Unilateral Pyramidotomy of the Corticospinal Tract in Rats for Assessment of Neuroplasticity-inducing Therapies

The corticospinal tract (CST) can be completely severed unilaterally in the medullary pyramids of the rodent brainstem. The CST is a motor tract that has ...

King's College London

&#x8F74;&#x7A81;&#x65E0;&#x6CD5;&#x91CD;&#x65B0;&#x751F;&#x6210;&#x540E;&#x6210;&#x5E74;&#x54FA;&#x4E73;&#x52A8;&#x7269;&#x4E2D;&#x67A2;&#x795E;&#x7ECF;&#x7CFB;&#x7EDF; (CNS) &#x810A;&#x9AD3;&#x635F;&#x4F24;&#x53EF;&#x5BFC;&#x81F4;&#x6C38;&#x4E45;&#x6027;&#x762B;&#x75EA;&#x3002;&#x5728;&#x4E2D;&#x67A2;&#x795E;&#x7ECF;&#x7CFB;&#x7EDF;&#x635F;&#x4F24;&#x7684;&#x5730;&#x76D8;&#xFF0C;&#x80F6;&#x8D28;&#x7622;&#x75D5;&#x5F62;&#x6210;&#x53D1;&#x5C55;&#xFF0C;&#x5305;&#x542B;&#x5305;&#x62EC;&#x786B;&#x9178;&#x8F6F;&#x9AA8;&#x7D20;&#x86CB;&#x767D;&#x805A;&#x7CD6; (CSPGs) &#x7684;&#x7EC6;&#x80DE;&#x5916;&#x57FA;&#x8D28;&#x5206;&#x5B50;&#x3002;CSPGs &#x662F;&#x5230;&#x4F53;&#x5916;&#xFF0C;&#x8F74;&#x7A81;&#x751F;&#x957F;&#x6291;&#x5236;&#x548C;&#x518D;&#x751F;&#x7EA4;&#x7EF4;&#x505C;&#x6B62;&#x5728;&#x4F53;&#x5185; CSPG-&#x4E30;&#x5BCC;&#x7684;&#x5730;&#x533A;&#x3002;&#x5220;&#x9664; CSPG &#x7CD6;&#x80FA;&#x805A;&#x7CD6; &#xFF08;GAG&#xFF09; &#x94FE;&#x6291;&#x5236; CSPG &#x6291;&#x5236;&#x6D3B;&#x6027;&#x3002;&#x82E5;&#x8981;&#x6D4B;&#x8BD5;&#x529F;&#x80FD;&#x7684;&#x5F71;&#x54CD;&#xFF0C;&#x6709;&#x8FB1;&#x4EBA;&#x683C;&#x7684;&#x786B;&#x9178;&#x8F6F;&#x9AA8;&#x7D20; (CS)-&#x538B;&#x5236;&#x810A;&#x9AD3;&#x635F;&#x4F24;&#x540E;&#x6211;&#x4EEC;&#x9001;&#x4EA4;&#x8F6F;&#x9AA8; ABC (ChABC) &#x7684;&#x6210;&#x5E74;&#x5927;&#x9F20;&#x5DF4;&#x80FA;&#x80CC;&#x5217;&#x3002;&#x6211;&#x4EEC;&#x663E;&#x793A; ChABC &#x9798;&#x5185;&#x6CE8;&#x5C04;&#x6CBB;&#x7597;&#x9000;&#x5316; CS GAG &#x5728;&#x53D7;&#x4F24;&#x90E8;&#x4F4D;&#xFF0C;&#x53D7;&#x635F;&#x4F24;&#x7684;&#x795E;&#x7ECF;&#x5143;&#x548C;&#x4FC3;&#x8FDB;&#x7684;&#x518D;&#x751F;&#x7684;&#x90FD;&#x611F;&#x89C9;&#x9884;&#x6D4B;&#x7684;&#x5347;&#x5E8F;&#x548C;&#x964D;&#x5E8F;&#x76AE;&#x8D28;&#x810A;&#x9AD3;&#x675F;&#x795E;&#x7ECF;&#x8F74;&#x7A81;&#x518D;&#x751F;&#x76F8;&#x5173;&#x86CB;&#x767D;&#x589E;&#x9AD8;&#x3002;ChABC &#x6CBB;&#x7597;&#x8FD8;&#x540E;&#x7535;&#x523A;&#x6FC0;&#x76AE;&#x8D28;&#x810A;&#x9AD3;&#x795E;&#x7ECF;&#x5143;&#xFF0C;&#x6062;&#x590D;&#x4EE5;&#x4E0B;&#x75C5;&#x53D8;&#x90E8;&#x4F4D;&#x7684;&#x7A81;&#x89E6;&#x6D3B;&#x52A8;&#x548C;&#x4FC3;&#x8FDB;&#x529F;&#x80FD;&#x6062;&#x590D;&#x7684;&#x81EA;&#x53D1;&#x548C;&#x672C;&#x4F53;&#x611F;&#x53D7;&#x7684;&#x884C;&#x4E3A;&#x3002;&#x6211;&#x4EEC;&#x7684;&#x7814;&#x7A76;&#x7ED3;&#x679C;&#x8868;&#x660E; CSPGs &#x662F;&#x4F53;&#x5185;&#x91CD;&#x8981;&#x7684;&#x6291;&#x5236;&#x5206;&#x5B50;&#xFF0C;&#x5EFA;&#x8BAE;&#x4ED6;&#x4EEC;&#x64CD;&#x7EB5;&#x5C06;&#x6709;&#x52A9;&#x4E8E;&#x4EBA;&#x7C7B;&#x810A;&#x9AD3;&#x635F;&#x4F24;&#x7684;&#x6CBB;&#x7597;&#x3002;

&#x8F6F;&#x9AA8; ABC &#x4FC3;&#x8FDB;&#x810A;&#x9AD3;&#x635F;&#x4F24;&#x540E;&#x7684;&#x529F;&#x80FD;&#x6062;&#x590D;&#x3002;

The inability of axons to regenerate after a spinal cord injury in the adult mammalian central nervous system (CNS) can lead to permanent paralysis. At sites of CNS injury, a glial scar develops, containing extracellular matrix molecules including chondroitin sulphate proteoglycans (CSPGs). CSPGs are inhibitory to axon growth in vitro, and regenerating axons stop at CSPG-rich regions in vivo. Removing CSPG glycosaminoglycan (GAG) chains attenuates CSPG inhibitory activity. To test the functional effects of degrading chondroitin sulphate (CS)-GAG after spinal cord injury, we delivered chondroitinase ABC (ChABC) to the lesioned dorsal columns of adult rats. We show that intrathecal treatment with ChABC degraded CS-GAG at the injury site, upregulated a regeneration-associated protein in injured neurons, and promoted regeneration of both ascending sensory projections and descending corticospinal tract axons. ChABC treatment also restored post-synaptic activity below the lesion after electrical stimulation of corticospinal neurons, and promoted functional recovery of locomotor and proprioceptive behaviours. Our results demonstrate that CSPGs are important inhibitory molecules in vivo and suggest that their manipulation will be useful for treatment of human spinal injuries.

Chondroitinase ABC promotes functional recovery after spinal cord injury.

L&#x26;#39;incapacit&#xE9; des axones &#xE0; se r&#xE9;g&#xE9;n&#xE9;rer apr&#xE8;s une l&#xE9;sion de la moelle &#xE9;pini&#xE8;re au niveau du syst&#xE8;me nerveux des mammif&#xE8;res adultes central (SNC) peut conduire &#xE0; une paralysie permanente. Sur les sites de l&#xE9;sion du SNC, une cicatrice gliale d&#xE9;veloppe, contenant des mol&#xE9;cules de la matrice extracellulaire, y compris de chondro&#xEF;tine sulfate prot&#xE9;oglycanes (CSPG). CSPG sont des inhibiteurs de la croissance axonale in vitro, et les axones s&#x26;#39;arr&#xEA;ter &#xE0; GCEP r&#xE9;gions riches in vivo. Retrait GCEP glycosaminoglycanes (GAG) att&#xE9;nue les cha&#xEE;nes GCEQP activit&#xE9; inhibitrice. Pour tester les effets fonctionnels de la d&#xE9;gradation du sulfate de chondro&#xEF;tine (CS)-GAG apr&#xE8;s l&#xE9;sion de la moelle &#xE9;pini&#xE8;re, nous avons livr&#xE9; chondro&#xEF;tinase ABC (ChABC) pour les colonnes dorsales de rats l&#xE9;s&#xE9;s adultes. Nous montrons que le traitement par voie intrath&#xE9;cale avec ChABC d&#xE9;grad&#xE9; CS-GAG au site de la l&#xE9;sion, une prot&#xE9;ine r&#xE9;gul&#xE9;e &#xE0; la hausse de r&#xE9;g&#xE9;n&#xE9;ration associ&#xE9;e dans les neurones l&#xE9;s&#xE9;s, et la r&#xE9;g&#xE9;n&#xE9;ration des deux ascendants promu projections sensorielles et descendant axones des voies cortico. Traitement ChABC &#xE9;galement restaur&#xE9; l&#x26;#39;activit&#xE9; post-synaptique en dessous de la l&#xE9;sion apr&#xE8;s la stimulation &#xE9;lectrique des neurones cortico, et promu la r&#xE9;cup&#xE9;ration fonctionnelle des comportements locomoteurs et proprioceptives. Nos r&#xE9;sultats d&#xE9;montrent que les CSPGs sont importantes mol&#xE9;cules inhibitrices in vivo et sugg&#xE8;rent que leur manipulation sera utile pour le traitement de l&#x26;#39;homme des l&#xE9;sions m&#xE9;dullaires.

Chondro&#xEF;tinase ABC favorise la r&#xE9;cup&#xE9;ration fonctionnelle apr&#xE8;s un traumatisme m&#xE9;dullaire

Chondroitinase ABC f&#xF6;rdert die Rehabilitation nach einer R&#xFC;ckenmarksverletzung.

L&#39;incapacit&agrave; di assoni di rigenerarsi dopo una lesione del midollo spinale nel nervoso sistema centrale dei mammiferi adulti (CNS) pu&ograve; portare alla paralisi permanente. Ai luoghi della ferita del CNS, si sviluppa una cicatrice gliale, contenenti molecole di matrice extracellulare tra cui condroitina proteoglicani dei solfato (CSPG). CSPG sono inibitori di crescita axon in vitro, e smettere di assoni rigeneranti in regioni ricche di CSPG in vivo. Rimozione di catene di glicosaminoglicano (GAG) CSPG attenua attivit&agrave; inibitoria CSPG. Per testare gli effetti funzionali della degradante Condroitin solfato (CS)-GAG dopo la ferita del midollo spinale, abbiamo consegnato chondroitinase ABC (ChABC) per le colonne dorsali elettivamente dei ratti adulti. Dimostriamo che il trattamento intratecale con ChABC degradati CS-bavaglio al sito di lesione, sovraregolati una rigenerazione-associated protein in neuroni feriti e rigenerazione promosso sia ascendente proiezioni sensoriali e decrescente assoni del tratto corticospinale. ChABC trattamento anche restaurato dei attivit&agrave; di sotto della lesione dopo stimolazione elettrica dei neuroni corticospinale e promosso il recupero funzionale dei comportamenti dell&#39;apparato locomotore e propriocettivi. I nostri risultati dimostrano che CSPG sono importanti molecole inibitorie in vivo e suggeriscono che la loro manipolazione sar&agrave; utile per il trattamento delle lesioni spinali umane.

Chondroitinase ABC promuove il recupero funzionale dopo lesione del midollo spinale.

&#x54FA;&#x4E73;&#x985E;&#x6210;&#x4F53;&#x4E2D;&#x67A2;&#x795E;&#x7D4C;&#x7CFB;&#xFF08;CNS&#xFF09;&#x306B;&#x304A;&#x3051;&#x308B;&#x810A;&#x9AC4;&#x640D;&#x50B7;&#x5F8C;&#x306E;&#x518D;&#x751F;&#x3059;&#x308B;&#x8EF8;&#x7D22;&#x306E;&#x7121;&#x529B;&#x306F;&#x6C38;&#x4E45;&#x9EBB;&#x75FA;&#x306B;&#x3064;&#x306A;&#x304C;&#x308B;&#x53EF;&#x80FD;&#x6027;&#x304C;&#x3042;&#x308A;&#x307E;&#x3059;&#x3002; CNS&#x50B7;&#x5BB3;&#x306E;&#x30B5;&#x30A4;&#x30C8;&#x3067;&#x306F;&#x3001;&#x30B0;&#x30EA;&#x30A2;&#x6027;&#x7622;&#x75D5;&#x306F;&#x3001;&#x30B3;&#x30F3;&#x30C9;&#x30ED;&#x30A4;&#x30C1;&#x30F3;&#x786B;&#x9178;&#x30D7;&#x30ED;&#x30C6;&#x30AA;&#x30B0;&#x30EA;&#x30AB;&#x30F3;&#xFF08;&#x67D4;&#x6BDB;&#xFF09;&#x3092;&#x542B;&#x3080;&#x7D30;&#x80DE;&#x5916;&#x30DE;&#x30C8;&#x30EA;&#x30C3;&#x30AF;&#x30B9;&#x5206;&#x5B50;&#x3092;&#x542B;&#x3080;&#x3001;&#x958B;&#x767A;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x67D4;&#x6BDB;&#x306F;&#x3001;in vitro&#x3067;&#x306E;&#x8EF8;&#x7D22;&#x6210;&#x9577;&#x3092;&#x963B;&#x5BB3;&#x3067;&#x3042;&#x308A;&#x3001;&#x518D;&#x751F;&#x8EF8;&#x7D22;&#x306F;&#x3001;in vivo&#x3067;&#x306E;CSPG&#x30EA;&#x30C3;&#x30C1;&#x9818;&#x57DF;&#x3067;&#x505C;&#x6B62;&#x3057;&#x307E;&#x3059;&#x3002; CSPG&#x30B0;&#x30EA;&#x30B3;&#x30B5;&#x30DF;&#x30CE;&#x30B0;&#x30EA;&#x30AB;&#x30F3;&#xFF08;GAG&#xFF09;&#x9396;&#x3092;&#x524A;&#x9664;&#x3059;&#x308B;&#x3068;&#x3001;&#x963B;&#x5BB3;&#x6D3B;&#x6027;&#x3092;CSPG&#x6E1B;&#x8870;&#x3057;&#x307E;&#x3059;&#x3002;&#x5206;&#x89E3;&#x3059;&#x308B;&#x30B3;&#x30F3;&#x30C9;&#x30ED;&#x30A4;&#x30C1;&#x30F3;&#x786B;&#x9178;&#xFF08;CS&#xFF09;-GAG&#x810A;&#x9AC4;&#x640D;&#x50B7;&#x5F8C;&#x306E;&#x6A5F;&#x80FD;&#x7684;&#x52B9;&#x679C;&#x3092;&#x30C6;&#x30B9;&#x30C8;&#x3059;&#x308B;&#x305F;&#x3081;&#x306B;&#x3001;&#x6211;&#x3005;&#x306F;&#x3001;&#x6210;&#x4F53;&#x30E9;&#x30C3;&#x30C8;&#x306E;&#x75C5;&#x5909;&#x80CC;&#x5074;&#x5217;&#x306B;&#x30B3;&#x30F3;&#x30C9;&#x30ED;&#x30A4;&#x30C1;&#x30CA;&#x30FC;&#x30BC;ABC&#xFF08;ChABC&#xFF09;&#x3092;&#x914D;&#x4FE1;&#x3055;&#x308C;&#x307E;&#x3059;&#x3002;&#x6211;&#x3005;&#x306F;&#x3001;&#x518D;&#x751F;&#x306B;&#x95A2;&#x9023;&#x3057;&#x305F;&#x8CA0;&#x50B7;&#x3057;&#x305F;&#x30CB;&#x30E5;&#x30FC;&#x30ED;&#x30F3;&#x306B;&#x304A;&#x3051;&#x308B;&#x86CB;&#x767D;&#x8CEA;&#x3001;&#x304A;&#x3088;&#x3073;&#x6607;&#x9806;&#x611F;&#x899A;&#x7A81;&#x8D77;&#x3068;&#x964D;&#x9806;&#x306E;&#x76AE;&#x8CEA;&#x810A;&#x9AC4;&#x8DEF;&#x306E;&#x8EF8;&#x7D22;&#x306E;&#x4E21;&#x65B9;&#x3092;&#x4FC3;&#x9032;&#x3057;&#x518D;&#x751F;&#x3092;&#x30A2;&#x30C3;&#x30D7;&#x30EC;&#x30AE;&#x30E5;&#x30EC;&#x30FC;&#x30C8;&#x3055;&#x308C;&#x3001;&#x640D;&#x50B7;&#x90E8;&#x4F4D;&#x3067;ChABC&#x52A3;&#x5316;CS-GAG&#x3068;&#x305D;&#x306E;&#x9AC4;&#x8154;&#x5185;&#x6CBB;&#x7642;&#x3092;&#x793A;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002; ChABC&#x306E;&#x6CBB;&#x7642;&#x306B;&#x3082;&#x76AE;&#x8CEA;&#x795E;&#x7D4C;&#x7D30;&#x80DE;&#x306E;&#x96FB;&#x6C17;&#x523A;&#x6FC0;&#x5F8C;&#x306E;&#x75C5;&#x5909;&#x4E0B;&#x306E;&#x30DD;&#x30B9;&#x30C8;&#x30B7;&#x30CA;&#x30D7;&#x30B9;&#x6D3B;&#x6027;&#x3092;&#x56DE;&#x5FA9;&#x3057;&#x3001;&#x904B;&#x52D5;&#x3068;&#x81EA;&#x5DF1;&#x53D7;&#x5BB9;&#x884C;&#x52D5;&#x306E;&#x6A5F;&#x80FD;&#x56DE;&#x5FA9;&#x3092;&#x4FC3;&#x9032;&#x3057;&#x305F;&#x3002;&#x6211;&#x3005;&#x306E;&#x7D50;&#x679C;&#x306F;&#x67D4;&#x6BDB;&#x304C;&#x751F;&#x4F53;&#x5185;&#x3067;&#x91CD;&#x8981;&#x306A;&#x963B;&#x5BB3;&#x5206;&#x5B50;&#x3067;&#x3042;&#x308A;&#x3001;&#x305D;&#x306E;&#x64CD;&#x4F5C;&#x306F;&#x4EBA;&#x9593;&#x306E;&#x810A;&#x9AC4;&#x640D;&#x50B7;&#x306E;&#x6CBB;&#x7642;&#x306B;&#x6709;&#x7528;&#x3067;&#x3042;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x5506;&#x3057;&#x3066;&#x3044;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x3057;&#x3066;&#x3044;&#x308B;&#x3002;

&#x30B3;&#x30F3;&#x30C9;&#x30ED;&#x30A4;&#x30C1;&#x30CA;&#x30FC;&#x30BC;ABC&#x306F;&#x3001;&#x810A;&#x9AC4;&#x640D;&#x50B7;&#x5F8C;&#x306E;&#x6A5F;&#x80FD;&#x56DE;&#x5FA9;&#x3092;&#x4FC3;&#x9032;&#x3059;&#x308B;

&#xC7AC;&#xC0DD;&#xC131; &#xC131;&#xC778; &#xD3EC;&#xC720;&#xB958; &#xC911;&#xC559; &#xC2E0;&#xACBD; &#xC2DC;&#xC2A4;&#xD15C; (CNS)&#xC5D0;&#xC11C; &#xCC99;&#xC218; &#xC190;&#xC0C1; &#xD6C4; &#xCD95; &#xC0AD;&#xC758; &#xBB34; &#xB2A5;&#xB825;&#xC740; &#xC601;&#xAD6C;&#xC801;&#xC778; &#xB9C8;&#xBE44;&#xB85C; &#xC774;&#xC5B4;&#xC9C8; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;. CNS &#xC0C1;&#xD574;&#xC758; &#xC0AC;&#xC774;&#xD2B8;, &#xAD50; &#xD749;&#xD130;, &#xC138;&#xD3EC; &#xC678; &#xAE30;&#xC9C8; &#xBD84;&#xC790; chondroitin &#xD669;&#xC0B0; &#xC5FC; proteoglycans (CSPGs) &#xB4F1;&#xC774; &#xD3EC;&#xD568; &#xB41C; &#xAC1C;&#xBC1C;. Cspgs&#xB294; &#xC2DC;&#xD5D8;&#xAD00;&#xC5D0;&#xC11C; &#xCD95; &#xC0AD; &#xC131;&#xC7A5; &#xC5B5;&#xC81C; &#xBC0F; &#xC7AC;&#xC0DD; axons CSPG &#xD48D;&#xBD80;&#xD55C; &#xC9C0;&#xC5ED; &#xC0DD;&#xCCB4; &#xC870;&#xAC74;&#xC5D0;&#xC11C; &#xC911;&#xC9C0;. CSPG &#xAE08;&#xC9C0; &#xD65C;&#xB3D9;&#xC744; &#xC57D;&#xD654; CSPG glycosaminoglycan (&#xAC1C; &#xADF8;) &#xCCB4;&#xC778;&#xC744; &#xC81C;&#xAC70; &#xD569;&#xB2C8;&#xB2E4;. Chondroitin &#xD669;&#xC0B0; (CS) &#xC800;&#xD558;&#xC758; &#xAE30;&#xB2A5; &#xD6A8;&#xACFC; &#xD14C;&#xC2A4;&#xD2B8; &#xD558;&#xB824;&#xBA74;-&#xAC1C; &#xADF8; &#xCC99;&#xC218; &#xC190;&#xC0C1; &#xD6C4; &#xC6B0;&#xB9AC; &#xC131;&#xC778; &#xC950;&#xC758; lesioned &#xC9C0; &#xC5F4; chondroitinase ABC (ChABC)&#xC744; &#xC804;&#xB2EC; &#xD569;&#xB2C8;&#xB2E4;. &#xC6B0;&#xB9AC;&#xB294; ChABC intrathecal &#xCE58;&#xB8CC; &#xBD80;&#xC0C1; &#xC0AC;&#xC774;&#xD2B8; upregulated &#xBD80;&#xC0C1;&#xB41C; &#xC2E0;&#xACBD; &#xBC0F; &#xC2B9;&#xACA9;&#xB41C; &#xC911;&#xC0DD; &#xBAA8;&#xB450; &#xAC10;&#xAC01; &#xD504;&#xB85C;&#xC81D;&#xC158; &#xC624;&#xB984;&#xCC28;&#xC21C;&#xACFC; &#xB0B4;&#xB9BC;&#xCC28;&#xC21C; corticospinal&#xB85C; &#xCD95; &#xC0AD;&#xC758; &#xC7AC;&#xC0DD;&#xC5D0; &#xAD00;&#xB828; &#xB41C; &#xB2E8;&#xBC31;&#xC9C8;&#xC5D0;&#xC11C; CS &#xAC1C; &#xADF8; &#xD0C0;&#xB77D;&#xC744; &#xBCF4;&#xC5EC;&#xC90D;&#xB2C8;&#xB2E4;. ChABC &#xCE58;&#xB8CC; &#xB610;&#xD55C; corticospinal &#xB274;&#xB7F0;&#xC758; &#xC804;&#xAE30; &#xC790;&#xADF9; &#xD6C4; &#xBCD1; &#xBCC0; &#xC544;&#xB798; post-synaptic &#xD65C;&#xB3D9;&#xC744; &#xBCF5;&#xC6D0; &#xD558; &#xACE0; &#xC6B4;&#xC804; &#xD558; &#xACE0; &#xACE0;&#xC720;&#xC758; &#xD589;&#xB3D9;&#xC758; &#xAE30;&#xB2A5; &#xD68C;&#xBCF5;&#xC744; &#xCD94;&#xC9C4;. &#xC6B0;&#xB9AC;&#xC758; &#xACB0;&#xACFC; &#xC785;&#xC99D; CSPGs &#xC911;&#xC694; &#xD55C; &#xC5B5;&#xC81C; &#xBD84;&#xC790; &#xC0DD;&#xCCB4; &#xC870;&#xAC74; &#xBC0F; &#xADF8;&#xB4E4;&#xC758; &#xC870;&#xC791; &#xC778;&#xAC04;&#xC758; &#xCC99;&#xCD94; &#xBD80;&#xC0C1;&#xC758; &#xCE58;&#xB8CC;&#xB97C; &#xC704;&#xD574; &#xB354; &#xC720;&#xC6A9;&#xD560; &#xAC83; &#xC774;&#xB2E4;&#xB294; &#xAC83;&#xC774; &#xC88B;&#xC2B5;&#xB2C8;&#xB2E4;.

Chondroitinase ABC &#xCC99;&#xC218; &#xC190;&#xC0C1; &#xD6C4; &#xAE30;&#xB2A5; &#xD68C;&#xBCF5;&#xC744; &#xCD09;&#xC9C4;&#xD569;&#xB2C8;&#xB2E4;.

La incapacidad de los axones pueden regenerarse despu&#xE9;s de una lesi&#xF3;n de la m&#xE9;dula espinal en el adulto de mam&#xED;feros sistema nervioso central (SNC) puede causar par&#xE1;lisis permanente. En los sitios de lesi&#xF3;n del SNC, una cicatriz glial se desarrolla, que contiene mol&#xE9;culas de la matriz extracelular incluyendo los proteoglicanos de sulfato de condroitina (CSPGs). CSPGs son inhibitorio para el crecimiento axonal in vitro, y regeneraci&#xF3;n de los axones parar en CSPG regiones ricas en vivo. Extracci&#xF3;n CSPG glicosaminoglicanos (GAG) aten&#xFA;a las cadenas CSPG actividad inhibitoria. Para probar los efectos funcionales de degradar el sulfato de condroitina (CS)-GAG despu&#xE9;s de una lesi&#xF3;n de la m&#xE9;dula espinal, hemos entregado condroitinasa ABC (ChABC) a las columnas dorsales lesionadas de ratas adultas. Nos muestran que el tratamiento por v&#xED;a intratecal con ChABC degradada CS-GAG en el sitio de la lesi&#xF3;n, upregulated una prote&#xED;na asociada a la regeneraci&#xF3;n de las neuronas lesionadas, y la regeneraci&#xF3;n de promover que las proyecciones ascendentes sensoriales y descendentes axones del tracto corticoespinal. El tratamiento ChABC tambi&#xE9;n restaur&#xF3; despu&#xE9;s de la actividad sin&#xE1;ptica debajo de la lesi&#xF3;n despu&#xE9;s de la estimulaci&#xF3;n el&#xE9;ctrica de las neuronas corticoespinal, y la recuperaci&#xF3;n funcional de promover comportamientos locomotores y propioceptiva. Nuestros resultados demuestran que CSPGs son importantes mol&#xE9;culas inhibidoras in vivo y sugieren que su manipulaci&#xF3;n ser&#xE1; &#xFA;til para el tratamiento de lesiones de la m&#xE9;dula humana.

Condroitinasa ABC promueve la recuperaci&#xF3;n funcional despu&#xE9;s de una lesi&#xF3;n de la m&#xE9;dula espinal

&#x5F88;&#x591A;&#x786B;&#x9178;&#x8F6F;&#x9AA8;&#x7D20;&#x86CB;&#x767D;&#x805A;&#x7CD6; (CSPGs) &#x8868;&#x660E;&#xFF0C;&#x5F71;&#x54CD;&#x4E2D;&#x67A2;&#x795E;&#x7ECF;&#x7CFB;&#x7EDF;&#x8F74;&#x7A81;&#x751F;&#x957F;&#x5728;&#x4F53;&#x5916;&#x548C;&#x4F53;&#x5185;&#x3002;&#x901A;&#x8FC7;&#x6838;&#x5FC3;&#x86CB;&#x767D;&#x6216;&#x786B;&#x9178;&#x8F6F;&#x9AA8;&#x7D20; (CS) &#x7CD6;&#x80FA;&#x805A;&#x7CD6; &#xFF08;GAG&#xFF09; &#x4FA7;&#x94FE;&#xFF0C;&#x53EF;&#x4EE5;&#x4ECB;&#x5BFC;&#x8FD9;&#x4E9B;&#x4EA4;&#x4E92;&#x4F5C;&#x7528;&#x3002;&#x6211;&#x4EEC;&#x4EE5;&#x524D;&#x6240;&#x793A;&#x6709;&#x8FB1;&#x4EBA;&#x683C;&#x7684; CS &#x538B;&#x5236;&#x4FA7;&#x94FE;&#x4F7F;&#x7528;&#x8F6F;&#x9AA8; ABC &#x589E;&#x5F3A;&#x4F53;&#x5185;&#x591A;&#x5DF4;&#x80FA;&#x9ED1;&#x8D28;&#x7EB9;&#x72B6;&#x4F53;&#x8F74;&#x7A81;&#x518D;&#x751F;&#x3002;&#x6211;&#x4EEC;&#x6D4B;&#x8BD5;&#x7684;&#x5047;&#x8BBE;&#x5E72;&#x6270;&#x5B8C;&#x6574; CSPGs &#x8FD8;&#x9650;&#x5236;&#x8F74;&#x7A81;&#x751F;&#x957F;&#x7684;&#x5B9E;&#x9A8C;&#x7814;&#x7A76;&#x3002;Neurocan&#x3001; versican&#x3001; &#x86CB;&#x767D;&#x805A;&#x7CD6;&#xFF0C;&#x4E0A;&#x8C03; CSPGs &#x53EF;&#x4EE5;&#x56FA;&#x5B9A;&#x5728;&#x7EC6;&#x80DE;&#x5916;&#x57FA;&#x8D28;&#x5185;&#x901A;&#x8FC7;&#x7ED1;&#x5B9A;&#x5230;&#x900F;&#x660E;&#x8D28;&#x9178;&#x7CD6;&#x80FA;&#x805A;&#x7CD6;&#x3002;&#x6211;&#x4EEC;&#x68C0;&#x67E5;&#x662F;&#x5426;&#x4F7F;&#x7528;&#x900F;&#x660E;&#x8D28;&#x9178;&#x9176;&#x900F;&#x660E;&#x8D28;&#x9178;&#x7684;&#x9000;&#x5316;&#x53EF;&#x80FD;&#x91CA;&#x653E;&#x8FD9;&#x4E9B;&#x6291;&#x5236; CSPGs &#x4ECE;&#x7EC6;&#x80DE;&#x5916;&#x57FA;&#x8D28;&#xFF0C;&#x4ECE;&#x800C;&#x52A0;&#x5F3A;&#x5207;&#x9ED1;&#x8D28;&#x7EB9;&#x72B6;&#x4F53;&#x795E;&#x7ECF;&#x8F74;&#x7A81;&#x518D;&#x751F;&#x3002;&#x9EBB;&#x9189;&#x7684;&#x6210;&#x5E74;&#x5927;&#x9F20;&#x5207;&#x5200;&#x5207;&#x7684;&#x53F3;&#x534A;&#x8111;&#x9ED1;&#x8D28;&#x7EB9;&#x72B6;&#x4F53;&#x547C;&#x5438;&#x9053;&#x75C5;&#x53D8;&#x53CA;&#x7618;&#x6709;&#x62C5;&#x4FDD; transcranially &#x4ECE;&#x800C;&#x5141;&#x8BB8;&#x91CD;&#x590D;&#x7684;&#x5468;&#x56F4;&#x704C;&#x6CE8;&#x7684;&#x76D0;&#x6C34;&#x6216;&#x751F;&#x7406;&#x76D0;&#x6C34;&#x542B;&#x6709;&#x900F;&#x660E;&#x8D28;&#x9178;&#x9176;&#x540E;&#x6BCF;&#x65E5;&#x7684; 10 &#x5929;&#x540E;&#x5207;&#x65AD;&#x3002;&#x5341;&#x4E00;&#x5929; post-transection &#x4ECE;&#x7EC8;&#x7AEF;&#x9EBB;&#x9189;&#x4E0B;&#x52A8;&#x7269;&#x7684;&#x5927;&#x8111;&#x88AB;&#x5BFB;&#x56DE;&#x7684;&#x7EC4;&#x7EC7;&#x5B66;&#x8BC4;&#x4EF7;&#x3002;&#xFF08;&#x76F8;&#x5BF9;&#x4E8E;&#x6E0D;) &#x900F;&#x660E;&#x8D28;&#x9178;&#x9176;&#x6CBB;&#x7597;&#x540E;&#x5728; neurocan &#x548C; versican &#x5468;&#x56F4;&#x514D;&#x75AB;&#x53CD;&#x5E94;&#x4E2D;&#x63A8;&#x65AD;&#x51FA;&#x89C2;&#x5BDF;&#x5230;&#x7684;&#x51CF;&#x5C11;&#x6709;&#x6548;&#x4EA4;&#x4ED8;&#x7684;&#x5B9E;&#x8D28;&#x5185;&#x5BB9;&#x3002;&#x4F7F;&#x7528;&#x6297;&#x4F53;&#x916A;&#x6C28;&#x9178;&#x7F9F;&#x5316;&#x9176;&#x7684;&#x5E94;&#x7528;&#x7528;&#x6765;&#x68C0;&#x67E5;&#x5207;&#x591A;&#x5DF4;&#x80FA;&#x9ED1;&#x8D28;&#x795E;&#x7ECF;&#x5143;&#x7684;&#x53CD;&#x5E94;&#x3002;&#x540E;&#x6A2A;&#x65AD;&#x548C;&#x751F;&#x7406;&#x76D0;&#x6C34;&#x6CBB;&#x7597;&#xFF0C;&#x9ED1;&#x8D28;&#x591A;&#x5DF4;&#x80FA;&#x80FD;&#x795E;&#x7ECF;&#x5143;&#x53D1;&#x82BD;&#x661F;&#x5F62;&#x80F6;&#x8D28;&#x7EC6;&#x80DE;&#x3001; neurocan &#x548C; versican &#x7F3A;&#x4E4F;&#x7684;&#x5730;&#x533A;&#x3002;&#x8F74;&#x7A81;&#x786E;&#x5B9E;&#x4E0D;&#x518D;&#x751F;&#x5230;&#x661F;&#x5F62;&#x80F6;&#x8D28;&#x7EC6;&#x80DE;&#x548C;&#x4E30;&#x5BCC;&#x7684; neurocan &#x548C; versican &#x6240;&#x8F7D;&#x7684;&#x75C5;&#x53D8;&#x73AF;&#x7ED5;&#x3002;&#x6A2A;&#x65AD;&#x548C;&#x900F;&#x660E;&#x8D28;&#x9178;&#x9176;&#x6CBB;&#x7597;&#x540E;, &#x88AB;&#x5207;&#x591A;&#x5DF4;&#x80FA;&#x9ED1;&#x8D28;&#x8F74;&#x7A81;&#x751F;&#x957F; 800 microm &#x524D;&#x6A2A;&#x65AD;&#x7684;&#x7AD9;&#x70B9;&#x7684;&#x6570;&#x76EE;&#x663E;&#x8457;&#x589E;&#x52A0;&#x3002;&#x4F46;&#x662F;&#xFF0C;&#x5207;&#x591A;&#x5DF4;&#x80FA;&#x9ED1;&#x8D28;&#x8F74;&#x7A81;&#x4ECD;&#x6CA1;&#x6709;&#x4E0D;&#x91CD;&#x65B0;&#x751F;&#x6210;&#x6240;&#x8F7D;&#x7684;&#x75C5;&#x53D8;&#x73AF;&#x7ED5;&#x5230;&#x51CF;&#x5C11; &#xFF08;&#x5C3D;&#x7BA1;&#x6B8B;&#x4F59;) neurocan &#x548C; versican &#x7684;&#x514D;&#x75AB;&#x53CD;&#x5E94;&#x3002;&#x56E0;&#x6B64;&#xFF0C;&#x90E8;&#x5206;&#x9000;&#x5316;&#x7684;&#x900F;&#x660E;&#x8D28;&#x9178;&#x3001; &#x786B;&#x9178;&#x8F6F;&#x9AA8;&#x7D20;&#x548C;&#x900F;&#x660E;&#x8D28;&#x9178;&#x7ED1;&#x5B9A; CSPGs &#x8017;&#x635F;&#x589E;&#x5F3A;&#x4E86;&#x672C;&#x5730;&#x53D1;&#x82BD;&#x7684;&#x795E;&#x7ECF;&#x8F74;&#x7A81;&#xFF0C;CNS &#x5207;&#x4F46;&#x957F;&#x9014;&#x518D;&#x751F;&#x5931;&#x8D25;&#x5730;&#x533A;&#x542B;&#x6B8B;&#x4F59;&#x900F;&#x660E;&#x8D28;&#x9178;&#x7ED1;&#x5B9A; CSPGs.&#x900F;&#x660E;&#x8D28;&#x9178;&#x3001; &#x786B;&#x9178;&#x8F6F;&#x9AA8;&#x7D20;&#x548C;&#x900F;&#x660E;&#x8D28;&#x9178;&#x7ED1;&#x5B9A; CSPGs &#x56E0;&#x6B64;&#x53EF;&#x80FD;&#x6709;&#x52A9;&#x4E8E;&#x81EA;&#x53D1;&#x8F74;&#x7A81;&#x518D;&#x751F;&#x7684;&#x53D7;&#x4F24;&#x6210;&#x5E74;&#x54FA;&#x4E73;&#x52A8;&#x7269;&#x8111;&#x548C;&#x810A;&#x9AD3;&#x4E2D;&#x7684;&#x5931;&#x8D25;&#x3002;

&#x6210;&#x5E74;&#x5927;&#x9F20;&#x8111;&#x4E0E;&#x900F;&#x660E;&#x8D28;&#x9178;&#x9176;&#x6CBB;&#x7597;&#x540E;&#x7684;&#x65AD;&#x6307;&#x4E2D;&#x67A2;&#x795E;&#x7ECF;&#x7CFB;&#x7EDF;&#x795E;&#x7ECF;&#x8F74;&#x7A81;&#x7684;&#x589E;&#x957F;&#x6709;&#x9650;&#x3002;

Many chondroitin sulfate proteoglycans (CSPGs) have been shown to influence CNS axon growth in vitro and in vivo. These interactions can be mediated through the core protein or through the chondroitin sulfate (CS) glycosaminoglycan (GAG) side chains. We have shown previously that degrading CS GAG side chains using chondroitinase ABC enhances dopaminergic nigrostriatal axon regeneration in vivo. We test the hypothesis that interfering with complete CSPGs also limit axon growth in vivo. Neurocan, versican, aggrecan, and brevican CSPGs may be anchored within extracellular matrix through binding to hyaluronan glycosaminoglycan. We examine whether degradation of hyaluronan using hyaluronidase might release these inhibitory CSPGs from the extracellular matrix and thereby enhance regeneration of cut nigrostriatal axons. Anesthetized adult rats were given knife cut lesions of the right hemisphere nigrostriatal tract and cannulae were secured transcranially thereby allowing repeated perilesional infusion of saline or saline containing hyaluronidase once daily for 10 days post-axotomy. Eleven days post-transection brains from animals under terminal anesthesia were recovered for histological evaluation. Effective delivery of substance was inferred from the observed reduction in perilesional immunoreactivity for neurocan and versican after treatment with hyaluronidase (relative to saline). Immunolabeling using antibodies against tyrosine hydroxylase was used to examine the response of cut dopaminergic nigral neurons. After transection and treatment with saline, dopaminergic nigral neurons sprouted in a region lacking astrocytes, neurocan and versican. Axons did not regenerate into the lesion surround that contained astrocytes and abundant neurocan and versican. After transection and treatment with hyaluronidase, there was a significant increase in the number of cut dopaminergic nigral axons growing up to 800 microm anterior to the site of transection. However, cut dopaminergic nigral axons still did not regenerate into the lesion surround that contained reduced (albeit residual) neurocan and versican immunoreactivity. Thus, partial degradation of hyaluronan and chondroitin sulfate and depletion of hyaluronan-binding CSPGs enhances local sprouting of cut CNS axons, but long-distance regeneration fails in regions containing residual hyaluronan-binding CSPGs. Hyaluronan, chondroitin sulfate and hyaluronan-binding CSPGs therefore likely contribute toward the failure of spontaneous axon regeneration in the injured adult mammalian brain and spinal cord.

Limited growth of severed CNS axons after treatment of adult rat brain with hyaluronidase.

Beaucoup de prot&#xE9;oglycanes chondro&#xEF;tine sulfate (CSPG) ont &#xE9;t&#xE9; montr&#xE9; pour influencer la croissance des axones du SNC in vitro et in vivo. Ces interactions peuvent &#xEA;tre m&#xE9;di&#xE9;e par la prot&#xE9;ine de base ou par le sulfate de chondro&#xEF;tine (CS) cha&#xEE;nes de glycosaminoglycanes (GAG secondaires). Nous avons montr&#xE9; pr&#xE9;c&#xE9;demment que la d&#xE9;gradation des cha&#xEE;nes lat&#xE9;rales CS GAG utilisant chondro&#xEF;tinase ABC am&#xE9;liore dopaminergique nigro la r&#xE9;g&#xE9;n&#xE9;ration des axones in vivo. Nous testons l&#x26;#39;hypoth&#xE8;se que l&#x26;#39;interf&#xE9;rence avec les CSPGs complets aussi limiter la croissance des axones in vivo. Neurocan, versicane, aggr&#xE9;cane et CSPGs BREVICAN peut &#xEA;tre ancr&#xE9;e au sein de la matrice extracellulaire se liant &#xE0; l&#x26;#39;acide hyaluronique glycosaminoglycane. Nous examinons si la d&#xE9;gradation de l&#x26;#39;acide hyaluronique en utilisant la hyaluronidase peut lib&#xE9;rer ces CSPGs inhibiteurs de la matrice extracellulaire et d&#x26;#39;am&#xE9;liorer ainsi la r&#xE9;g&#xE9;n&#xE9;ration des axones coup&#xE9;s nigrostriataux. Rats adultes anesth&#xE9;si&#xE9;s ont &#xE9;t&#xE9; donn&#xE9;s l&#xE9;sions Cut Knife de l&#x26;#39;h&#xE9;misph&#xE8;re droit nigrostriatal voies et des canules ont &#xE9;t&#xE9; fix&#xE9;s transcranially permettant ainsi r&#xE9;p&#xE9;t&#xE9; perfusion p&#xE9;ri-l&#xE9;sionnelle de la hyaluronidase contenant une solution saline ou une solution saline une fois par jour pendant 10 jours post-axotomie. Onze jours apr&#xE8;s transsection cerveaux des animaux sous anesth&#xE9;sie terminale ont &#xE9;t&#xE9; r&#xE9;cup&#xE9;r&#xE9;s pour l&#x26;#39;&#xE9;valuation histologique. La prestation efficace de la substance a &#xE9;t&#xE9; d&#xE9;duite de la r&#xE9;duction observ&#xE9;e de la immunor&#xE9;activit&#xE9; p&#xE9;ril&#xE9;sionnel pour neurocan et versicane apr&#xE8;s le traitement avec l&#x26;#39;hyaluronidase (par rapport &#xE0; une solution saline). Immunomarquage utilisant des anticorps contre la tyrosine hydroxylase a &#xE9;t&#xE9; utilis&#xE9; pour examiner la r&#xE9;ponse des neurones dopaminergiques de coupe nigrales. Apr&#xE8;s r&#xE9;section et le traitement avec du s&#xE9;rum physiologique, les neurones dopaminergiques nigrales germ&#xE9; dans une r&#xE9;gion d&#xE9;pourvue astrocytes, neurocan et versicane. Les axones ne se r&#xE9;g&#xE9;n&#xE8;rent pas dans l&#x26;#39;encadrement des l&#xE9;sions que les astrocytes contenues et abondante neurocan et versicane. Apr&#xE8;s r&#xE9;section et le traitement avec de la hyaluronidase, il y avait une augmentation significative du nombre d&#x26;#39;axones coup&#xE9;s nigrales dopaminergiques qui grandissent &#xE0; 800 microm ant&#xE9;rieure sur le site de la section transversale. Cependant, couper dopaminergiques axones nigrales n&#x26;#39;a toujours pas se r&#xE9;g&#xE9;n&#xE9;rer dans l&#x26;#39;encadrement l&#xE9;sion qui contenait r&#xE9;duite (quoique r&#xE9;siduelle) neurocan et immunor&#xE9;activit&#xE9; versicane. Ainsi, la d&#xE9;gradation partielle de sulfate de chondro&#xEF;tine et l&#x26;#39;acide hyaluronique et de l&#x26;#39;appauvrissement de l&#x26;#39;hyaluronane contraignantes CSPGs am&#xE9;liore locale pousse des axones du SNC coup&#xE9;es, mais &#xE0; longue distance de r&#xE9;g&#xE9;n&#xE9;ration &#xE9;choue dans les r&#xE9;gions contenant des r&#xE9;sidus hyaluronane contraignantes CSPG. L&#x26;#39;acide hyaluronique, chondro&#xEF;tine sulfate et l&#x26;#39;acide hyaluronique CSPGs contraignant donc probable contribuer &#xE0; l&#x26;#39;&#xE9;chec de la r&#xE9;g&#xE9;n&#xE9;ration des axones spontan&#xE9;e dans le cerveau adulte des mammif&#xE8;res bless&#xE9;s et la moelle &#xE9;pini&#xE8;re.

Croissance limit&#xE9;e des axones du SNC Severed Apr&#xE8;s traitement du cerveau de rat adulte avec hyaluronidase

Begrenztes Wachstum von abgetrennten ZNS Axone nach der Behandlung von Gehirn einer erwachsenen Ratte mit Hyaluronidase.

Molti dei proteoglicani Condroitin solfato (CSPG) hanno dimostrati di influenzare la crescita di assoni CNS in vitro e in vivo. Queste interazioni possono essere mediate attraverso la proteina core o le catene laterali di glicosaminoglicano (GAG) Condroitin solfato (CS). Abbiamo dimostrato in precedenza che degradante CS GAG catene laterali utilizzando chondroitinase ABC migliora dopaminergico Sonografia rigenerazione assone in vivo. Ci prova l&#39;ipotesi che anche interferire con completa CSPG limitare assone crescita in vivo. Neurocan, versicano, aggrecan e brevican CSPG possono essere ancorati all&#39;interno della matrice extracellulare tramite l&#39;associazione di acido ialuronico glicosaminoglicano. Esaminiamo se la degradazione dell&#39;acido ialuronico utilizzando ialuronidasi potrebbe rilasciare questi CSPG inibitoria da matrice extracellulare e quindi migliorare la rigenerazione degli assoni Sonografia tagliato. Ratti anestetizzati adulti erano dato coltello tagliata le lesioni del tratto Sonografia emisfero destro e cannule sono stati garantiti transcranially consentendo in tal modo regioni ripetute infusione di soluzione fisiologica o di soluzione fisiologica contenente ialuronidasi una volta al giorno per 10 giorni post-axotomy. Undici giorni di cervello post-transection da animali sotto anestesia terminale sono stati recuperati per la valutazione istologica. Effettiva consegna della sostanza &egrave; stato dedotto dalla riduzione osservata in regioni immunoreattivit&agrave; per neurocan e versicano dopo trattamento con ialuronidasi (rispetto alla soluzione fisiologica). Immunomarcatura usando gli anticorpi contro la tirosina idrossilasi &egrave; stato utilizzato per esaminare la risposta di taglio dopaminergico neuroni nigral. Dopo il trattamento con soluzione fisiologica e transezione, Neuroni dopaminergici nigral germogliato in una regione mancano gli astrociti, neurocan e versicano. Assoni non ha fatto rigenerare in surround la lesione che conteneva gli astrociti e abbondanti neurocan e versicano. Dopo transezione e trattamento con ialuronidasi, c&#39;&egrave; stato un aumento significativo del numero di taglio dopaminergico nigral assoni crescono fino a 800 microm situata davanti al sito di transezione. Tuttavia, taglio dopaminergico nigral assoni ancora non rigenerato in surround la lesione che conteneva ridotto (quantunque residuali) neurocan e versicano immunoreattivit&agrave;. Cos&igrave;, parziale degradazione dell&#39;acido ialuronico e Condroitin solfato e impoverimento di acido ialuronico-associazione CSPG migliora la germinazione locale di tagliati assoni CNS, ma interurbano rigenerazione fallisce in regioni contenenti residui hyaluronan binding CSPG. Hyaluronan, Condroitin solfato e acido ialuronico-associazione CSPG quindi probabilmente contribuire verso il fallimento della rigenerazione spontanea assone nel cervello dei mammiferi adulti ferito e del midollo spinale.

Limitata crescita degli assoni CNS mozzate dopo trattamento del cervello del ratto adulto con ialuronidasi.

&#x591A;&#x304F;&#x306E;&#x30B3;&#x30F3;&#x30C9;&#x30ED;&#x30A4;&#x30C1;&#x30F3;&#x786B;&#x9178;&#x30D7;&#x30ED;&#x30C6;&#x30AA;&#x30B0;&#x30EA;&#x30AB;&#x30F3;&#xFF08;&#x67D4;&#x6BDB;&#xFF09;&#x306F;&#x3001;in vitro&#x304A;&#x3088;&#x3073;in vivo&#x306E;CNS&#x8EF8;&#x7D22;&#x306E;&#x6210;&#x9577;&#x306B;&#x5F71;&#x97FF;&#x3092;&#x53CA;&#x307C;&#x3059;&#x3053;&#x3068;&#x304C;&#x793A;&#x3055;&#x308C;&#x3066;&#x3044;&#x308B;&#x3002;&#x3053;&#x308C;&#x3089;&#x306E;&#x76F8;&#x4E92;&#x4F5C;&#x7528;&#x306F;&#x3001;&#x30B3;&#x30A2;&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;&#x3092;&#x4ECB;&#x3057;&#x3066;&#x3001;&#x307E;&#x305F;&#x306F;&#x30B3;&#x30F3;&#x30C9;&#x30ED;&#x30A4;&#x30C1;&#x30F3;&#x786B;&#x9178;&#xFF08;CS&#xFF09;&#x30B0;&#x30EA;&#x30B3;&#x30B5;&#x30DF;&#x30CE;&#x30B0;&#x30EA;&#x30AB;&#x30F3;&#xFF08;GAG&#xFF09;&#x5074;&#x9396;&#x3092;&#x4ECB;&#x3057;&#x3066;&#x5A92;&#x4ECB;&#x3055;&#x308C;&#x308B;&#x3053;&#x3068;&#x304C;&#x3067;&#x304D;&#x307E;&#x3059;&#x3002;&#x6211;&#x3005;&#x306F;&#x3001;&#x30B3;&#x30F3;&#x30C9;&#x30ED;&#x30A4;&#x30C1;&#x30CA;&#x30FC;&#x30BC;ABC&#x3092;&#x7528;&#x3044;&#x3066;&#x5206;&#x89E3;&#x3059;&#x308B;CS&#x306E;GAG&#x5074;&#x9396;&#x304C;&#x751F;&#x4F53;&#x5185;&#x3067;&#x30C9;&#x30FC;&#x30D1;&#x30DF;&#x30F3;&#x4F5C;&#x52D5;&#x6027;&#x9ED2;&#x8CEA;&#x7DDA;&#x6761;&#x4F53;&#x8EF8;&#x7D22;&#x306E;&#x518D;&#x751F;&#x3092;&#x9AD8;&#x3081;&#x308B;&#x3053;&#x3068;&#x304C;&#x4EE5;&#x524D;&#x306B;&#x793A;&#x3055;&#x308C;&#x3066;&#x3044;&#x308B;&#x3002;&#x6211;&#x3005;&#x306F;&#x5B8C;&#x5168;&#x306B;&#x67D4;&#x6BDB;&#x306B;&#x5E72;&#x6E09;&#x3059;&#x308B;&#x3053;&#x3068;&#x3082;&#x3001;in vivo&#x3067;&#x306E;&#x8EF8;&#x7D22;&#x306E;&#x6210;&#x9577;&#x3092;&#x5236;&#x9650;&#x3059;&#x308B;&#x3068;&#x3044;&#x3046;&#x4EEE;&#x8AAC;&#x3092;&#x30C6;&#x30B9;&#x30C8;&#x3057;&#x307E;&#x3059;&#x3002;&#x30CB;&#x30E5;&#x30FC;&#x30ED;&#x3001;&#x30D0;&#x30FC;&#x30B7;&#x30AB;&#x30F3;&#x3001;&#x30A2;&#x30B0;&#x30EA;&#x30AB;&#x30F3;&#x3001;&#x304A;&#x3088;&#x3073;&#x30D6;&#x30EC;&#x30D3;&#x30AB;&#x30F3;&#x67D4;&#x6BDB;&#x306F;&#x3001;&#x30D2;&#x30A2;&#x30EB;&#x30ED;&#x30F3;&#x9178;&#x30B0;&#x30EA;&#x30B3;&#x30B5;&#x30DF;&#x30CE;&#x30B0;&#x30EA;&#x30AB;&#x30F3;&#x3078;&#x306E;&#x7D50;&#x5408;&#x3092;&#x4ECB;&#x3057;&#x3066;&#x7D30;&#x80DE;&#x5916;&#x30DE;&#x30C8;&#x30EA;&#x30C3;&#x30AF;&#x30B9;&#x5185;&#x306B;&#x56FA;&#x5B9A;&#x3055;&#x308C;&#x308B;&#x3053;&#x3068;&#x304C;&#x3042;&#x308A;&#x307E;&#x3059;&#x3002;&#x6211;&#x3005;&#x306F;&#x3001;&#x30D2;&#x30A2;&#x30EB;&#x30ED;&#x30CB;&#x30C0;&#x30FC;&#x30BC;&#x3092;&#x4F7F;&#x7528;&#x3057;&#x3066;&#x30D2;&#x30A2;&#x30EB;&#x30ED;&#x30F3;&#x9178;&#x306E;&#x5206;&#x89E3;&#x306F;&#x7D30;&#x80DE;&#x5916;&#x30DE;&#x30C8;&#x30EA;&#x30C3;&#x30AF;&#x30B9;&#x304B;&#x3089;&#x3053;&#x308C;&#x3089;&#x306E;&#x963B;&#x5BB3;&#x67D4;&#x6BDB;&#x3092;&#x89E3;&#x653E;&#x3057;&#x3001;&#x305D;&#x308C;&#x306B;&#x3088;&#x3063;&#x3066;&#x30AB;&#x30C3;&#x30C8;&#x9ED2;&#x8CEA;&#x7DDA;&#x6761;&#x4F53;&#x8EF8;&#x7D22;&#x306E;&#x518D;&#x751F;&#x3092;&#x5411;&#x4E0A;&#x3055;&#x305B;&#x308B;&#x53EF;&#x80FD;&#x6027;&#x304C;&#x3042;&#x308B;&#x304B;&#x3069;&#x3046;&#x304B;&#x3092;&#x8ABF;&#x3079;&#x307E;&#x3059;&#x3002;&#x9EBB;&#x9154;&#x6210;&#x4F53;&#x30E9;&#x30C3;&#x30C8;&#x306F;&#x3001;&#x53F3;&#x534A;&#x7403;&#x9ED2;&#x8CEA;&#x7DDA;&#x6761;&#x4F53;&#x8DEF;&#x3068;&#x30AB;&#x30CB;&#x30E5;&#x30FC;&#x30EC;&#x306E;&#x30CA;&#x30A4;&#x30D5;&#x30AB;&#x30C3;&#x30C8;&#x75C5;&#x5909;&#x306F;10&#x65E5;&#x5F8C;&#x306E;&#x8EF8;&#x7D22;&#x5207;&#x65AD;&#x306E;&#x305F;&#x3081;&#x306B;&#x4E00;&#x65E5;&#x4E00;&#x56DE;&#x751F;&#x7406;&#x98DF;&#x5869;&#x6C34;&#x307E;&#x305F;&#x306F;&#x751F;&#x7406;&#x98DF;&#x5869;&#x6C34;&#x3092;&#x542B;&#x3080;&#x30D2;&#x30A2;&#x30EB;&#x30ED;&#x30CB;&#x30C0;&#x30FC;&#x30BC;&#x306E;&#x7E70;&#x308A;&#x8FD4;&#x3057;&#x75C5;&#x5909;&#x90E8;&#x5468;&#x56F2;&#x306E;&#x6CE8;&#x5165;&#x3092;&#x53EF;&#x80FD;&#x306B;&#x3059;&#x308B;&#x3053;&#x3068;&#x306B;&#x3088;&#x308A;&#x3001;transcranially&#x78BA;&#x4FDD;&#x3055;&#x308C;&#x3066;&#x4E0E;&#x3048;&#x3089;&#x308C;&#x305F;&#x3002;&#x30BF;&#x30FC;&#x30DF;&#x30CA;&#x30EB;&#x9EBB;&#x9154;&#x4E0B;&#x306E;&#x52D5;&#x7269;&#x304B;&#x3089;11&#x65E5;&#x5F8C;&#x306B;&#x96E2;&#x65AD;&#x8133;&#x3092;&#x7D44;&#x7E54;&#x5B66;&#x7684;&#x8A55;&#x4FA1;&#x306E;&#x305F;&#x3081;&#x306B;&#x56DE;&#x53CE;&#x3057;&#x305F;&#x3002;&#x7269;&#x8CEA;&#x306E;&#x52B9;&#x679C;&#x7684;&#x306A;&#x914D;&#x4FE1;&#x306F;&#x30D2;&#x30A2;&#x30EB;&#x30ED;&#x30CB;&#x30C0;&#x30FC;&#x30BC;&#xFF08;&#x751F;&#x7406;&#x98DF;&#x5869;&#x6C34;&#x304B;&#x3089;&#x306E;&#x76F8;&#x5BFE;&#x30D1;&#x30B9;&#xFF09;&#x3067;&#x51E6;&#x7406;&#x3057;&#x305F;&#x5F8C;&#x306B;&#x30CB;&#x30E5;&#x30FC;&#x30ED;&#x30AB;&#x30F3;&#x3068;&#x30D0;&#x30FC;&#x30B7;&#x30AB;&#x30F3;&#x306E;&#x305F;&#x3081;&#x306B;&#x75C5;&#x5909;&#x90E8;&#x5468;&#x56F2;&#x306E;&#x514D;&#x75AB;&#x53CD;&#x5FDC;&#x6027;&#x3067;&#x89B3;&#x5BDF;&#x3055;&#x308C;&#x305F;&#x6E1B;&#x5C11;&#x304B;&#x3089;&#x63A8;&#x6E2C;&#x3055;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;&#x30C1;&#x30ED;&#x30B7;&#x30F3;&#x6C34;&#x9178;&#x5316;&#x9175;&#x7D20;&#x306B;&#x5BFE;&#x3059;&#x308B;&#x6297;&#x4F53;&#x3092;&#x7528;&#x3044;&#x3066;&#x514D;&#x75AB;&#x6A19;&#x8B58;&#x306F;&#x3001;&#x30AB;&#x30C3;&#x30C8;&#x30C9;&#x30FC;&#x30D1;&#x30DF;&#x30F3;&#x4F5C;&#x52D5;&#x6027;&#x9ED2;&#x8CEA;&#x30CB;&#x30E5;&#x30FC;&#x30ED;&#x30F3;&#x306E;&#x5FDC;&#x7B54;&#x3092;&#x8ABF;&#x3079;&#x308B;&#x305F;&#x3081;&#x306B;&#x4F7F;&#x7528;&#x3055;&#x308C;&#x3066;&#x3044;&#x307E;&#x3057;&#x305F;&#x3002;&#x751F;&#x7406;&#x98DF;&#x5869;&#x6C34;&#x3001;&#x30C9;&#x30FC;&#x30D1;&#x30DF;&#x30F3;&#x4F5C;&#x52D5;&#x6027;&#x9ED2;&#x8CEA;&#x795E;&#x7D4C;&#x7D30;&#x80DE;&#x306E;&#x96E2;&#x65AD;&#x3068;&#x6CBB;&#x7642;&#x5F8C;&#x306E;&#x30A2;&#x30B9;&#x30C8;&#x30ED;&#x30B5;&#x30A4;&#x30C8;&#x3001;&#x30CB;&#x30E5;&#x30FC;&#x30ED;&#x3068;&#x30D0;&#x30FC;&#x30B7;&#x30AB;&#x30F3;&#x3092;&#x6B20;&#x3044;&#x3066;&#x3044;&#x308B;&#x5730;&#x57DF;&#x3067;&#x82BD;&#x751F;&#x3048;&#x305F;&#x3002;&#x8EF8;&#x7D22;&#x306F;&#x542B;&#x307E;&#x308C;&#x3066;&#x3044;&#x308B;&#x30A2;&#x30B9;&#x30C8;&#x30ED;&#x30B5;&#x30A4;&#x30C8;&#x3068;&#x8C4A;&#x5BCC;&#x306A;&#x30CB;&#x30E5;&#x30FC;&#x30ED;&#x3068;&#x30D0;&#x30FC;&#x30B7;&#x30AB;&#x30F3;&#x305D;&#x306E;&#x75C5;&#x5909;&#x306E;&#x30B5;&#x30E9;&#x30A6;&#x30F3;&#x30C9;&#x306B;&#x518D;&#x751F;&#x3057;&#x307E;&#x305B;&#x3093;&#x3067;&#x3057;&#x305F;&#x3002;&#x96E2;&#x65AD;&#x3068;&#x30D2;&#x30A2;&#x30EB;&#x30ED;&#x30CB;&#x30C0;&#x30FC;&#x30BC;&#x3067;&#x51E6;&#x7406;&#x3057;&#x305F;&#x5F8C;&#x3001;&#x96E2;&#x65AD;&#x306E;&#x30B5;&#x30A4;&#x30C8;&#x3078;&#x306E;&#x524D;&#x65B9;800&#x30DE;&#x30A4;&#x30AF;&#x30ED;&#x30E2;&#x30EB;&#x306B;&#x6210;&#x9577;&#x30AB;&#x30C3;&#x30C8;&#x30C9;&#x30FC;&#x30D1;&#x30DF;&#x30F3;&#x4F5C;&#x52D5;&#x6027;&#x9ED2;&#x8CEA;&#x306E;&#x8EF8;&#x7D22;&#x6570;&#x306E;&#x8457;&#x3057;&#x3044;&#x5897;&#x52A0;&#x304C;&#x3042;&#x3063;&#x305F;&#x3002;&#x3057;&#x304B;&#x3057;&#x3001;&#x307E;&#x3060;&#xFF08;&#x6B8B;&#x7559;&#x3068;&#x306F;&#x3044;&#x3048;&#xFF09;&#x30CB;&#x30E5;&#x30FC;&#x30ED;&#x3068;&#x30D0;&#x30FC;&#x30B7;&#x30AB;&#x30F3;&#x306E;&#x514D;&#x75AB;&#x53CD;&#x5FDC;&#x6027;&#x3092;&#x6E1B;&#x5C11;&#x542B;&#x307E;&#x308C;&#x3066;&#x3044;&#x308B;&#x75C5;&#x5909;&#x306E;&#x30B5;&#x30E9;&#x30A6;&#x30F3;&#x30C9;&#x306B;&#x518D;&#x751F;&#x3057;&#x307E;&#x305B;&#x3093;&#x3067;&#x3057;&#x305F;&#x30C9;&#x30FC;&#x30D1;&#x30DF;&#x30F3;&#x4F5C;&#x52D5;&#x6027;&#x9ED2;&#x8CEA;&#x795E;&#x7D4C;&#x8EF8;&#x7D22;&#x3092;&#x5207;&#x3063;&#x305F;&#x3002;&#x3057;&#x305F;&#x304C;&#x3063;&#x3066;&#x3001;&#x30D2;&#x30A2;&#x30EB;&#x30ED;&#x30F3;&#x9178;&#x7D50;&#x5408;&#x67D4;&#x6BDB;&#x306E;&#x30D2;&#x30A2;&#x30EB;&#x30ED;&#x30F3;&#x9178;&#x3068;&#x30B3;&#x30F3;&#x30C9;&#x30ED;&#x30A4;&#x30C1;&#x30F3;&#x786B;&#x9178;&#x3068;&#x67AF;&#x6E07;&#x306E;&#x90E8;&#x5206;&#x7684;&#x306A;&#x52A3;&#x5316;&#x304C;&#x30AB;&#x30C3;&#x30C8;CNS&#x8EF8;&#x7D22;&#x306E;&#x767A;&#x82BD;&#x30ED;&#x30FC;&#x30AB;&#x30EB;&#x304C;&#x5411;&#x4E0A;&#x3057;&#x307E;&#x3059;&#x304C;&#x3001;&#x9577;&#x8DDD;&#x96E2;&#x306E;&#x518D;&#x751F;&#x306F;&#x3001;&#x6B8B;&#x7559;&#x30D2;&#x30A2;&#x30EB;&#x30ED;&#x30F3;&#x9178;&#x7D50;&#x5408;&#x67D4;&#x6BDB;&#x3092;&#x200B;&#x200B;&#x542B;&#x3080;&#x9818;&#x57DF;&#x306B;&#x5931;&#x6557;&#x3057;&#x307E;&#x3059;&#x3002;&#x30D2;&#x30A2;&#x30EB;&#x30ED;&#x30F3;&#x9178;&#x3001;&#x30B3;&#x30F3;&#x30C9;&#x30ED;&#x30A4;&#x30C1;&#x30F3;&#x786B;&#x9178;&#x3084;&#x30D2;&#x30A2;&#x30EB;&#x30ED;&#x30F3;&#x9178;&#x7D50;&#x5408;&#x67D4;&#x3057;&#x305F;&#x304C;&#x3063;&#x3066;&#x3001;&#x304A;&#x305D;&#x3089;&#x304F;&#x8CA0;&#x50B7;&#x3057;&#x305F;&#x6210;&#x4EBA;&#x54FA;&#x4E73;&#x985E;&#x306E;&#x8133;&#x3068;&#x810A;&#x9AC4;&#x306E;&#x81EA;&#x767A;&#x7684;&#x306A;&#x8EF8;&#x7D22;&#x518D;&#x751F;&#x306E;&#x969C;&#x5BB3;&#x306B;&#x5411;&#x304B;&#x3063;&#x3066;&#x8CA2;&#x732E;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;

&#x30D2;&#x30A2;&#x30EB;&#x30ED;&#x30CB;&#x30C0;&#x30FC;&#x30BC;&#x306B;&#x3088;&#x308B;&#x6210;&#x4F53;&#x30E9;&#x30C3;&#x30C8;&#x8133;&#x306E;&#x6CBB;&#x7642;&#x5F8C;&#x30BB;&#x30F4;&#x30A1;&#x30FC;&#x30C9;CNS&#x8EF8;&#x7D22;&#x306E;&#x9650;&#x3089;&#x308C;&#x305F;&#x6210;&#x9577;

&#xB9CE;&#xC740; &#xCF58; proteoglycans (CSPGs) CNS &#xCD95; &#xC0C9; &#xC131;&#xC7A5;&#xC744; &#xC0DD;&#xCCB4; &#xC678; &#xBC0F; &#xC0DD;&#xCCB4; &#xC870;&#xAC74;&#xC5D0; &#xC601;&#xD5A5;&#xC744; &#xBCF4;&#xC5EC;&#xC654;&#xB2E4;. &#xC774;&#xB7EC;&#xD55C; &#xC0C1;&#xD638; &#xC791;&#xC6A9; &#xD575;&#xC2EC; &#xB2E8;&#xBC31;&#xC9C8; &#xB610;&#xB294; chondroitin &#xD669;&#xC0B0; (CS) glycosaminoglycan (&#xAC1C; &#xADF8;) &#xC0AC;&#xC774;&#xB4DC; &#xCCB4;&#xC778;&#xC744; &#xD1B5;&#xD574; &#xC911;&#xC7AC; &#xB420; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC774;&#xC804;&#xC5D0; vivo&#xC5D0;&#xC11C; dopaminergic nigrostriatal &#xCD95; &#xC0AD; &#xC7AC;&#xC0DD; &#xD5A5;&#xC0C1; CS &#xAC1C; &#xADF8; &#xCE21;&#xBA74; &#xCCB4;&#xC778; chondroitinase ABC&#xB97C; &#xC0AC;&#xC6A9; &#xD558; &#xC5EC; &#xC800;&#xD558; &#xBCF4;&#xC5EC; &#xC8FC;&#xC5C8;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC6B0;&#xB9AC;&#xAC00; &#xBC29;&#xD574; &#xD558; &#xACE0; &#xC644;&#xC804; &#xD55C; CSPGs &#xCD95; &#xC0C9; &#xC131;&#xC7A5;&#xC744; &#xC0DD;&#xCCB4; &#xC870;&#xAC74; &#xB610;&#xD55C; &#xC81C;&#xD55C; &#xD55C;&#xB2E4;&#xB294; &#xAC00;&#xC124;&#xC744; &#xD14C;&#xC2A4;&#xD2B8;. Neurocan, versican, aggrecan, &#xBC0F; brevican CSPGs hyaluronan glycosaminoglycan &#xBC14;&#xC778;&#xB529;&#xC744; &#xD1B5;&#xD574; &#xC138;&#xD3EC; &#xC678; &#xAE30;&#xC9C8; &#xB0B4;&#xC5D0;&#xC11C; &#xACE0;&#xC815; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC6B0;&#xB9AC;&#xB294; hyaluronan hyaluronidase&#xB97C; &#xC0AC;&#xC6A9; &#xD558; &#xC5EC; &#xC800;&#xD558; &#xC138;&#xD3EC; &#xC678; &#xB9E4;&#xD2B8;&#xB9AD;&#xC2A4;&#xC5D0;&#xC11C; &#xC774;&#xB7EC;&#xD55C; &#xAE08;&#xC9C0; Cspgs&#xB97C; &#xB193;&#xACE0; &#xB530;&#xB77C;&#xC11C; &#xCEF7;&#xB41C; nigrostriatal &#xCD95; &#xC0AD;&#xC758; &#xC7AC;&#xC0DD;&#xC744; &#xD5A5;&#xC0C1; &#xC2DC;&#xD0AC; &#xC218; &#xC788;&#xB294;&#xC9C0; &#xC5EC;&#xBD80;&#xB97C; &#xAC80;&#xC0AC; &#xD569;&#xB2C8;&#xB2E4;. &#xCDE8; &#xC131;&#xC778; &#xC950; &#xC624;&#xB978;&#xCABD; &#xB1CC;&#xB97C; nigrostriatal&#xB85C; &#xBCD1; &#xBCC0;&#xC744; &#xC798;&#xB77C; &#xCE7C; &#xD55C; cannulae &#xC2DD; &#xC5FC; &#xC218;&#xC758; &#xC5FC; &#xBD84;&#xC744; &#xD3EC;&#xD568; &#xD558;&#xB294; 10 &#xC77C; &#xD3EC;&#xC2A4;&#xD2B8; axotomy&#xC744; &#xC704;&#xD574; &#xD558;&#xB8E8;&#xC5D0; &#xD55C; &#xBC88;&#xC529; hyaluronidase &#xBC18;&#xBCF5;&#xB41C; perilesional &#xC8FC;&#xC785; &#xB418;&#xBBC0;&#xB85C; transcranially&#xB97C; &#xD655;&#xBCF4; &#xD588;&#xB2E4;. &#xC870;&#xC9C1;&#xD559; &#xD3C9;&#xAC00; &#xC704;&#xD574; 11 &#xC77C; post-transection &#xB450;&#xB1CC; &#xD130;&#xBBF8;&#xB110; &#xB9C8; &#xCDE8;&#xB294; &#xB3D9;&#xBB3C;&#xC5D0;&#xC11C; &#xBC1C;&#xACAC; &#xD588;&#xB2E4;. &#xBB3C;&#xC9C8;&#xC758; &#xD6A8;&#xACFC;&#xC801;&#xC778; &#xC804;&#xB2EC; (&#xC5FC; &#xBD84;)&#xC744; &#xAE30;&#xC900;&#xC73C;&#xB85C; hyaluronidase &#xCE58;&#xB8CC; &#xD6C4; versican&#xC5D0; &#xB300; &#xD55C; neurocan perilesional immunoreactivity&#xC5D0;&#xC11C; &#xAD00;&#xCC30; &#xB41C; &#xAC10;&#xC18C;&#xC5D0;&#xC11C; &#xC720;&#xCD94; &#xD588;&#xB2E4;. Immunolabeling &#xD2F0;&#xB85C;&#xC2E0; hydroxylase&#xC5D0; &#xB300;&#xD558;&#xC5EC; &#xD56D; &#xCCB4;&#xB97C; &#xC0AC;&#xC6A9; &#xD558; &#xC5EC; &#xCEF7;&#xB41C; dopaminergic nigral &#xC2E0;&#xACBD; &#xC751;&#xB2F5;&#xC744; &#xAC80;&#xC0AC; &#xD558;&#xB294; &#xB370; &#xC0AC;&#xC6A9;&#xD55C;. Transection &#xC2DD; &#xC5FC; &#xC218;&#xB85C; &#xCE58;&#xB8CC; &#xD6C4; dopaminergic nigral &#xB274;&#xB7F0; &#xC774;&#xB2E4;, neurocan &#xBC0F; versican &#xBD80;&#xC871; &#xC9C0;&#xC5ED;&#xC5D0;&#xC11C; &#xBD80; &#xD654; &#xD55C;. &#xCD95; &#xC0AD; &#xC774;&#xB2E4; &#xD48D;&#xBD80;&#xD55C; neurocan &#xBC0F; versican &#xD3EC;&#xD568; &#xB41C; &#xBCD1; &#xBCC0; &#xC8FC;&#xC704;&#xC5D0; &#xB2E4;&#xC2DC; &#xC0DD;&#xC131; &#xD558;&#xC9C0; &#xC54A;&#xC558;&#xB2E4;. Transection hyaluronidase &#xCE58;&#xB8CC; &#xD6C4; &#xCEF7;&#xB41C; dopaminergic nigral axons 800 microm transection &#xC0AC;&#xC774;&#xD2B8; &#xC55E;&#xCABD;&#xAE4C;&#xC9C0; &#xC131;&#xC7A5; &#xD558;&#xB294; &#xC218;&#xC5D0; &#xC0C1;&#xB2F9;&#xD55C; &#xC99D;&#xAC00; &#xD588;&#xB2E4;. &#xADF8;&#xB7EC;&#xB098;, axons &#xD3EC;&#xD568; &#xB41C; &#xBCD1; &#xBCC0; &#xC8FC;&#xC704;&#xC5D0; &#xC7AC;&#xC0DD;&#xC131; &#xD558;&#xC9C0; &#xC54A;&#xC558;&#xB2E4; &#xC544;&#xC9C1;&#xB3C4; &#xCEF7;&#xB41C; dopaminergic nigral &#xAC10;&#xC18C; (&#xC774;&#xAE30;&#xB294; &#xD558;&#xC9C0;&#xB9CC; &#xC794;&#xB958;) neurocan &#xBC0F; versican immunoreactivity. &#xB530;&#xB77C;&#xC11C;, hyaluronan&#xC640; &#xCF58;&#xC758; &#xBD80;&#xBD84; &#xC800;&#xD558; &#xBC0F; hyaluronan &#xBC14;&#xC778;&#xB529; Cspgs&#xC758; &#xACE0;&#xAC08; &#xD5A5;&#xC0C1; &#xCEF7;&#xB41C; CNS axons&#xC758; &#xB85C;&#xCEEC; &#xB3CB; &#xC544; &#xC788;&#xC9C0;&#xB9CC; &#xC794;&#xC5EC; hyaluronan &#xBC14;&#xC778;&#xB529; CSPGs. Hyaluronan&#xC774; &#xD3EC;&#xD568; &#xB41C; &#xC9C0;&#xC5ED;&#xC5D0;&#xC11C; &#xC7A5;&#xAC70;&#xB9AC; &#xC7AC;&#xC0DD;&#xC131;&#xC774; &#xC2E4;&#xD328;, &#xCF58; &#xBC0F; hyaluronan &#xBC14;&#xC778;&#xB529; CSPGs &#xB530;&#xB77C;&#xC11C; &#xAC00;&#xB2A5;&#xC131;&#xC774; &#xAE30;&#xC5EC; &#xBD80;&#xC0C1;&#xB41C; &#xC131;&#xC778; &#xD3EC;&#xC720;&#xB958; &#xB450;&#xB1CC; &#xBC0F; &#xCC99;&#xC218;&#xC5D0; &#xC790;&#xBC1C;&#xC801;&#xC778; &#xCD95; &#xC0AD; &#xC7AC;&#xC0DD; &#xC2E4;&#xD328; &#xCABD;&#xC73C;&#xB85C;.

Hyaluronidase&#xC640; &#xC131;&#xC778; &#xC950; &#xB450;&#xB1CC;&#xC758; &#xCC98;&#xB9AC; &#xD6C4; &#xC798;&#xB9B0;&#xB41C; CNS axons&#xC758; &#xD55C;&#xC815; &#xB41C; &#xC131;&#xC7A5;.

Muchos proteoglicanos sulfato de condroitina (CSPGs) han demostrado que influyen en el crecimiento del SNC axonal in vitro e in vivo. Estas interacciones pueden ser mediada a trav&#xE9;s de la prote&#xED;na de la base o por el sulfato de condroitina (CS) de glicosaminoglicanos (GAG) cadenas laterales. Hemos demostrado anteriormente que la degradaci&#xF3;n de CS cadenas laterales GAG con condroitinasa ABC mejora dopamin&#xE9;rgica nigroestriatal regeneraci&#xF3;n de los axones in vivo. Ponemos a prueba la hip&#xF3;tesis de que interfiera con CSPGs completos tambi&#xE9;n limitar el crecimiento de los axones in vivo. Neurocan, versicano, aggrecan y CSPGs brevican puede estar anclada dentro de la matriz extracelular a trav&#xE9;s de la uni&#xF3;n a &#xE1;cido hialur&#xF3;nico glicosaminoglicanos. Examinamos si la degradaci&#xF3;n del &#xE1;cido hialur&#xF3;nico con hialuronidasa podr&#xED;a liberar estos CSPGs inhibidores de la matriz extracelular y por lo tanto mejorar la regeneraci&#xF3;n de los axones cortados nigroestriatales. Ratas anestesiadas adultos recibieron lesiones cuchillo de corte del hemisferio derecho del tracto nigroestriatal y las c&#xE1;nulas fueron asegurados transcranially lo que permite la infusi&#xF3;n repetida perilesional de hialuronidasa que contiene soluci&#xF3;n salina o soluci&#xF3;n salina una vez al d&#xED;a durante 10 d&#xED;as despu&#xE9;s de axotom&#xED;a. Once d&#xED;as despu&#xE9;s de la transecci&#xF3;n cerebros de los animales bajo anestesia terminales fueron recuperados para su evaluaci&#xF3;n histol&#xF3;gica. La entrega efectiva de la sustancia se deduce de la reducci&#xF3;n observada en la inmunorreactividad perilesional de neurocan y versican despu&#xE9;s del tratamiento con hialuronidasa (en relaci&#xF3;n con la soluci&#xF3;n salina). Immunolabeling utilizando anticuerpos contra la tirosina hidroxilasa se utiliz&#xF3; para examinar la respuesta de cortadas las neuronas dopamin&#xE9;rgicas nigrales. Despu&#xE9;s de la transecci&#xF3;n y el tratamiento con las neuronas dopamin&#xE9;rgicas salinas, la sustancia nigra brotado en una regi&#xF3;n que carece de los astrocitos, neurocan y versican. Los axones no se repusieron en la envolvente de las lesiones que los astrocitos y abundantes contenidos neurocan y versican. Despu&#xE9;s de la transecci&#xF3;n y el tratamiento con hialuronidasa, hubo un aumento significativo en el n&#xFA;mero de axones cortados dopamin&#xE9;rgicas nigrales crecientes hasta 800 micras anterior al sitio de transecci&#xF3;n. Sin embargo, los axones dopamin&#xE9;rgicos corte nigrales a&#xFA;n no se repusieron en la envolvente de la lesi&#xF3;n que conten&#xED;a reducida (aunque residual) y la inmunorreactividad neurocan versicano. Por lo tanto, la degradaci&#xF3;n parcial de sulfato de condroitina y el &#xE1;cido hialur&#xF3;nico y el agotamiento de &#xE1;cido hialur&#xF3;nico de enlace CSPGs mejora local de la brotaci&#xF3;n de los axones del sistema nervioso central de corte, pero a larga distancia se producen errores en las regiones que contienen &#xE1;cido hialur&#xF3;nico residuales vinculantes CSPGs. &#xC1;cido hialur&#xF3;nico, condroit&#xED;n sulfato y &#xE1;cido hialur&#xF3;nico CSPGs vinculante-por lo tanto, es probable contribuir al fracaso de la regeneraci&#xF3;n axonal espont&#xE1;nea en el cerebro adulto de mam&#xED;feros y lesionado la m&#xE9;dula espinal.

Limitado crecimiento de los axones del sistema nervioso central Severed Despu&#xE9;s del tratamiento de cerebro de rata adulta, con hialuronidasa

Freeze-dried poly(D,L-lactic acid) macroporous scaffold filled with a fibrin solution containing Schwann cells (SCs) lentivirally transduced to produce and secrete D15A, a bi-functional neurotrophin with brain-derived neurotrophic factor and neurotrophin-3 activity, and to express green fluorescent protein (GFP) were implanted in the completely transected adult rat thoracic spinal cord. Control rats were similarly injured and then implanted with scaffolds containing the fibrin solution with SCs lentivirally transduced to produce express GFP only or with the fibrin solution only. Transgene production and biological activity in vitro, SC survival within the scaffold in vitro and in vivo, scaffold integration, axonal regeneration and myelination, and hind limb motor function were analyzed at 1, 2, and 6 weeks after implantation. In vitro, lentivirally transduced SCs produced 87.5 ng/24 h/10(6) cells of D15A as measured by neurotrophin-3 activity in ELISA. The secreted D15A was biologically active as evidenced by its promotion of neurite outgrowth of dorsal root ganglion neurons in culture. In vitro, SCs expressing GFP were present in the scaffolds for up to 6 h, the end of a typical surgery session. Implantation of SC-seeded scaffolds caused modest loss of spinal nervous tissue. Reactive astrocytes and chondroitin sulfate glycosaminoglycans were present in spinal tissue adjacent to the scaffold. Vascularization of the scaffold was ongoing at 1 week post-implantation. There were no apparent differences in scaffold integration and blood vessel formation between groups. A decreasing number of implanted (GFP-positive) SCs were found within the scaffold during the first 3 days after implantation. Apoptosis was identified as one of the mechanisms of cell death. At 1 week and later time points after implantation, few of the implanted SCs were present in the scaffold. Neurofilament-positive axons were found in the scaffold. At 6 weeks post-grafting, myelinated axons were observed within and at the external surface of the scaffold. Axons did not grow from the scaffold into the caudal cord. All groups demonstrated a similar improvement of hind limb motor function. Our findings demonstrated that few seeded SCs survived in vivo, which could account for the modest axonal regeneration response into and across the scaffold. For the development of SC-seeded macroporous scaffolds that effectively promote axonal regeneration in the injured spinal cord, the survival and/or total number of SCs in the scaffold needs to be improved.

Poly (D,L-lactic acid) macroporous guidance scaffolds seeded with Schwann cells genetically modified to secrete a bi-functional neurotrophin implanted in the completely transected adult rat thoracic spinal cord.

Although transplanted Schwann cells (SCs) can promote axon regeneration and remyelination and improve recovery in models of spinal cord injury, little is known about their survival and how they interact with host tissue. Using labeled SCs from transgenic rats expressing human placental alkaline phosphatase (PLAP), SC survival in a spinal cord contusion lesion was assessed. Few PLAP SCs survived at 2 weeks after acute transplantation. They died early due to necrosis and apoptosis. Delaying transplantation until 7 days after injury improved survival. A second wave of cell death occurred after surviving cells had integrated into the spinal cord. Survival of PLAP SCs was enhanced by immunosuppression with cyclosporin; delayed transplantation in conjunction with immunosuppression resulted in the best survival. In all cases, transplantation of SCs resulted in extensive infiltration of endogenous p75+ cells into the injury site, suggesting that endogenous SCs may play an important role in the repair observed after SC transplantation.

Labeled Schwann cell transplantation: cell loss, host Schwann cell replacement, and strategies to enhance survival.

Spinal cord injury (SCI) can lead to paraplegia or quadriplegia. Although there are no fully restorative treatments for SCI, various rehabilitative, cellular and molecular therapies have been tested in animal models. Many of these have reached, or are approaching, clinical trials. Here, we review these potential therapies, with an emphasis on the need for reproducible evidence of safety and efficacy. Individual therapies are unlikely to provide a panacea. Rather, we predict that combinations of strategies will lead to improvements in outcome after SCI. Basic scientific research should provide a rational basis for tailoring specific combinations of clinical therapies to different types of SCI.

Therapeutic interventions after spinal cord injury.

While neuroimmune interactions are increasingly recognized as important in nociceptive processing, the nature and functional significance of these interactions is not well defined. There are multiple reports that the activation of spinal microglia is a critical event in the generation of neuropathic pain behaviors but the mediators of this activation remain disputed. Here we show that the chemokine CCL2, produced by both damaged and undamaged primary sensory neurons in neuropathic pain states in rats, is released in an activity dependent manner from the central terminals of these fibres. We also demonstrate that intraspinal CCL2 in naïve rats leads to activation of spinal microglia and neuropathic pain-like behavior. An essential role for spinal CCL2 is demonstrated by the inhibition of neuropathic pain behavior and microglial activation by a specific neutralising antibody to CCL2 administered intrathecally. Thus, the neuronal expression of CCL2 provides a mechanism for immune activation, which in turn regulates the sensitivity of pain signaling systems in neuropathic pain states.

CCL2 is a key mediator of microglia activation in neuropathic pain states.

A large number of different cells including embryonic and adult stem cells have been transplanted into animal models of spinal cord injury, and in many cases these procedures have resulted in modest sensorimotor benefits. In October 2010 the world's first clinical trial using human embryonic stem cells began, using stem cells converted into oligodendrocyte precursor cells.

Will stem cell therapies be safe and effective for treating spinal cord injuries?

Following an injury, central nervous system (CNS) neurons show a very limited regenerative response which results in their failure to successfully form functional connections with their original target. This is due in part to the reduced intrinsic growth state of CNS neurons, which is characterized by their failure to express key regeneration-associated genes (RAGs) and by the presence of growth inhibitory molecules in CNS environment that form a molecular and physical barrier to regeneration. Here we have optimized a 96-well electroporation and neurite outgrowth assay for postnatal rat cerebellar granule neurons (CGNs) cultured upon an inhibitory cellular substrate expressing myelin-associated glycoprotein or a mixture of growth inhibitory chondroitin sulfate proteoglycans. Optimal electroporation parameters resulted in 28% transfection efficiency and 51% viability for postnatal rat CGNs. The neurite outgrowth of transduced neurons was quantitatively measured using a semi-automated image capture and analysis system. The neurite outgrowth was significantly reduced by the inhibitory substrates which we demonstrated could be partially reversed using a Rho Kinase inhibitor. We are now using this assay to screen large sets of RAGs for their ability to increase neurite outgrowth on a variety of growth inhibitory and permissive substrates.

Optimization of a 96-Well Electroporation Assay for Postnatal Rat CNS Neurons Suitable for Cost-Effective Medium-Throughput Screening of Genes that Promote Neurite Outgrowth.

Stroke is the dominant cause of sensorimotor disability that primarily affects the elderly. We now show that neuroplasticity and functional recovery after stroke is constrained by inhibitory chondroitin sulphates. In two blinded, randomized preclinical trials, degradation of chondroitin sulphate using chondroitinase ABC reactivated neuroplasticity and promoted sensorimotor recovery after stroke in elderly rats. Three days after stroke, chondroitinase ABC was microinjected into the cervical spinal cord to induce localized plasticity of forelimb sensorimotor spinal circuitry. Chondroitinase ABC effectively removed chondroitin sulphate from the extracellular matrix and perineuronal nets. Three different tests of sensorimotor function showed that chondroitinase ABC promoted recovery of forelimb function. Anterograde and retrograde tracing showed that chondroitinase ABC also induced sprouting of the contralesional corticospinal tract in the aged treated hemicord. Chondroitinase ABC did not neuroprotect the peri-infarct region. We show for the first time delayed chondroitinase ABC treatment promotes neuroanatomical and functional recovery after focal ischaemic stroke in an elderly nervous system.

Delayed treatment with chondroitinase ABC promotes sensorimotor recovery and plasticity after stroke in aged rats.

Knocking down neuronal LINGO-1 using short hairpin RNAs (shRNAs) might enhance axon regeneration in the central nervous system (CNS). Integration-deficient lentiviral vectors have great potential as a therapeutic delivery system for CNS injuries. However, recent studies have revealed that shRNAs can induce an interferon response resulting in off-target effects and cytotoxicity.

Lentiviral vectors encoding short hairpin RNAs efficiently transduce and knockdown LINGO-1 but induce an interferon response and cytotoxicity in central nervous system neurones.

Neurorestorative therapies for stroke aim to reverse disability by reparative mechanisms (rather than to thrombolyse or to neuroprotect). A substantial and persuasive body of pre-clinical evidence has come from the evaluation of antibodies against Nogo-A (a myelin-associated inhibitor of plasticity) in rat models of stroke. Particularly impressive is the benefit of this therapy in models of permanent middle cerebral artery occlusion (MCAO) when given to elderly animals after a one week delay, in adult rats with co-morbidities, and in adult rats when treatment is delayed by up to 9 weeks after stroke (although antibodies against Nogo-A did not reverse disability in mice after proximal MCAO with reperfusion). We predict that antibodies against Nogo-A will improve outcome further when combined with suitable additional rehabilitation, and also that antibodies against Nogo-A will improve outcome in animal models of haemmorhagic stroke that affect the same brain regions as ischemic stroke caused by MCAO. Antibodies against Nogo-A have been shown to be safe in Phase I clinical trials for acute spinal cord injury, and this may eventually facilitate a trial in stroke.

Therapeutics targeting Nogo-A hold promise for stroke restoration.

RNA silencing is an established method for investigating gene function and has attracted particular interest because of the potential for generating RNA-based therapeutics. Using lentiviral vectors as an efficient delivery system that offers stable, long-term expression in postmitotic cells further enhances the applicability of an RNA-based gene therapy for the CNS. In this review we provide an overview of both lentiviral vectors and RNA silencing along with design considerations for generating lentiviral vectors capable of RNA silencing. We go on to describe the current preclinical data regarding lentiviral vector-mediated RNA silencing for CNS disorders and discuss the concerns of side effects associated with lentiviral vectors and small interfering RNAs and how these might be mitigated.

Lentiviral vector-mediated RNA silencing in the central nervous system.

Assessment of high-throughput-omics data initially focuses on relative or raw levels of a particular feature, such as an expression value for a transcript, protein, or metabolite. At a second level, analyses of annotations including known or predicted functions and associations of each individual feature, attempt to distill biological context. Most currently available comparative- and meta-analyses methods are dependent on the availability of identical features across data sets, and concentrate on determining features that are differentially expressed across experiments, some of which may be considered "biomarkers." The heterogeneity of measurement platforms and inherent variability of biological systems confounds the search for robust biomarkers indicative of a particular condition. In many instances, however, multiple data sets show involvement of common biological processes or signaling pathways, even though individual features are not commonly measured or differentially expressed between them. We developed a methodology, categoryCompare, for cross-platform and cross-sample comparison of high-throughput data at the annotation level. We assessed the utility of the approach using hypothetical data, as well as determining similarities and differences in the set of processes in two instances: (1) denervated skin vs. denervated muscle, and (2) colon from Crohn's disease vs. colon from ulcerative colitis (UC). The hypothetical data showed that in many cases comparing annotations gave superior results to comparing only at the gene level. Improved analytical results depended as well on the number of genes included in the annotation term, the amount of noise in relation to the number of genes expressing in unenriched annotation categories, and the specific method in which samples are combined. In the skin vs. muscle denervation comparison, the tissues demonstrated markedly different responses. The Crohn's vs. UC comparison showed gross similarities in inflammatory response in the two diseases, with particular processes specific to each disease.

Lawrence D. F. Moon

Neurorestoration,
Wolfson Centre for Age-Related Diseases,
Neurorestoration, Wolfson Centre for Age-Related Diseases

King's College London

Unilateral Pyramidotomy of the Corticospinal Tract in Rats for Assessment of Neuroplasticity-inducing Therapies

Lawrence D. F. Moon

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Neurorestoration,Wolfson Centre for Age-Related Diseases,Neurorestoration, Wolfson Centre for Age-Related Diseases

King's College London

Unilateral Pyramidotomy of the Corticospinal Tract in Rats for Assessment of Neuroplasticity-inducing Therapies

Neurorestoration,
Wolfson Centre for Age-Related Diseases,
Neurorestoration, Wolfson Centre for Age-Related Diseases