a-novel-in-vitro-model-of-blast-traumatic-brain-injury

A Novel <em>In Vitro</em> Model of Blast Traumatic Brain Injury

Traumatic brain injury is a leading cause of death and disability in military and civilian populations. Blast traumatic brain injury results from the ...

Imperial College London

For many with Chronic Obstructive Pulmonary Disease (COPD), arterial oxygen saturation while receiving Long-Term Oxygen Therapy (LTOT) falls below an acceptable threshold (SpO(2) < 90%) for extended periods during routine daily activities. Using a closed-loop controller, we have evaluated a simulated method to automatically regulate the oxygen flow-rate in response to the measured oxygen demand.

Oximetry feedback flow control simulation for oxygen therapy.

Inhibition of N-methyl-D-aspartate (NMDA) receptors by anesthetic gases and vapors may play an important role in anesthesia and neuroprotection. However, the site of action of these agents on the NMDA receptor is unknown. The authors show that xenon and isoflurane compete for the binding of the coagonist glycine on the NMDA receptor NR1 subunit.

Competitive inhibition at the glycine site of the N-methyl-D-aspartate receptor by the anesthetics xenon and isoflurane: evidence from molecular modeling and electrophysiology.

The general anesthetic gas xenon is neuroprotective and is undergoing clinical trials as a treatment for ischemic brain injury. A small number of molecular targets for xenon have been identified, the N-methyl-D-aspartate (NMDA) receptor, the two-pore-domain potassium channel TREK-1, and the adenosine triphosphate-sensitive potassium channel (KATP). However, which of these targets are relevant to acute xenon neuroprotection is not known. Xenon inhibits NMDA receptors by competing with glycine at the glycine-binding site. We test the hypothesis that inhibition of the NMDA receptor at the glycine site underlies xenon neuroprotection against hypoxia-ischemia.

Competitive inhibition at the glycine site of the N-methyl-D-aspartate receptor mediates xenon neuroprotection against hypoxia-ischemia.

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.

Bench-to-bedside review: Molecular pharmacology and clinical use of inert gases in anesthesia and neuroprotection.

: Xen&oacute;n es un anest&eacute;sico general con propiedades neuroprotectoras. Inhibici&oacute;n de xen&oacute;n en el sitio de glicina-Uni&oacute;n del receptor N-metil-D-aspartato (NMDA) media xen&oacute;n neuroprotecci&oacute;n contra lesi&oacute;n isqu&eacute;mica in vitro. Aqu&iacute; identificamos amino&aacute;cidos espec&iacute;ficos importantes para el enlace de xen&oacute;n para el receptor NMDA, con el objetivo de encontrar mutaciones silenciosas que eliminan enlace de xen&oacute;n pero dejan intacta la funci&oacute;n normal del receptor.

Identificaci&oacute;n de dos mutaciones (F758W y F758Y) en el sitio de uni&oacute;n a receptores de glicina N-metil-D-aspartato selectivamente evitar inhibici&oacute;n competitiva por xen&oacute;n sin afectar glicina vinculante.

&#xFF1A; &#x6C19;&#x706F;&#x662F;&#x5168;&#x8EAB;&#x9EBB;&#x9189;&#x4E0E;&#x795E;&#x7ECF;&#x4FDD;&#x62A4;&#x5C5E;&#x6027;&#x3002;&#x6C19;&#x6291;&#x5236;&#x7684;&#x7518;&#x6C28;&#x9178;&#x7ED1;&#x5B9A;&#x7AD9;&#x70B9;&#x4E0A;&#x7684; N-&#x7532;&#x57FA;-D-&#x5929;&#x51AC;&#x6C28;&#x9178; (NMDA) &#x53D7;&#x4F53;&#x4ECB;&#x5BFC;&#x6C19;&#x5BF9;&#x4F53;&#x5916;&#x7F3A;&#x8840;&#x6027;&#x635F;&#x4F24;&#x7684;&#x795E;&#x7ECF;&#x4FDD;&#x62A4;&#x4F5C;&#x7528;&#x3002;&#x5728;&#x8FD9;&#x91CC;&#x6211;&#x4EEC;&#x627E;&#x51FA;&#x7279;&#x5B9A;&#x6C28;&#x57FA;&#x9178;&#x91CD;&#x8981;&#x7684;&#x6C19;&#x7ED1;&#x5B9A;&#x5230; NMDA &#x53D7;&#x4F53;&#xFF0C;&#xFF0C;&#x76EE;&#x7684;&#x662F;&#x627E;&#x5230;&#x6C89;&#x9ED8;&#x7684;&#x7A81;&#x53D8;&#xFF0C;&#x6D88;&#x9664;&#x6C19;&#x5177;&#x6709;&#x7EA6;&#x675F;&#x529B;&#xFF0C;&#x4F46;&#x4FDD;&#x7559;&#x6B63;&#x5E38;&#x7684;&#x53D7;&#x4F53;&#x529F;&#x80FD;&#x4E0D;&#x53D8;&#x3002;

N-&#x7532;&#x57FA;-D-&#x5929;&#x51AC;&#x6C28;&#x9178;&#x7518;&#x6C28;&#x9178;&#x53D7;&#x4F53;&#x7ED1;&#x5B9A;&#x7AD9;&#x70B9;&#xFF0C;&#x6709;&#x9009;&#x62E9;&#x6027;&#x5730;&#x9632;&#x6B62;&#x7ADE;&#x4E89;&#x6027;&#x6291;&#x5236;&#x7531;&#x6C19;&#x706F;&#x4E0D;&#x5F71;&#x54CD;&#x7518;&#x6C28;&#x9178;&#x7ED1;&#x5B9A;&#x4E2D;&#x7684;&#x4E24;&#x4E2A;&#x7A81;&#x53D8; &#xFF08;F758W &#x548C; F758Y&#xFF09; &#x7684;&#x6807;&#x8BC6;&#x3002;

: 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.

Identification of Two Mutations (F758W and F758Y) in the N-methyl-D-aspartate Receptor Glycine-binding Site that Selectively Prevent Competitive Inhibition by Xenon without Affecting Glycine Binding.

: Xenon est un anesth&eacute;sique g&eacute;n&eacute;ral avec propri&eacute;t&eacute;s neuroprotectrices. Inhibition du x&eacute;non au site de glycine-liaison du r&eacute;cepteur N-m&eacute;thyl-D-aspartate (NMDA) intervient dans la neuroprotection x&eacute;non contre une l&eacute;sion isch&eacute;mique in vitro. Ici, nous identifions des acides amin&eacute;s importants pour la liaison de x&eacute;non pour le r&eacute;cepteur NMDA, dans le but de trouver des mutations silencieuses qui &eacute;liminent les liaison de x&eacute;non, mais laissent la fonction du r&eacute;cepteur normal intacte.

Identification de deux Mutations (F758W et F758Y) sur le Site de liaison du r&eacute;cepteur Glycine N-m&eacute;thyl-D-aspartate que s&eacute;lectivement &eacute;viter Inhibition comp&eacute;titive par Xenon sans affecter la liaison de Glycine.

: Xenon ist eine Vollnarkose mit neuroprotektive Eigenschaften. Xenon Hemmung an der Glycin-Bindungsstelle des N-Methyl-D-Aspartat (NMDA)-Rezeptors vermittelt Xenon Neuroprotection gegen in-vitro-isch&auml;mische Sch&auml;digung. Hier ermitteln wir bestimmte Aminos&auml;uren wichtig f&uuml;r Xenon Bindung an den NMDA-Rezeptor, mit dem Ziel, der Suche nach Stille Mutationen, die zu beseitigen Xenon Bindung aber normalen Rezeptor-Funktion beizubehalten.

Ermittlung von zwei Mutationen (F758W und F758Y) in die N-Methyl-D-Aspartat Rezeptor Glycin-Bindungsstelle, dass selektiv verhindern kompetitive Hemmung von Xenon ohne Beeintr&auml;chtigung der Glycin-Bindung.

: Xenon &egrave; un anestetico generale con propriet&agrave; neuroprotettive. Inibizione di xeno presso il sito di glicina-legame del recettore N-metil-D-aspartato (NMDA) media xeno neuroprotezione contro la lesione ischemica in vitro. Qui noi identificare specifici amminoacidi importanti per l&#39;associazione allo xeno per il recettore NMDA, con l&#39;obiettivo di trovare mutazioni silenziose che eliminano associazione xenon ma lasciano intatte la funzione normale del recettore.

Identificazione di due mutazioni (F758W e F758Y) nel sito di N-metil-D-aspartato Glycine Receptor-binding che selettivamente evitare inibizione competitiva da Xenon senza associazione di glicina che interessano.

: &#x30AD;&#x30BB;&#x30CE;&#x30F3;&#x5168;&#x8EAB;&#x9EBB;&#x9154;&#x795E;&#x7D4C;&#x4FDD;&#x8B77;&#x7279;&#x6027;&#x3092;&#x6301;&#x3064;&#x3067;&#x3059;&#x3002;&#x30AD;&#x30BB;&#x30CE;&#x30F3;&#x963B;&#x5BB3;&#x30B0;&#x30EA;&#x30B7;&#x30F3; &#x30D0;&#x30A4;&#x30F3;&#x30C7;&#x30A3;&#x30F3;&#x30B0; &#x30B5;&#x30A4;&#x30C8;&#x3067;&#x306E; N-&#x30E1;&#x30C1;&#x30EB;-D-&#x30A2;&#x30B9;&#x30D1;&#x30E9;&#x30AE;&#x30F3;&#x9178; (NMDA) &#x53D7;&#x5BB9;&#x4F53;&#x306E; in vitro &#x865A;&#x306B;&#x5BFE;&#x3059;&#x308B;&#x30AD;&#x30BB;&#x30CE;&#x30F3;&#x795E;&#x7D4C;&#x4FDD;&#x8B77;&#x3092;&#x4EF2;&#x4ECB;&#x3057;&#x307E;&#x3059;&#x3002;&#x3053;&#x3053;&#x3067;&#x30AD;&#x30BB;&#x30CE;&#x30F3; &#x30D0;&#x30A4;&#x30F3;&#x30C9; NMDA &#x53D7;&#x5BB9;&#x4F53;&#x306E;&#x30AD;&#x30BB;&#x30CE;&#x30F3; &#x30D0;&#x30A4;&#x30F3;&#x30C7;&#x30A3;&#x30F3;&#x30B0;&#x3092;&#x6392;&#x9664;&#x3059;&#x308B;&#x304C;&#x3001;&#x901A;&#x5E38;&#x306E;&#x53D7;&#x5BB9;&#x4F53;&#x306E;&#x6A5F;&#x80FD;&#x3092;&#x305D;&#x306E;&#x307E;&#x307E;&#x306B;&#x30B5;&#x30A4;&#x30EC;&#x30F3;&#x30C8;&#x306E;&#x5909;&#x7570;&#x3092;&#x898B;&#x3064;&#x3051;&#x308B;&#x3053;&#x3068;&#x3092;&#x76EE;&#x7684;&#x3068;&#x3059;&#x308B;&#x305F;&#x3081;&#x306B;&#x91CD;&#x8981;&#x306A;&#x7279;&#x5B9A;&#x306E;&#x30A2;&#x30DF;&#x30CE;&#x9178;&#x3092;&#x8B58;&#x5225;&#x3057;&#x307E;&#x3059;&#x3002;

N &#x30E1;&#x30C1;&#x30EB;-D-&#x30A2;&#x30B9;&#x30D1;&#x30E9;&#x30AE;&#x30F3;&#x9178;&#x30B0;&#x30EA;&#x30B7;&#x30F3;&#x53D7;&#x5BB9;&#x4F53;&#x7D50;&#x5408;&#x90E8;&#x4F4D;&#x305D;&#x306E;&#x9078;&#x629E;&#x7684;&#x306B;&#x9632;&#x6B62;&#x7AF6;&#x4E89;&#x306B;&#x3088;&#x308B;&#x963B;&#x5BB3;&#x30AD;&#x30BB;&#x30CE;&#x30F3; &#x30B0;&#x30EA;&#x30B7;&#x30F3; &#x30D0;&#x30A4;&#x30F3;&#x30C7;&#x30A3;&#x30F3;&#x30B0;&#x306B;&#x5F71;&#x97FF;&#x306A;&#x3057;&#x306E; 2 &#x3064;&#x306E;&#x5909;&#x7570; (F758W &#x304A;&#x3088;&#x3073; F758Y) &#x306E; id&#x3002;

: &#xD06C; &#xC138; &#xB17C;&#xC740; &#xC2E0;&#xACBD; &#xBCF4;&#xD638; &#xC18D;&#xC131;&#xC744; &#xAC00;&#xC9C4; &#xC77C;&#xBC18; &#xB9C8; &#xCDE8;. &#xD06C; &#xC138; &#xB17C; &#xC5B5;&#xC81C; &#xAE00;&#xB9AC;&#xC2E0; &#xBC14;&#xC778;&#xB529; &#xC0AC;&#xC774;&#xD2B8;&#xC5D0; N-&#xBA54; &#xD2F8;-D-aspartate (NMDA) &#xC218;&#xC6A9; &#xCCB4;&#xC758; &#xC0DD;&#xCCB4; &#xC678;&#xC5D0;&#xC11C; &#xD5C8; &#xD608; &#xC131; &#xC190;&#xC0C1;&#xC5D0; &#xB300; &#xD55C; &#xC81C; &#xB17C; neuroprotection &#xC911;&#xC7AC;. &#xC5EC;&#xAE30; &#xC6B0;&#xB9AC; &#xC2DD;&#xBCC4; &#xD2B9;&#xC815; &#xC544;&#xBBF8;&#xB178;&#xC0B0; &#xC81C; &#xB17C; &#xBC14;&#xC778;&#xB529; NMDA &#xC218;&#xC6A9; &#xCCB4; &#xD06C; &#xC138; &#xB17C; &#xBC14;&#xC778;&#xB529; &#xC81C;&#xAC70; &#xD558;&#xC9C0;&#xB9CC; &#xC815;&#xC0C1;&#xC801;&#xC778; &#xC218;&#xC6A9; &#xCCB4; &#xAE30;&#xB2A5;&#xC744; &#xADF8;&#xB300;&#xB85C; &#xCE68;&#xBB35; &#xB3CC;&#xC5F0;&#xBCC0;&#xC774; &#xCC3E;&#xB294; &#xAC83;&#xC744; &#xBAA9;&#xC801;&#xC73C;&#xB85C; &#xD558;&#xB294; &#xAC83;&#xC774; &#xC911;&#xC694; &#xD569;&#xB2C8;&#xB2E4;.

N-&#xBA54; &#xD2F8;-D-aspartate &#xAE00;&#xB9AC;&#xC2E0; &#xC218;&#xC6A9; &#xCCB4; &#xBC14;&#xC778;&#xB529; &#xC0AC;&#xC774;&#xD2B8;&#xB294; &#xC120;&#xD0DD;&#xC801;&#xC73C;&#xB85C; &#xBC29;&#xC9C0; &#xACBD;&#xC7C1; &#xC800;&#xD574; &#xAE00;&#xB9AC;&#xC2E0; &#xBC14;&#xC778;&#xB529;&#xC5D0; &#xC601;&#xD5A5;&#xC744; &#xC8FC;&#xC9C0; &#xC54A;&#xACE0; &#xC81C; &#xB17C;&#xC5D0; &#xC758;&#xD574; &#xB450; &#xAC1C;&#xC758; &#xBCC0;&#xC774; (F758W &#xBC0F; F758Y)&#xC758; &#xC2DD;&#xBCC4;.

Hospitals nowadays have to serve numerous patients with limited medical staff and equipment while maintaining healthcare quality. Clinical pathway informatics is regarded as an efficient way to solve a series of hospital challenges. To date, conventional research lacks a mathematical model to describe clinical pathways. Existing vague descriptions cannot fully capture the complexities accurately in clinical pathways and hinders the effective management and further optimization of clinical pathways.

Modelling and performance analysis of clinical pathways using the stochastic process algebra PEPA.

Xenon, the inert anesthetic gas, is neuroprotective in models of brain injury. The authors investigate the neuroprotective mechanisms of the inert gases such as xenon, argon, krypton, neon, and helium in an in vitro model of traumatic brain injury.

Neuroprotection against traumatic brain injury by xenon, but not argon, is mediated by inhibition at the N-methyl-D-aspartate receptor glycine site.

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.

Xenon improves neurologic outcome and reduces secondary injury following trauma in an in vivo model of traumatic brain injury.

Argon: A Noble Foe for Subarachnoid Hemorrhage.

Systems Biology is an approach to biology and medicine that has the potential to lead to a better understanding of how biological properties emerge from the interaction of genes, proteins, molecules, cells and organisms. The approach aims at elucidating how these interactions govern biological function by employing experimental data, mathematical models and computational simulations. As Systems Biology is inherently multidisciplinary, education within this field meets numerous hurdles including departmental barriers, availability of all required expertise locally, appropriate teaching material and example curricula. As university education at the Bachelor's level is traditionally built upon disciplinary degrees, we believe that the most effective way to implement education in Systems Biology would be at the Master's level, as it offers a more flexible framework. Our team of experts and active performers of Systems Biology education suggest here (i) a definition of the skills that students should acquire within a Master's programme in Systems Biology, (ii) a possible basic educational curriculum with flexibility to adjust to different application areas and local research strengths, (iii) a description of possible career paths for students who undergo such an education, (iv) conditions that should improve the recruitment of students to such programmes and (v) mechanisms for collaboration and excellence spreading among education professionals. With the growing interest of industry in applying Systems Biology approaches in their fields, a concerted action between academia and industry is needed to build this expertise. Here we present a reflection of the European situation and expertise, where most of the challenges we discuss are universal, anticipating that our suggestions will be useful internationally. We believe that one of the overriding goals of any Systems Biology education should be a student's ability to phrase and communicate research questions in such a manner that they can be solved by the integration of experiments and modelling, as well as to communicate and collaborate productively across different experimental and theoretical disciplines in research and development.

Strategies for structuring interdisciplinary education in Systems Biology: an European perspective.

The aim of this study was to evaluate the neuroprotective efficacy of the inert gas xenon as a treatment for patients with blast-induced traumatic brain injury in an in vitro laboratory model. We developed a novel blast traumatic brain injury model using C57BL/6N mouse organotypic hippocampal brain-slice cultures exposed to a single shockwave, with the resulting injury quantified using propidium iodide fluorescence. A shock tube blast generator was used to simulate open field explosive blast shockwaves, modeled by the Friedlander waveform. Exposure to blast shockwave resulted in significant (p < 0.01) injury that increased with peak-overpressure and impulse of the shockwave, and which exhibited a secondary injury development up to 72 h after trauma. Blast-induced propidium iodide fluorescence overlapped with cleaved caspase-3 immunofluorescence, indicating that shock-wave-induced cell death involves apoptosis. Xenon (50% atm) applied 1 h after blast exposure reduced injury 24 h (p < 0.01), 48 h (p < 0.05), and 72 h (p < 0.001) later, compared with untreated control injury. Xenon-treated injured slices were not significantly different from uninjured sham slices at 24 h and 72 h. We demonstrate for the first time that xenon treatment after blast traumatic brain injury reduces initial injury and prevents subsequent injury development in vitro. Our findings support the idea that xenon may be a potential first-line treatment for those with blast-induced traumatic brain injury.

Article	Year
Oximetry feedback flow control simulation for oxygen therapy. Journal of clinical monitoring and computing\| PubMed ID: 17205376	2007
Competitive inhibition at the glycine site of the N-methyl-D-aspartate receptor by the anesthetics xenon and isoflurane: evidence from molecular modeling and electrophysiology. Anesthesiology\| PubMed ID: 18073551	2007
Competitive inhibition at the glycine site of the N-methyl-D-aspartate receptor mediates xenon neuroprotection against hypoxia-ischemia. Anesthesiology\| PubMed ID: 20124979	2010
Bench-to-bedside review: Molecular pharmacology and clinical use of inert gases in anesthesia and neuroprotection. Critical care (London, England)\| PubMed ID: 20836899	2010
Identification of Two Mutations (F758W and F758Y) in the N-methyl-D-aspartate Receptor Glycine-binding Site that Selectively Prevent Competitive Inhibition by Xenon without Affecting Glycine... Anesthesiology\| PubMed ID: 22634870	2012
Modelling and performance analysis of clinical pathways using the stochastic process algebra PEPA. BMC bioinformatics\| PubMed ID: 23095226	2012
Neuroprotection against traumatic brain injury by xenon, but not argon, is mediated by inhibition at the N-methyl-D-aspartate receptor glycine site. Anesthesiology\| PubMed ID: 23867231	2013
Xenon improves neurologic outcome and reduces secondary injury following trauma in an in vivo model of traumatic brain injury. Critical care medicine\| PubMed ID: 25188549	2015
Argon: A Noble Foe for Subarachnoid Hemorrhage. Critical care medicine\| PubMed ID: 27309177	2016
Strategies for structuring interdisciplinary education in Systems Biology: an European perspective. NPJ systems biology and applications\| PubMed ID: 28725471	2016
Xenon Protects against Blast-Induced Traumatic Brain Injury in an In Vitro Model. Journal of neurotrauma\| PubMed ID: 29285980	2018

Robert Dickinson

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