Positive modulation of human gamma-aminobutyric acid type A and glycine receptors by the inhalation anesthetic isoflurane.
ABSTRACT The interactions of the inhalation anesthetic agent isoflurane with ligand-gated chloride channels were studied using transient expression of recombinant human receptors in a mammalian cell line. Isoflurane enhanced gamma-aminobutyric acid (GABA)-activated chloride currents in cells that expressed heteromeric GABAA receptors consisting of combinations of alpha 1 or alpha 2, beta 1, and gamma 2 subunits and in cells that expressed receptors consisting of combinations of only alpha and beta subunits. Receptors consisting of alpha 2 and gamma 2 subunits were poorly expressed but were sensitive to isoflurane. Receptors consisting of beta 1 and gamma 2 subunits were not expressed. Isoflurane also enhanced glycine-activated chloride currents through homomeric alpha glycine receptors but did not enhance GABA currents in cells expressing homomeric rho 1 receptors. These results show that not all ligand-gated chloride channel receptors are sensitive to isoflurane and, therefore, that the anesthetic interacts with specific structural determinants of these ion channel proteins.
SourceAvailable from: Andrey V. Zakharov[Show abstract] [Hide abstract]
ABSTRACT: Objective Isoflurane and other volatile anesthetics are widely used in children to induce deep and reversible coma, but they may also exert neurotoxic actions. The effects of volatile anesthetics on the immature brain activity remain elusive, however. Methods The effects of isoflurane on spontaneous and sensory-evoked activity were explored using intracortical extracellular field potential and multiple unit recordings in the rat barrel cortex from birth to adulthood. ResultsDuring the first postnatal week, isoflurane suppressed cortical activity in a concentration-dependent manner. At surgical anesthesia levels (1.5–2%), isoflurane completely suppressed the electroencephalogram and silenced cortical neurons. Although sensory potentials evoked by the principal whisker deflection persisted, sensory-evoked early gamma and spindle-burst oscillations were completely suppressed by isoflurane. Isoflurane-induced burst-suppression pattern emerged during the second postnatal week and matured through the first postnatal month. Bursts in adolescent and adult rats were characterized by activation of entire cortical columns with a leading firing of infragranular neurons, and were triggered by principal and adjacent whiskers stimulation, and by auditory and visual stimuli, indicating an involvement of horizontal connections in their generation and horizontal spread. InterpretationThe effects of isoflurane on cortical activity shift from total suppression of activity to burst-suppression pattern at the end of the first postnatal week. Developmental emergence of bursts likely involves a development of the intracortical short- and long-range connections. We hypothesize that complete suppression of cortical activity under isoflurane anesthesia during the first postnatal week may explain neuronal apoptosis stimulated by volatile anesthetics in the neonatal rats.01/2014; 1(1). DOI:10.1002/acn3.16
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ABSTRACT: Although it has been more than 165 years since the first introduction of modern anesthesia to the clinic, there is surprisingly little understanding about the exact mechanisms by which general anesthetics induce unconsciousness. As a result, we do not know how general anesthetics produce anesthesia at different levels. The main handicap to understanding the mechanisms of general anesthesia is the diversity of chemically unrelated compounds including diethyl ether and halogenated hydrocarbons, gases nitrous oxide, ketamine, propofol, benzodiazepines and etomidate, as well as alcohols and barbiturates. Does this imply that general anesthesia is caused by many different mechanisms Until now, many receptors, molecular targets and neuronal transmission pathways have been shown to contribute to mechanisms of general anesthesia. Among these molecular targets, ion channels are the most likely candidates for general anesthesia, in particular γ-aminobutyric acid type A, potassium and sodium channels, as well as ion channels mediated by various neuronal transmitters like acetylcholine, amino acids amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid or N-methyl-D-aspartate. In addition, recent studies have demonstrated the involvement in general anesthesia of other ion channels with distinct gating properties such as hyperpolarization-activated, cyclic- nucleotide-gated channels. The main aim of the present review is to summarize some aspects of current knowledge of the effects of general anesthetics on various ion channels.06/2012; 1(3):80-93. DOI:10.5492/wjccm.v1.i3.80
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ABSTRACT: The use of resting-state functional MRI (rsfMRI) in preclinical research is expanding progressively, with the majority of resting-state imaging performed in anesthetized animals. Since anesthesia may change the physiology and, in particular, the neuronal activity of an animal considerably, it may also affect rsfMRI findings. Therefore, this study compared rsfMRI data from awake mice with rsfMRI results obtained from mice anesthetized with α-chloralose (120 mg/kg), urethane (2.5 g/kg), or isoflurane (1%). Functional connectivity (FC) was estimated using both independent component analysis (40 components) and ROI-based analysis to zoom in on the effect of different anesthetics on inter-hemispheric FC. The data revealed an important diminishment of cortical interhemispheric FC in both the α-chloralose and urethane groups in comparison with the isoflurane and awake groups. When performing FC analysis in anesthetized mice, the impact of anesthetics must be taken into account. The required doses for stable anesthesia during MRI significantly decrease interhemispheric FC. Magn Reson Med, 2013. © 2013 Wiley Periodicals, Inc.Magnetic Resonance in Medicine 10/2014; 72(4). DOI:10.1002/mrm.24990 · 3.40 Impact Factor