Publications
71 results found
Campos-Pires R, Sebastiani A, Hirnet T, et al., 2015, Xenon provides short term & long term neuroprotection in an in vivo model of traumatic brain injury, British Neuroscience Associaton
Koziakova M, Harris K, Campos-Pires R, et al., 2015, The neuroprotective efficacy of noble gases in an in vitro model of ischemic brain injury., British Neuroscience Association, Publisher: BNA
Campos-Pires R, Armstrong SP, Sebastiani A, et al., 2015, Xenon improves neurologic outcome and reduces secondary injury following trauma in an in vivo model of traumatic brain injury, Critical Care Medicine, Vol: 43, Pages: 149-158, ISSN: 1530-0293
Objectives: To determine the neuroprotective efficacy of the inert gas xenon following traumatic brain injury and to determine whether application of xenon has a clinically relevant therapeutic time window.Design: Controlled animal study.Setting: University research laboratory.Subjects: Male C57BL/6N mice (n = 196).Interventions: Seventy-five percent xenon, 50% xenon, or 30% xenon, with 25% oxygen (balance nitrogen) treatment following mechanical brain lesion by controlled cortical impact.Measurements and Main Results: Outcome following trauma was measured using 1) functional neurologic outcome score, 2) histological measurement of contusion volume, and 3) analysis of locomotor function and gait. Our study shows that xenon treatment improves outcome following traumatic brain injury. Neurologic outcome scores were significantly (p < 0.05) better in xenon-treated groups in the early phase (24 hr) and up to 4 days after injury. Contusion volume was significantly (p < 0.05) reduced in the xenon-treated groups. Xenon treatment significantly (p < 0.05) reduced contusion volume when xenon was given 15 minutes after injury or when treatment was delayed 1 or 3 hours after injury. Neurologic outcome was significantly (p < 0.05) improved when xenon treatment was given 15 minutes or 1 hour after injury. Improvements in locomotor function (p < 0.05) were observed in the xenon-treated group, 1 month after trauma.Conclusions: These results show for the first time that xenon improves neurologic outcome and reduces contusion volume following traumatic brain injury in mice. In this model, xenon application has a therapeutic time window of up to at least 3 hours. These findings support the idea that xenon may be of benefit as a neuroprotective treatment in patients with brain trauma.
Bertaccini EJ, Dickinson R, Trudell JR, et al., 2014, Molecular modeling of a tandem two pore domain potassium channel reveals a putative binding Site for general anesthetics, ACS Chemical Neuroscience, Vol: 5, Pages: 1246-1252, ISSN: 1948-7193
Anesthetics are thought to mediate a portion of their activity via binding to and modulation of potassium channels. In particular, tandem pore potassium channels (K2P) are transmembrane ion channels whose current is modulated by the presence of general anesthetics and whose genetic absence has been shown to confer a level of anesthetic resistance. While the exact molecular structure of all K2P forms remains unknown, significant progress has been made toward understanding their structure and interactions with anesthetics via the methods of molecular modeling, coupled with the recently released higher resolution structures of homologous potassium channels to act as templates. Such models reveal the convergence of amino acid regions that are known to modulate anesthetic activity onto a common three- dimensional cavity that forms a putative anesthetic binding site. The model successfully predicts additional important residues that are also involved in the putative binding site as validated by the results of suggested experimental mutations. Such a model can now be used to further predict other amino acid residues that may be intimately involved in the target-based structure–activity relationships that are necessary for anesthetic binding.
Harris K, Armstrong SP, Campos-Pires R, et al., 2013, Neuroprotection against traumatic brain injury by xenon but not argon, is mediated by inhibition at the NMDA receptor glycine site, Anesthesiology, Vol: 119, Pages: 1137-1148, ISSN: 1528-1175
Background. The inert anesthetic gas xenon is neuroprotective in models of brain injury. Weinvestigate the neuroprotective mechanisms of the inert gases xenon, argon, krypton, neon andhelium in an in vitro model of traumatic brain injury.Methods. We use an in vitro model using mouse organotypic hippocampal brain-slices, subjectedto a focal mechanical trauma, with injury quantified by propidium-iodide fluorescence. Patch-clampelectrophysiology is used to investigate the effect of the inert gases on N-methyl-D-aspartate(NMDA)-receptors and TREK-1 channels, two molecular targets likely to play a role inneuroprotection.Results. Xenon(50%) and, to a lesser extent, argon(50%) are neuroprotective against traumaticinjury when applied following injury [xenon 43±1% protection 72hours after injury (N=104); argon30±6% protection (N=44); mean±SEM]. Helium, neon and krypton are devoid of neuroprotectiveeffect. Xenon(50%) prevents development of secondary injury up to 48 hours after trauma.Argon(50%) attenuates secondary injury, but is less effective than xenon [xenon 50±5% reductionin secondary injury 72hours after injury (N=104); argon 34±8% reduction (N=44); mean±SEM].Glycine reverses the neuroprotective effect of xenon, but not argon, consistent with competitiveinhibition at the NMDA receptor glycine-site mediating xenon neuroprotection against traumaticbrain injury. Xenon inhibits NMDA receptors and activates TREK-1 channels, while argon,krypton, neon and helium have no effect on these ion-channels.Conclusions. Xenon neuroprotection against traumatic brain injury can be reversed by elevatingthe glycine concentration, consistent with inhibition at the NMDA-receptor glycine site playing asignificant role in xenon neuroprotection. Argon and xenon do not act via the same mechanism.
Yip GMS, Chen Z-W, Edge CJ, et al., 2013, A propofol binding site on mammalian GABA<sub>A</sub> receptors identified by photolabeling (vol 9, pg 715, 2013), NATURE CHEMICAL BIOLOGY, Vol: 9, ISSN: 1552-4450
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- Citations: 3
Yip GM, Chen ZW, Edge CJ, et al., 2013, A propofol binding site on mammalian GABAA receptors identified by photolabeling, Nature Chemical Biology, Vol: 9, Pages: 715-720, ISSN: 1552-4469
Propofol is the most important intravenous general anesthetic in current clinical use. It acts by potentiating GABAA (γ-aminobutyric acid type A) receptors, but where it binds to this receptor is not known and has been a matter of some debate. We synthesized a new propofol analog photolabeling reagent whose biological activity is very similar to that of propofol. We confirmed that this reagent labeled known propofol binding sites in human serum albumin that have been identified using X-ray crystallography. Using a combination of protiated and deuterated versions of the reagent to label mammalian receptors in intact membranes, we identified a new binding site for propofol in GABAA receptors consisting of both β3 homopentamers and α1β3 heteropentamers. The binding site is located within the β subunit at the interface between the transmembrane domains and the extracellular domain and lies close to known determinants of anesthetic sensitivity in the transmembrane segments TM1 and TM2.
Harris K, Campos-Pires R, Kiru L, et al., 2013, The NMDA receptor glycine site mediates xenon neuroprotection against traumatic brain injury in vitro, British Neuroscience Association Meeting
Geldart CH, McKitrick TJW, Armstrong SP, et al., 2012, Identification of two mutations (F758W & F758Y) in the N-Methyl-D-Aspartate receptor glycine-binding site that selectively prevent competitive inhibition by xenon without affecting glycine binding, Anaesthetic Research Society Meeting, London
Geldart CH, McKitrick TJW, Armstrong SP, et al., 2012, Identification of two mutations (F758W & F758Y) in the N-Methyl-D-Aspartate receptor glycine-binding site that selectively prevent competitive inhibition by xenon without affecting glycine binding, Anaesthetic Reasearch Society Meeting
Armstrong SP, Banks P, McKitrick T, et al., 2012, Mutations in the NMDA receptor glycine site prevent competitive inhibition by xenon without affecting inhibition by sevoflurane or isoflurane, Society for Neuroscsince Meeting, New Orleans
Armstrong SP, Banks PJ, McKitrick TJW, et al., 2012, Identification of two mutations (F758W & F758Y) in the NMDA receptor glycine-binding site that prevent competitive inhibition by xenon without affecting glycine binding, Anesthesiology, Vol: 117, Pages: 38-47, ISSN: 1528-1175
BACKGROUND: Xenon is a general anesthetic with neuroprotective properties. Xenon inhibition at the glycine-binding site of the N-Methyl-D-aspartate (NMDA) receptor mediates xenon neuroprotection against ischemic injury in vitro. Here we identify specific amino acids important for xenon binding to the NMDA receptor, with the aim of finding silent mutations that eliminate xenon binding but leave normal receptor function intact.METHODS:Site-directed mutagenesis was used to mutate specific amino-acids in the GluN1 subunit of rat NMDA receptors. Mutant GluN1/GluN2A receptors were expressed in HEK 293 cells and were assessed functionally using patch-clamp electrophysiology. The responses of the mutant receptors to glycine and anesthetics were determined.RESULTS:Mutation of phenylalanine 758 to an aromatic tryptophan or tyrosine left glycine affinity unchanged, but eliminated xenon binding without affecting the binding of sevoflurane or isoflurane.CONCLUSIONS:These findings confirm xenon binds to the glycine site of the GluN1 subunit of the NMDA receptor and indicate that interactions between xenon and the aromatic ring of the phenylalanine 758 residue are important for xenon binding. Our most important finding is that we have identified two mutations, F758W and F758Y, that eliminate xenon binding to the NMDA receptor glycine site without changing the glycine affinity of the receptor or the binding of volatile anesthetics. The identification of these selective mutations will allow knock-in animals to be used to dissect the mechanism(s) of xenon's neuroprotective and anesthetic properties in vivo.
Banks P, Franks NP, 2011, The NMDA receptor glycine site mediates xenon neuroprotection against hypoxic/ischemic injury, 25th International Symposium on Cerebral Blood Flow, Metabolism & Function, Barcelona
Geldart CH, Banks P, Mckitrick TJW, et al., 2011, A specific amino acid in the glycine-binding site of the N-methyl-D-aspartate receptor is involved in xenon inhibition of the N-methyl-D-aspartate receptor, British Journal of Anaesthesia, Vol: 106
Dickinson R, Franks NP, 2010, Bench-to-bedside review: molecular pharmacology and clinical use of inert gases in anesthesia and neuroprotection, Critical Care, Vol: 14, ISSN: 1364-8535
In the past decade there has been a resurgence of interest in the clinical use of inert gases. In the present paper we review the use of inert gases as anesthetics and neuroprotectants, with particular attention to the clinical use of xenon. We discuss recent advances in understanding the molecular pharmacology of xenon and we highlight specific pharmacological targets that may mediate its actions as an anesthetic and neuroprotectant. We summarize recent in vitro and in vivo studies on the actions of helium and the other inert gases, and discuss their potential to be used as neuroprotective agents.
Banks P, Franks NP, Dickinson R, 2010, Xenon neuroprotection against hypoxia-ischaemia is mediated by the <i>N</i>-methyl-D-aspartate receptor glycine site, Meeting of the Anaesthetic-Research-Society, Publisher: OXFORD UNIV PRESS, Pages: 526-526, ISSN: 0007-0912
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- Citations: 1
Banks P, Franks NP, Dickinson R, 2010, Competitive Inhibition at the Glycine Site of the <i>N</i>-Methyl-D-Aspartate Receptor Mediates Xenon Neuroprotection against Hypoxia-Ischemia, ANESTHESIOLOGY, Vol: 112, Pages: 614-622, ISSN: 0003-3022
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- Citations: 69
Geldart CH, Banks P, McKitrick TJW, et al., 2010, A specific amino acid in the glycine-binding site of the N-methyl-D-aspartate receptor is involved in xenon inhibition of the N-methyl-D-aspartate receptor, Anaesthetic Research Society Meeting
Banks P, Franks NP, Dickinson R, 2010, Xenon neuroprotection against hypoxia-ischemia is mediated by the N-methyl-D-aspartate receptor glycine site, British Journal of Anaesthesia, Vol: 104
Dickinson R, Franks NP, 2010, Molecular Pharmacology of Inert Gases as Anaesthetics and Neuroprotectants, Critical Care, Vol: 14
Banks P, Franks NP, Dickinson R, 2010, Xenon neuroprotection against hypoxic/ischemic injury is mediated by inhibition of the NMDA-receptor at the glycine site, 8th International Conference on Anaesthetic Mechanisms
Banks P, Franks NP, Dickinson R, 2009, Xenon neuroprotection against hypoxia-ischemia is mediated by the NMDA-receptor glycine site, Anesthetic Research Society
Dickinson R, Peterson B, Banks P, et al., 2007, Competitive Inhibition at the Glycine Site of the NMDA Receptor by the Anesthetics Xenon and Isoflurane: Evidence from Molecular Modeling and Electrophysiology, Anesthesiology, Vol: 107, Pages: 756-767
Andres-Enguix I, Caley A, Yustos R, et al., 2007, Determinants of the anesthetic sensitivity of two-pore domain acid-sensitive potassium channels: molecular cloning of an anesthetic-activated potassium channelfrom Lymnaea stagnalis, Journal of Biological Chemistry, Vol: 282, Pages: 20977-20990, ISSN: 0021-9258
White IL, Franks NP, Dickinson R, 2005, Effects of isoflurane and xenon on Ba<SUP>2+</SUP>-currents mediated by N-type calcium channels, BRITISH JOURNAL OF ANAESTHESIA, Vol: 94, Pages: 784-790, ISSN: 0007-0912
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- Citations: 16
Dickinson R, Awaiz S, Whittington MA, et al., 2003, The effects of general anaesthetics on carbachol-evoked gamma oscillations in the rat hippocampus in vitro, NEUROPHARMACOLOGY, Vol: 44, Pages: 864-872, ISSN: 0028-3908
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- Citations: 69
Dickinson R, de Sousa SLM, Lieb WR, et al., 2002, Selective synaptic actions of thiopental and its enantiomers, ANESTHESIOLOGY, Vol: 96, Pages: 884-892, ISSN: 0003-3022
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- Citations: 18
Dickinson R, De Sousa SLM, Lieb WR, et al., 2001, The effects of xenon on NMDA and GABA<inf>A</inf> receptors, Pages: 34-36, ISSN: 0941-4223
Dickinson R, White I, Lieb WR, et al., 2000, Stereoselective loss of righting reflex in rats by isoflurane, ANESTHESIOLOGY, Vol: 93, Pages: 837-843, ISSN: 0003-3022
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- Citations: 37
de Sousa SLM, Dickinson R, Lieb WR, et al., 2000, Contrasting synaptic actions of the inhalational general anesthetics isoflurane and xenon, ANESTHESIOLOGY, Vol: 92, Pages: 1055-1066, ISSN: 0003-3022
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- Citations: 198
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