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

Royal Berkshire Hospital NHS Foundation Trust

&#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;.

: 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.

Argon: A Noble Foe for Subarachnoid Hemorrhage.

Glycine receptors are important players in pain perception and movement disorders and therefore important therapeutic targets. Glycine receptors can be modulated by the intravenous anaesthetic propofol (2,6-diisopropylphenol). However, the drug is more potent, by at least one order of magnitude, on GABA receptors. It has been proposed that halogenation of the propofol molecule generates compounds with selective enhancement of glycinergic modulatory properties.

Activation and modulation of recombinant glycine and GABA receptors by 4-halogenated analogues of propofol.

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
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
Argon: A Noble Foe for Subarachnoid Hemorrhage. Critical care medicine\| PubMed ID: 27309177	2016
Activation and modulation of recombinant glycine and GABA receptors by 4-halogenated analogues of propofol. British journal of pharmacology\| PubMed ID: 27459129	2016
Xenon Protects against Blast-Induced Traumatic Brain Injury in an In Vitro Model. Journal of neurotrauma\| PubMed ID: 29285980	2018

Christopher J. Edge

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