were investigated in acutely prepared brain slices from adult wild-type mice with the whole-cell patch-clamp technique, using voltage-clamp and current-clamp protocols. Sevoflurane dose-dependently depressed membrane biophysics and HCN-mediated parameters of neuronal excitability. Respective half-maximal inhibitory and effective concentrations ranged between 0.30 (95% CI, 0.18-0.50) mM and 0.88 (95% CI, 0.40-2.20) mM. We witnessed a pronounced reduction of HCN dependent I current amplitude starting at a concentration of 0.45 mM [relative change at -133 mV; 0.45 mM sevoflurane: 0.85 (interquartile range, 0.79-0.92), = 12, = 0.011; 1.47 mM sevoflurane: 0.37 (interquartile range, 0.34-0.62), = 5, < 0.001] with a half-maximal inhibitory concentration of 0.88 (95% CI, 0.40-2.20) mM. In contrast, effects on voltage-dependent channel gating were modest with significant changes only occurring at 1.47 mM [absolute change of half-maximal activation potential; 1.47 mM: -7.2 (interquartile range, -10.3 to -5.8) mV, = 5, = 0.020]. In this study, we demonstrate that sevoflurane inhibits the excitability of thalamocortical relay neurons in a concentration-dependent manner within a clinically relevant range. Especially concerning its effects on native HCN channel function, our findings indicate substance-specific differences in comparison to other anesthetic agents. Considering the importance of HCN channels, the observed effects might mechanistically contribute to the hypnotic properties of sevoflurane.
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http://dx.doi.org/10.3389/fncel.2020.606687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858256PMC
January 2021

Age-Related EEG Features of Bursting Activity During Anesthetic-Induced Burst Suppression.

Front Syst Neurosci 2020 3;14:599962. Epub 2020 Dec 3.

Department of Anesthesiology and Intensive Care Medicine, School of Medicine, Technical University Munich, Munich, Germany.

Electroencephalographic (EEG) Burst Suppression (BSUPP) is a discontinuous pattern characterized by episodes of low voltage disrupted by bursts of cortical synaptic activity. It can occur while delivering high-dose anesthesia. Current research suggests an association between BSUPP and the occurrence of postoperative delirium in the post-anesthesia care unit (PACU) and beyond. We investigated burst micro-architecture to further understand how age influences the neurophysiology of this pharmacologically-induced state. We analyzed a subset of EEG recordings ( = 102) taken from a larger data set previously published. We selected the initial burst that followed a visually identified "silent second," i.e., at least 1 s of iso-electricity of the EEG during propofol induction. We derived the (normalized) power spectral density [(n)PSD], the alpha band power, the maximum amplitude, the maximum slope of the EEG as well as the permutation entropy (PeEn) for the first 1.5 s of the initial burst of each patient. In the old patients >65 years, we observed significantly lower ( < 0.001) EEG power in the 1-15 Hz range. In general, their EEG contained a significantly higher amount of faster oscillations (>15 Hz). Alpha band power ( < 0.001), EEG amplitude ( = 0.001), and maximum EEG slope ( = 0.045) all significantly decreased with age, whereas PeEn increased ( = 0.008). Hence, we can describe an age-related change in features during EEG burst suppression. Sub-group analysis revealed no change in results based on pre-medication. These EEG changes add knowledge to the impact of age on cortical synaptic activity. In addition to a reduction in EEG amplitude, age-associated burst features can complicate the identification of excessive anesthetic administration in patients under general anesthesia. Knowledge of these neurophysiologic changes may not only improve anesthesia care through improved detection of burst suppression but might also provide insight into changes in neuronal network organization in patients at risk for age-related neurocognitive problems.
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http://dx.doi.org/10.3389/fnsys.2020.599962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744408PMC
December 2020

The anaesthetic xenon partially restores an amyloid beta-induced impairment in murine hippocampal synaptic plasticity.

Neuropharmacology 2019 06 30;151:21-32. Epub 2019 Mar 30.

Department of Anaesthesiology and Intensive Care Medicine, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675 Munich, Germany.

Background: It is controversially discussed whether general anaesthesia increases the risk of Alzheimer's disease (AD) or accelerates its progression. One important factor in AD pathogenesis is the accumulation of soluble amyloid beta (Aβ) oligomers which affect N-methyl-d-aspartate (NMDA) receptor function and abolish hippocampal long-term potentiation (LTP). NMDA receptor antagonists, at concentrations allowing physiological activation, can prevent Aβ-induced deficits in LTP. The anaesthetics xenon and S-ketamine both act as NMDA receptor antagonists and have been reported to be neuroprotective. In this study, we investigated the effects of subanaesthetic concentrations of these drugs on LTP deficits induced by different Aβ oligomers and compared them to the effects of radiprodil, a NMDA subunit 2B (GluN2B)-selective antagonist.

Methods: We applied different Aβ oligomers to murine brain slices and recorded excitatory postsynaptic field potentials before and after high-frequency stimulation in the CA1 region of hippocampus. Radiprodil, xenon and S-ketamine were added and recordings evoked from a second input were measured.

Results: Xenon and radiprodil, applied at low concentrations, partially restored the LTP deficit induced by pre-incubated Aβ. S-ketamine showed no effect. None of the drugs tested were able to ameliorate Aβ-induced LTP-deficits.

Conclusions: Xenon administered at subanaesthetic concentrations partially restored Aβ-induced impairment of LTP, presumably via its weak NMDA receptor antagonism. The effects were in a similar range than those obtained with the NMDA-GluN2B antagonist radiprodil. Our results point to protective properties of xenon in the context of pathological distorted synaptic physiology which might be a meaningful alternative for anaesthesia in AD patients.
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http://dx.doi.org/10.1016/j.neuropharm.2019.03.031DOI Listing
June 2019

Modulation of frontal EEG alpha oscillations during maintenance and emergence phases of general anaesthesia to improve early neurocognitive recovery in older patients: protocol for a randomised controlled trial.

Trials 2019 Feb 22;20(1):146. Epub 2019 Feb 22.

Department of Anaesthesiology, Waikato Clinical Campus, University of Auckland, Hamilton, New Zealand.

Background: Postoperative delirium may manifest in the immediate post-anaesthesia care period. Such episodes appear to be predictive of further episodes of inpatient delirium and associated adverse outcomes. Frontal electroencephalogram (EEG) findings of suppression patterns and low proprietary index values have been associated with postoperative delirium and poor outcomes. However, the efficacy of titrating anaesthesia to proprietary index targets for preventing delirium remains contentious. We aim to assess the efficacy of two strategies which we hypothesise could prevent post-anaesthesia care unit (PACU) delirium by maximising the alpha oscillation observed in frontal EEG channels during the maintenance and emergence phases of anaesthesia.

Methods: This is a 2 × 2 factorial, double-blind, stratified, randomised control trial of 600 patients. Eligible patients are those aged 60 years or over who are undergoing non-cardiac, non-intracranial, volatile-based anaesthesia of expected duration of more than 2 h. Patients will be stratified by pre-operative cognitive status, surgery type and site. For the maintenance phase of anaesthesia, patients will be randomised (1:1) to an alpha power-maximisation anaesthesia titration strategy versus standard care avoiding suppression patterns in the EEG. For the emergence phase of anaesthesia, patients will be randomised (1:1) to early cessation of volatile anaesthesia and emergence from an intravenous infusion of propofol versus standard emergence from volatile anaesthesia only. The primary study outcomes are the power of the frontal alpha oscillation during the maintenance and emergence phases of anaesthesia. Our main clinical outcome of interest is PACU delirium.

Discussion: This is a largely exploratory study; the extent to which EEG signatures can be modified by titration of pharmacological agents is not known. The underlying concept is maximisation of anaesthetic efficacy by individualised drug titration to a clearly defined EEG feature. The interventions are already clinically used strategies in anaesthetic practice, but have not been formally evaluated. The addition of propofol during the emergence phase of volatile-based general anaesthesia is known to reduce emergence delirium in children; however, the efficacy of this strategy in older patients is not known.

Trial Registration: Australian and New Zealand Clinical Trial Registry, ID: 12617001354370 . Registered on 27/09/2017.
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http://dx.doi.org/10.1186/s13063-019-3178-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387545PMC
February 2019

Substance-Specific Differences in Human Electroencephalographic Burst Suppression Patterns.

Front Hum Neurosci 2018 21;12:368. Epub 2018 Sep 21.

Department of Anesthesiology and Intensive Care, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.

Different anesthetic agents induce burst suppression in the electroencephalogram (EEG) at very deep levels of general anesthesia. EEG burst suppression has been identified to be a risk factor for postoperative delirium (POD). EEG based automated detection algorithms are used to detect burst suppression patterns during general anesthesia and a burst suppression ratio (BSR) is calculated. Unfortunately, applied algorithms do not give information as precisely as suggested, often resulting in an underestimation of the patients' burst suppression level. Additional knowledge of substance-specific burst suppression patterns could be of great importance to improve the ability of EEG based monitors to detect burst suppression. In a re-analysis of EEG recordings obtained from a previous study, we analyzed EEG data of 45 patients undergoing elective surgery under general anesthesia. The patients were anesthetized with sevoflurane, isoflurane or propofol ( = 15, for each group). After skin incision, the used agent was titrated to a level when burst suppression occurred. In a visual analysis of the EEG, blinded to the used anesthetic agent, we included the first distinct burst in our analysis. To avoid bias through changing EEG dynamics throughout the burst, we only focused on the first 2 s of the burst. These episodes were analyzed using the power spectral density (PSD) and normalized PSD, the absolute burst amplitude and absolute burst slope, as well as permutation entropy (PeEn). Our results show significant substance-specific differences in the architecture of the burst. Volatile-induced bursts showed higher burst amplitudes and higher burst power. Propofol-induced bursts had significantly higher relative power in the EEG alpha-range. Further, isoflurane-induced bursts had the steepest burst slopes. We can present the first systematic comparison of substance-specific burst characteristics during anesthesia. Previous observations, mostly derived from animal studies, pointing out the substance-specific differences in bursting behavior, concur with our findings. Our findings of substance-specific EEG characteristics can provide information to help improve automated burst suppression detection in monitoring devices. More specific detection of burst suppression may be helpful to reduce excessive EEG effects of anesthesia and therefore the incidence of adverse outcomes such as POD.
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http://dx.doi.org/10.3389/fnhum.2018.00368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160564PMC
September 2018

Propofol and Sevoflurane Differentially Modulate Cortical Depolarization following Electric Stimulation of the Ventrobasal Thalamus.

Front Comput Neurosci 2017 11;11:109. Epub 2017 Dec 11.

Department of Anesthesiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.

The neuronal mechanisms how anesthetics lead to loss of consciousness are unclear. Thalamocortical interactions are crucially involved in conscious perception; hence the thalamocortical network might be a promising target for anesthetic modulation of neuronal information pertaining to arousal and waking behavior. General anesthetics affect the neurophysiology of the thalamus and the cortex but the exact mechanisms of how anesthetics interfere with processing thalamocortical information remain to be elucidated. Here we investigated the effect of the anesthetic agents sevoflurane and propofol on thalamocortical network activity . We used voltage-sensitive dye imaging techniques to analyze the cortical depolarization in response to stimulation of the thalamic ventrobasal nucleus in brain slices from mice. Exposure to sevoflurane globally decreased cortical depolarization in a dose-dependent manner. Sevoflurane reduced the intensity and extent of cortical depolarization and delayed thalamocortical signal propagation. In contrast, propofol neither affected area nor amplitude of cortical depolarization. However, propofol exposure resulted in regional changes in spatial distribution of maximum fluorescence intensity in deep regions of the cortex. In summary, our experiments revealed substance-specific effects on the thalamocortical network. Functional changes of the neuronal network are known to be pivotally involved in the anesthetic-induced loss of consciousness. Our findings provide further evidence that the mechanisms of anesthetic-mediated loss of consciousness are drug- and pathway-specific.
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http://dx.doi.org/10.3389/fncom.2017.00109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732174PMC
December 2017

Tranexamic acid impairs hippocampal synaptic transmission mediated by gamma aminobutyric acid receptor type A.

Eur J Pharmacol 2017 Nov 5;815:49-55. Epub 2017 Oct 5.

Department of Anesthesiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. Electronic address:

High-dose application of tranexamic acid (TXA), a widely used antifibrinolytic drug, can cause seizures in patients undergoing surgery. Mechanistically, seizures are considered to arise from an imbalance between inhibitory and excitatory synaptic transmission, whose main transmitters are gamma-aminobutyric acid (GABA) and glutamate. In the present study, we investigated the effects of TXA on neuronal excitability and synaptic transmission in the hippocampus, a structure that plays a pivotal role in human epilepsy. In acute slices of the murine hippocampus, fast depolarization-mediated imaging signals (FDSs) and postsynaptic currents (PSCs) were recorded using voltage-sensitive dye imaging and whole-cell patch clamp technique, respectively. FDSs and PSCs were evoked upon stimulation of the dentate gyrus and Schaffer collateral/associational commissural pathway, respectively. GABA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and N-methyl-d-aspartate (NMDA) receptor-mediated postsynaptic currents were isolated pharmacologically. Application of TXA enhanced FDS propagation in the hippocampus. Neither the resting membrane potential of the investigated neurones nor synaptic transmission mediated by AMPA or NMDA receptors was changed by the application of 1mM TXA. In contrast, TXA dose-dependently reduced GABA receptor-mediated synaptic transmission. TXA induced the inhibition of GABA receptor-mediated synaptic transmission in the hippocampus with a potency similar to that of its antagonistic properties against GABA receptors in the basolateral amygdala (Kratzer et al., 2014). Since impairment of GABAergic transmission is a major cause of epileptic seizures, the observed effect might contribute to the proconvulsive properties of TXA.
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http://dx.doi.org/10.1016/j.ejphar.2017.10.001DOI Listing
November 2017

Intracerebroventricular injection of beta-amyloid in mice is associated with long-term cognitive impairment in the modified hole-board test.

Behav Brain Res 2017 05 10;324:15-20. Epub 2017 Feb 10.

Department of Anaesthesiology, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675 Munich, Germany.

Background: The intracerebroventricular injection of beta-amyloid (Aβ) in mice allows the investigation of acute effects on cognitive function and cellular pathology. The aim of this investigation was to further characterize the time course of Aβ-induced cognitive and behavioural changes and to detect potential molecular mechanisms.

Methods: Cannulas were implanted in the lateral cerebral ventricle. 14days after surgery the mice were injected with Aβ1-42 or phosphate buffered saline (PBS). Starting 2, 4 or 8 (PBS only 4) days after injection we evaluated cognitive and behavioural performance using the modified hole board test (mHBT). We determined tumour-necrosis factor alpha (TNF alpha) and caspase 3 by western blotting, on days 10, 12 and 16. Data were analysed using general linear modelling, Kruskall-Wallis and Mann-Whitney-U test.

Results: Aβ induced a decline in cognitive performance represented as an increased total number of wrong choices during the testing period from day 2-15 (p<0.05). Behavioural parameters were comparable between mice treated with Aβ and PBS. There was no difference regarding TNF alpha levels between the groups. Compared to day 16 Caspase 3 levels were increased on day 10 (p=0.004).

Conclusions: Application of Aβ in the lateral ventricle of mice is associated with cognitive impairment of declarative memory in the mHBT. There is no interference caused by altered behaviour. Therefore, it represents a valid model for acute Aβ-mediated neurotoxic effects. Although the exact mechanisms remain unclear, changes in levels of Caspase 3 suggest apoptosis as an important factor for the development of cognitive dysfunction.
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http://dx.doi.org/10.1016/j.bbr.2017.02.007DOI Listing
May 2017

Impact of Hyperpolarization-activated, Cyclic Nucleotide-gated Cation Channel Type 2 for the Xenon-mediated Anesthetic Effect: Evidence from In Vitro and In Vivo Experiments.

Anesthesiology 2015 May;122(5):1047-59

From the Department of Anesthesiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (C.M., S.K., M. Buerge, M.K., T.E., C.K., E.K., R.H., G.R.); Department Pharmazie-Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität München, Munich, Germany (M. Biel, V.H.); and Department of Anesthesiology, Weill Cornell Medical College, New York, New York (S.-W.Y., P.A.G.).

Background: The thalamus is thought to be crucially involved in the anesthetic state. Here, we investigated the effect of the inhaled anesthetic xenon on stimulus-evoked thalamocortical network activity and on excitability of thalamocortical neurons. Because hyperpolarization-activated, cyclic nucleotide-gated cation (HCN) channels are key regulators of neuronal excitability in the thalamus, the effect of xenon on HCN channels was examined.

Methods: The effects of xenon on thalamocortical network activity were investigated in acutely prepared brain slices from adult wild-type and HCN2 knockout mice by means of voltage-sensitive dye imaging. The influence of xenon on single-cell excitability in brain slices was investigated using the whole-cell patch-clamp technique. Effects of xenon on HCN channels were verified in human embryonic kidney cells expressing HCN2 channels.

Results: Xenon concentration-dependently diminished thalamocortical signal propagation. In neurons, xenon reduced HCN channel-mediated Ih current amplitude by 33.4 ± 12.2% (at -133 mV; n = 7; P = 0.041) and caused a left-shift in the voltage of half-maximum activation (V1/2) from -98.8 ± 1.6 to -108.0 ± 4.2 mV (n = 8; P = 0.035). Similar effects were seen in human embryonic kidney cells. The impairment of HCN channel function was negligible when intracellular cyclic adenosine monophosphate level was increased. Using HCN2 mice, we could demonstrate that xenon did neither attenuate in vitro thalamocortical signal propagation nor did it show sedating effects in vivo.

Conclusions: Here, we clearly showed that xenon impairs HCN2 channel function, and this impairment is dependent on intracellular cyclic adenosine monophosphate levels. We provide evidence that this effect reduces thalamocortical signal propagation and probably contributes to the hypnotic properties of xenon.
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http://dx.doi.org/10.1097/ALN.0000000000000635DOI Listing
May 2015

Tranexamic acid impairs γ-aminobutyric acid receptor type A-mediated synaptic transmission in the murine amygdala: a potential mechanism for drug-induced seizures?

Anesthesiology 2014 Mar;120(3):639-49

From the Department of Anesthesiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (S.K., H.I., C.M., M.B., E.K., G.R., and R.H.); Department of Anesthesiology, Deutsches Herzzentrum München, Klinik an der Technischen Universität München, Munich, Germany (J.K.); and RG Neuronal Network Dynamics, Max Planck Institut of Psychiatry, Munich, Germany (M.E.).

Background: Tranexamic acid (TXA) is commonly used to reduce blood loss in cardiac surgery and in trauma patients. High-dose application of TXA is associated with an increased risk of postoperative seizures. The neuronal mechanisms underlying this proconvulsant action of TXA are not fully understood. In this study, the authors investigated the effects of TXA on neuronal excitability and synaptic transmission in the basolateral amygdala.

Methods: Patch clamp recordings and voltage-sensitive dye imaging were performed in acute murine brain slices. Currents through N-methyl-D-aspartate, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and γ-aminobutyric acid receptor type A (GABAA) receptors were recorded. GABAA receptor-mediated currents were evoked upon electrical stimulation or upon photolysis of caged GABA. TXA was applied at different concentrations.

Results: Voltage-sensitive dye imaging demonstrates that TXA (1 mM) reversibly enhances propagation of neuronal excitation (mean ± SEM, 129 ± 6% of control; n = 5). TXA at concentrations of 0.1, 0.3, 1, 5, or 10 mM led to a dose-dependent reduction of GABAA receptor-mediated currents in patch clamp recordings. There was no difference in the half-maximal inhibitory concentration for electrically (0.76 mM) and photolytically (0.84 mM) evoked currents (n = 5 to 9 for each concentration), and TXA did not affect the paired-pulse ratio of GABAA receptor-mediated currents. TXA did not impact glutamatergic synaptic transmission.

Conclusions: This study clearly demonstrates that TXA enhances neuronal excitation by antagonizing inhibitory GABAergic neurotransmission. The results provide evidence that this effect is mediated via postsynaptic mechanisms. Because GABAA receptor antagonists are known to promote epileptiform activity, this effect might explain the proconvulsant action of TXA.
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http://dx.doi.org/10.1097/ALN.0000000000000103DOI Listing
March 2014

Activation of CRH receptor type 1 expressed on glutamatergic neurons increases excitability of CA1 pyramidal neurons by the modulation of voltage-gated ion channels.

Front Cell Neurosci 2013 19;7:91. Epub 2013 Jul 19.

Department of Anesthesiology, Klinikum Rechts der Isar der Technischen Universität München Munich, Germany.

Corticotropin-releasing hormone (CRH) plays an important role in a substantial number of patients with stress-related mental disorders, such as anxiety disorders and depression. CRH has been shown to increase neuronal excitability in the hippocampus, but the underlying mechanisms are poorly understood. The effects of CRH on neuronal excitability were investigated in acute hippocampal brain slices. Population spikes (PS) and field excitatory postsynaptic potentials (fEPSP) were evoked by stimulating Schaffer-collaterals and recorded simultaneously from the somatic and dendritic region of CA1 pyramidal neurons. CRH was found to increase PS amplitudes (mean ± Standard error of the mean; 231.8 ± 31.2% of control; n = 10) while neither affecting fEPSPs (104.3 ± 4.2%; n = 10) nor long-term potentiation (LTP). However, when Schaffer-collaterals were excited via action potentials (APs) generated by stimulation of CA3 pyramidal neurons, CRH increased fEPSP amplitudes (119.8 ± 3.6%; n = 8) and the magnitude of LTP in the CA1 region. Experiments in slices from transgenic mice revealed that the effect on PS amplitude is mediated exclusively by CRH receptor 1 (CRHR1) expressed on glutamatergic neurons. The effects of CRH on PS were dependent on phosphatase-2B, L- and T-type calcium channels and voltage-gated potassium channels but independent on intracellular Ca(2+)-elevation. In patch-clamp experiments, CRH increased the frequency and decay times of APs and decreased currents through A-type and delayed-rectifier potassium channels. These results suggest that CRH does not affect synaptic transmission per se, but modulates voltage-gated ion currents important for the generation of APs and hence elevates by this route overall neuronal activity.
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http://dx.doi.org/10.3389/fncel.2013.00091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3715697PMC
July 2013

Xenon attenuates hippocampal long-term potentiation by diminishing synaptic and extrasynaptic N-methyl-D-aspartate receptor currents.

Anesthesiology 2012 Mar;116(3):673-82

Department of Anesthesiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.

Background: The memory-blocking properties of general anesthetics are of high clinical relevance and scientific interest. The inhalational anesthetic xenon antagonizes N-methyl-D-aspartate (NMDA) receptors. It is unknown if xenon affects long-term potentiation (LTP), a cellular correlate for memory formation. In hippocampal brain slices, the authors investigated in area CA1 whether xenon affects LTP, NMDA receptor-mediated neurotransmission, and intracellular calcium concentrations.

Methods: In sagittal murine hippocampal brain slices, the authors investigated the effects of xenon on LTP by recording excitatory postsynaptic field potentials. Using fluorometric calcium imaging, the authors tested the influence of xenon on calcium influx during high-frequency stimulation. In addition, using the patch-clamp technique, the xenon effect on synaptic and extrasynaptic NMDA receptors and L-type calcium channels was examined.

Results: In the absence of xenon, high-frequency stimulation reliably induced LTP and potentiated field potential slopes to (mean ± SEM) 127.2 ± 5.8% (P < 0.001). In the presence of xenon, high-frequency stimulation induced only a short-term potentiation, and field potentials returned to baseline level after 15-20 min (105.9 ± 2.9%; P = 0.090). NMDA receptor-mediated excitatory postsynaptic currents were reduced reversibly by xenon to 65.9 ± 9.4% (P = 0.007) of control. When extrasynaptic receptors were activated, xenon decreased NMDA currents to 58.2 ± 5.8% (P < 0.001). Xenon reduced the increase in intracellular calcium during high-frequency stimulation without affecting L-type calcium channels.

Conclusions: N-methyl-D-aspartate receptor activation is crucial for the induction of CA1 LTP. Thus, the depression of NMDA receptor-mediated neurotransmission presumably contributes to the blockade of LTP under xenon. Because LTP is assumed to be involved in learning and memory, its blockade might be a key mechanism for xenon's amnestic properties.
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http://dx.doi.org/10.1097/ALN.0b013e3182475d66DOI Listing
March 2012

Xenon attenuates excitatory synaptic transmission in the rodent prefrontal cortex and spinal cord dorsal horn.

Anesthesiology 2009 Dec;111(6):1297-307

Department of Anesthesiology, Klinikum rechts der Isar, Technische Universität München, Ismaninger Strasse 22, 81675 Munich, Germany.

Background: The molecular mechanisms of the inhalational anesthetic xenon are not yet fully understood. Recently, the authors showed that xenon reduces both N-methyl-d-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated synaptic transmission in a brain slice preparation of the amygdala. In the current study, the authors examined the effects of xenon on synaptic transmission in the prefrontal cortex and the spinal cord dorsal horn (substantia gelatinosa).

Methods: In rodent brain or spinal cord slice preparations, the authors used patch clamp technique to investigate the impact of xenon on NMDA and AMPA receptor-mediated excitatory postsynaptic currents, as well as on gamma-aminobutyric acid type A receptor-mediated inhibitory postsynaptic currents. The currents were either evoked upon electrical stimulation (NMDA-eEPSCs and AMPA-eEPSCs) or upon photolysis of caged L-glutamate (p-NMDA-Cs and p-AMPA-Cs). In addition, the authors investigated the effects of xenon on AMPA receptor-mediated miniature excitatory postsynaptic currents.

Results: In both central nervous system regions, xenon had virtually no effect on inhibitory postsynaptic currents. In the prefrontal cortex (spinal cord), xenon reversibly reduced NMDA-eEPSCs to approximately 58% (72%) and AMPA-eEPSCs to approximately 67% (65%) of control. There was no difference in the xenon-induced reduction of NMDA-eEPSCs and p-NMDA-Cs, or AMPA-eEPSCs and p-AMPA-Cs. Xenon did not affect the frequency of miniature excitatory postsynaptic currents but reduced their amplitude.

Conclusions: In the current study, the authors found that xenon depresses NMDA and AMPA receptor-mediated synaptic transmission in the prefrontal cortex and the substantia gelatinosa without affecting gamma-aminobutyric acid type A receptor-mediated synaptic transmission. These results provide evidence that the effects of xenon are primarily due to postsynaptic mechanisms.
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http://dx.doi.org/10.1097/ALN.0b013e3181c14c05DOI Listing
December 2009

Isoflurane and sevoflurane dose-dependently impair hippocampal long-term potentiation.

Eur J Pharmacol 2009 Nov 16;623(1-3):47-51. Epub 2009 Sep 16.

Department of Anaesthesiology, Klinikum rechts der Isar, Technische Universität München, Ismaninger Strasse 22, 81675 Munich, Germany.

Isoflurane and sevoflurane are commonly used volatile anaesthetics. Although acting via similar cellular mechanisms, the effect of different volatile anaesthetics on synaptic plasticity might differ. In the present study, using acute murine brain slice preparations, we compared the effects of isoflurane and sevoflurane on synaptic transmission and synaptic plasticity (long-term potentiation, LTP) in the CA1 stratum radiatum of the hippocampus. Isoflurane and sevoflurane dose-dependently diminished excitatory postsynaptic field potentials. In the presence of isoflurane (sevoflurane) at concentrations of 0.19, 0.28 and 0.37mM (0.11, 0.21 and 0.42mM), which correspond to 0.7-, 1.0- and 1.4-fold (0.3-, 0.6- and 1.1-fold) minimum alveolar concentration (MAC), high frequency stimulation reliably induced LTP. When isoflurane (sevoflurane) was applied at concentrations of 0.56 and 0.74mM (0.63 and 0.84mM), which equal 2.1- and 2.7-fold (1.7- and 2.2-fold) MAC, LTP was blocked. Our results indicate, that both anaesthetics influence synaptic strength to a similar degree, with only high concentrations blocking hippocampal CA1 stratum radiatum long-term potentiation.
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http://dx.doi.org/10.1016/j.ejphar.2009.09.022DOI Listing
November 2009

The xenon-mediated antagonism against the NMDA receptor is non-selective for receptors containing either NR2A or NR2B subunits in the mouse amygdala.

Eur J Pharmacol 2009 Oct 15;619(1-3):33-7. Epub 2009 Aug 15.

Department of Anaesthesiology, Klinikum rechts der Isar, Technische Universität München, Ismaninger Strasse 22, 81675 Munich, Germany.

In pharmacological studies using cultured neurones or heterologous expression systems, the N-methyl-d-aspartate (NMDA) receptor has been found as a major target for the inhalational anaesthetic xenon (Xe). NMDA receptors play a crucial role in behavioural and cellular processes related to learning and memory, and NMDA receptor subunits type 2A (NR2A) and type 2B (NR2B) are critical determinants for synaptic plasticity. In the present study, we investigated in an acute mouse brain slice preparation of the basolateral amygdala whether the antagonism of Xe is subunit-selective against the NR2A or NR2B subunit. From principal neurones, pharmacologically isolated NMDA receptor-mediated currents (p-NMDA-Cs) were evoked upon focal photolysis of caged L-glutamate and recorded using the whole-cell patch-clamp technique. To test whether the Xe-induced inhibition of NMDA receptor-mediated currents is selective for NR2A or NR2B subunits, p-NMDA-Cs were recorded in the presence of the NR2A or NR2B subunit antagonists R-S-1-4-bromophenylethylamino-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl-methylphosphonic acid (NVP-AAM077, 50 nM) or R-R*,S*-alpha-4-Hydroxyphenyl-beta-methyl-4-phenylmethyl-1-piperidinepropanol hydrochloride (Ro 25-6981, 0.5 microM), respectively. The Xe-induced reduction under these conditions was not significantly different from that without NR2A or NR2B blockade. These results provide evidence, that the Xe-induced antagonism against NMDA receptors is non-selective against NR2A- or NR2B-containing receptors.
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http://dx.doi.org/10.1016/j.ejphar.2009.08.011DOI Listing
October 2009

Xenon reduces N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated synaptic transmission in the amygdala.

Anesthesiology 2008 Dec;109(6):998-1006

Department of Anesthesiology, Klinikum rechts der Isar, Technische Universität München, Ismaninger Strasse22, D-81675 Munich, Germany.

Background: The neuronal and molecular targets of the inhalational general anesthetic xenon are a matter of debate. The current knowledge is largely based on studies using neurons in culture or heterologous expression systems. In the current study, the authors evaluated for the first time the effect of xenon on synaptic transmission in the basolateral amygdala in an in vitro brain slice preparation of the mouse.

Methods: A patch clamp technique was used to evaluate the effects of xenon on N-methyl-d-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated excitatory postsynaptic currents (EPSCs), as well as on gamma-aminobutyric acid type A receptor-mediated inhibitory postsynaptic currents. The currents were either evoked upon electrical stimulation (NMDA-eEPSCs, AMPA-eEPSCs) or upon focal, laser-guided photolysis of caged l-glutamate (p-NMDA-Cs, p-AMPA-Cs). In addition, the authors investigated the effects of xenon on miniature EPSCs.

Results: Xenon reversibly reduced basal synaptic transmission but had no effect on gamma-aminobutyric acid type A receptor-mediated inhibitory synaptic transmission. Xenon concentration-dependently diminished NMDA-eEPSCs and p-NMDA-Cs to the same amount. Likewise, xenon-induced reduction of AMPA-eEPSCs and p-AMPA-Cs did not differ. Xenon did not affect the frequency of miniature EPSCs but reduced their amplitude.

Conclusions: In the current study, xenon considerably depressed NMDA and AMPA receptor-mediated synaptic transmission in the basolateral amygdala without affecting inhibitory synaptic transmission. The results provide evidence that the effects of xenon on NMDA- and AMPA-EPSCs are primarily mediated via postsynaptic mechanisms.
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http://dx.doi.org/10.1097/ALN.0b013e31818d6aeeDOI Listing
December 2008
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