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1. SWIFT DIRECT: Solitaire™ With the Intention For Thrombectomy Plus Intravenous t-PA Versus DIRECT Solitaire™ Stent-retriever Thrombectomy in Acute Anterior Circulation Stroke: Methodology of a randomized, controlled, multicentre study

Author

Jan Gralla, Anthony J. Furlan, Jenny Bressan, Urs Fischer, Patricia S Plattner, David S Liebeskind, René Chapot, Michael T. Froehler, Pasquale Mordasini, Martin Wiesmann, Adnan H. Siddiqui, Christoph Cognard, Vitor Mendes Pereira, Johannes Kaesmacher, Daniel Strbian, Jeffery L Saver, Lukas Bütikofer, Stefanie Lerch, and Sandro Deppeler

Subjects
Solitaire Cryptographic Algorithm, medicine.medical_specialty, Intention, Brain Ischemia, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Prospective Studies, 030212 general & internal medicine, Endovascular treatment, Acute ischemic stroke, Stroke, Solitaire stent, Ischemic Stroke, Thrombectomy, Stent retriever, business.industry, medicine.disease, 3. Good health, Mechanical thrombectomy, Treatment Outcome, Neurology, Tissue Plasminogen Activator, Quality of Life, Cardiology, Stents, business, 030217 neurology & neurosurgery, Large vessel occlusion
Abstract

Rationale Whether treatment with intravenous alteplase prior to mechanical thrombectomy (MT) in acute ischemic stroke patients with large vessel occlusion is beneficial remains unclear. Aim To determine whether patients experiencing acute ischemic stroke due to occlusion of the intracranial internal carotid artery or the M1 segment of the middle cerebral artery who are referred to an endovascular stroke center and who are candidates for intravenous alteplase will have non-inferior functional outcome at 90 days when treated with MT alone (direct MT) with stent retrievers compared to patients treated with combined intravenous thrombolysis (IVT) with alteplase plus MT (IVT + MT) with stent retrievers. Sample size To randomize 404 patients 1:1 to direct MT or combined IVT+MT. Methods and design A multicenter, prospective, randomized, open-label, blinded-endpoint (PROBE) trial utilizing an adaptive statistical design. Outcomes The primary efficacy endpoint is functional independence (modified Rankin Scale 0–2) at 90 days. Secondary clinical efficacy outcomes include change in National Institutes of Health Stroke Scale score from baseline to day 1 and health-related quality of life at 90 days. Secondary technical efficacy outcomes include successful reperfusion prior to start of MT and time from randomization to successful reperfusion. Safety outcomes include all serious adverse events, symptomatic intracranial hemorrhage, and mortality up to 90 days. Discussion SWIFT DIRECT will inform physicians whether direct MT in acute ischemic stroke patients with large vessel occlusion is equally or more efficacious than combined treatment with intravenous alteplase and MT. Trial registration ClinicalTrials.gov Identifier: NCT03192332

Published
2021
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2. Thrombectomy alone versus intravenous alteplase plus thrombectomy in patients with stroke: an open-label, blinded-outcome, randomised non-inferiority trial

Author

Urs Fischer, Johannes Kaesmacher, Daniel Strbian, Omer Eker, Christoph Cognard, Patricia S Plattner, Lukas Bütikofer, Pasquale Mordasini, Sandro Deppeler, Vitor M Pereira, Jean François Albucher, Jean Darcourt, Romain Bourcier, Guillon Benoit, Chrysanthi Papagiannaki, Ozlem Ozkul-Wermester, Gerli Sibolt, Marjaana Tiainen, Benjamin Gory, Sébastien Richard, Jan Liman, Marielle Sophie Ernst, Marion Boulanger, Charlotte Barbier, Laura Mechtouff, Liqun Zhang, Gaultier Marnat, Igor Sibon, Omid Nikoubashman, Arno Reich, Arturo Consoli, Bertrand Lapergue, Marc Ribo, Alejandro Tomasello, Suzana Saleme, Francisco Macian, Solène Moulin, Paolo Pagano, Guillaume Saliou, Emmanuel Carrera, Kevin Janot, María Hernández-Pérez, Raoul Pop, Lucie Della Schiava, Andreas R Luft, Michel Piotin, Jean Christophe Gentric, Aleksandra Pikula, Waltraud Pfeilschifter, Marcel Arnold, Adnan H Siddiqui, Michael T Froehler, Anthony J Furlan, René Chapot, Martin Wiesmann, Paolo Machi, Hans-Christoph Diener, Zsolt Kulcsar, Leo H Bonati, Claudio L Bassetti, Mikael Mazighi, David S Liebeskind, Jeffrey L Saver, Jan Gralla, Angelika Alonso, Caroline Arquizan, Xavier Barreau, Rémy Beaujeux, Daniel Behme, Tobias Boeckh-Behrens, Christian Boehme, Martí Boix, Grégoire Boulouis, Nicolas Bricout, Nicolas Broc, Carlo W. Cereda, Emmanuel Chabert, Tae-Hee Cho, Alessandro Cianfoni, Vincent Costalat, Christian Denier, Frederico Di Maria, Richard du Mesnil de Rochemont, Patricia Fearon, Anna Ferrier, Sebastian Fischer, Maxime Gauberti, Marie Gaudron, Laetitia Gimenez, Christoph Globas, Michael Görtler, Mayank Goyal, Ruediger Hilker-Roggendorf, Michael D. Hill, Vi Tuan Hua, Lisa Humbertjean, Olav Jansen, Simon Jung, Georg Kägi, Michael E. Kelly, Ilka Kleffner, Michael Knoflach, Krassen Nedeltchev, Lars Udo Krause, Kimmo Lappalainen, Margaux Lefebvre, Joe Leyon, Liang Liao, Jean-Sebastien Liegey, Christian Loehr, Patrik Michel, Stefania Nannoni, Patrick Nicholson, Lorena Nico, Michael Obadia, Julien Ognard, Ayokunle Ogungbemi, Jean-Marc Olivot, Simon Escalard, Marco Pasi, Lissa Peeling, Jane Perez, Martina Petersen, Eike Piechowiak, Roberto Raposo, Silja Räty, Sarah C. Reitz, Sebastià Remollo, Luca Remonda, Ian Rennie, Manuel Requena, Alexander Riabikin, Roberto Riva, Aymeric Rouchaud, Andrea Rosi, Marta Rubiera, Laurent Spelle, Marlena Schnieder, Joanna D. Schaafsma, Tilman Schubert, Jörg B. Schulz, Mohammed Siddiqui, Sébastien Soize, Michael Sonnberger, Emmanuel Touze, Aude Triquenot, Guillaume Turc, Lucy Vieira, Wagih Ben Hassen, Judith N. Wagner, Katrin Wasser, Johannes Weber, Holger Wenz, David Weisenburger-Lile, Fritz Wodarg, Valérie Wolff, Silke Wunderlich, University of Bern, Bern University Hospital [Berne] (Inselspital), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Service de neuroradiologie [Lyon], Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), CHU Toulouse [Toulouse], Département de Neuro-Radiologie [Bordeaux] (DNR - Bordeaux), CHU Bordeaux [Bordeaux], University of Toronto, Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Radiologie [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Service de neurologie [Rouen], Helsinki University Hospital [Finland] (HUS), Imagerie Adaptative Diagnostique et Interventionnelle (IADI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Département de neuroradiologie diagnostique et thérapeutique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service de neurologie [CHRU Nancy], University Medical Center Göttingen (UMG), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Interférométrie, In situ et Instrumentation pour la Microscopie Electronique (CEMES-I3EM), Centre d'élaboration de matériaux et d'études structurales (CEMES), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut de Neurosciences cognitives et intégratives d'Aquitaine (INCIA), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-SFR Bordeaux Neurosciences-Centre National de la Recherche Scientifique (CNRS), Universitätsklinikum RWTH Aachen - University Hospital Aachen [Aachen, Germany] (UKA), Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), Hôpital Foch [Suresnes], Institut de Ciencies del Cosmos (ICCUB), Universitat de Barcelona (UB), Observatoire océanologique de Banyuls (OOB), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Limoges, Environnement, Bioénergie, Microalgues et Plantes (EBMP), Institut de Biosciences et Biotechnologies d'Aix-Marseille (ex-IBEB) (BIAM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre Hospitalier Universitaire de Reims (CHU Reims), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Hôpitaux Universitaires de Genève (HUG), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Germans Trias i Pujol University Hospital [Badalona, Barcelona, Spain] (GTPUH), Département de Neuroradiologie [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), CHU Lille, University hospital of Zurich [Zurich], Fondation Ophtalmologique Adolphe de Rothschild [Paris], Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Toronto Western Hospital, Frankfurt University Hospital, University at Buffalo [SUNY] (SUNY Buffalo), State University of New York (SUNY), Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Case Western Reserve University [Cleveland], Alfried Krupp Krankenhaus [Essen], Geneva University Hospitals and Geneva University, Institute of Medical Informatics, Biometrics and Epidemiology [ Essen, Germany] (IMIBE), University Hospital Basel [Basel], University of Basel (Unibas), Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), FHU NeuroVasc [Site Sainte-Anne, Paris] (GHU-PPN), Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), University of California (UC), SWIFT DIRECT Collaborators: Angelika Alonso, Caroline Arquizan, Xavier Barreau, Rémy Beaujeux, Daniel Behme, Tobias Boeckh-Behrens, Christian Boehme, Martí Boix, Grégoire Boulouis, Nicolas Bricout, Nicolas Broc, Carlo W Cereda, Emmanuel Chabert, Tae-Hee Cho, Alessandro Cianfoni, Vincent Costalat, Christian Denier, Frederico Di Maria, Richard du Mesnil de Rochemont, Patricia Fearon, Anna Ferrier, Sebastian Fischer, Maxime Gauberti, Marie Gaudron, Laetitia Gimenez, Christoph Globas, Michael Görtler, Mayank Goyal, Ruediger Hilker-Roggendorf, Michael D Hill, Vi Tuan Hua, Lisa Humbertjean, Olav Jansen, Simon Jung, Georg Kägi, Michael E Kelly, Ilka Kleffner, Michael Knoflach, Krassen Nedeltchev, Lars Udo Krause, Kimmo Lappalainen, Margaux Lefebvre, Joe Leyon, Liang Liao, Jean-Sebastien Liegey, Christian Loehr, Patrik Michel, Stefania Nannoni, Patrick Nicholson, Lorena Nico, Michael Obadia, Julien Ognard, Ayokunle Ogungbemi, Jean-Marc Olivot, Simon Escalard, Marco Pasi, Lissa Peeling, Jane Perez, Martina Petersen, Eike Piechowiak, Roberto Raposo, Silja Räty, Sarah C Reitz, Sebastià Remollo, Luca Remonda, Ian Rennie, Manuel Requena, Alexander Riabikin, Roberto Riva, Aymeric Rouchaud, Andrea Rosi, Marta Rubiera, Laurent Spelle, Marlena Schnieder, Joanna D Schaafsma, Tilman Schubert, Jörg B Schulz, Mohammed Siddiqui, Sébastien Soize, Michael Sonnberger, Emmanuel Touze, Aude Triquenot, Guillaume Turc, Lucy Vieira, Wagih Ben Hassen, Judith N Wagner, Katrin Wasser, Johannes Weber, Holger Wenz, David Weisenburger-Lile, Fritz Wodarg, Valérie Wolff, Silke Wunderlich., Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), St George’s University Hospitals, Vall d'Hebron University Hospital [Barcelona], and CarMeN, laboratoire

Subjects
[SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], General Medicine, 610 Medicine & health
Abstract

Background Whether thrombectomy alone is equally as effective as intravenous alteplase plus thrombectomy remains controversial. We aimed to determine whether thrombectomy alone would be non-inferior to intravenous alteplase plus thrombectomy in patients presenting with acute ischaemic stroke. Methods In this multicentre, randomised, open-label, blinded-outcome trial in Europe and Canada, we recruited patients with stroke due to large vessel occlusion confirmed with CT or magnetic resonance angiography admitted to endovascular centres. Patients were randomly assigned (1:1) via a centralised web server using a deterministic minimisation method to receive stent-retriever thrombectomy alone or intravenous alteplase plus stent-retriever thrombectomy. In both groups, thrombectomy was initiated as fast as possible with any commercially available Solitaire stent-retriever revascularisation device (Medtronic, Irvine, CA, USA). In the combined treatment group, intravenous alteplase (0.9 mg/kg bodyweight, maximum dose 90 mg per patient) was administered as early as possible after randomisation for 60 min with 10% of the calculated dose given as an initial bolus. Personnel assessing the primary outcome were masked to group allocation; patients and treating physicians were not. The primary binary outcome was a score of 2 or less on the modified Rankin scale at 90 days. We assessed the non-inferiority of thrombectomy alone versus intravenous alteplase plus thrombectomy in all randomly assigned and consenting patients using the one-sided lower 95% confidence limit of the Mantel-Haenszel risk difference, with a prespecified non-inferiority margin of 12%. The main safety endpoint was symptomatic intracranial haemorrhage assessed in all randomly assigned and consenting participants. This trial is registered with ClinicalTrials.gov, NCT03192332, and is closed to new participants. Findings Between Nov 29, 2017, and May 7, 2021, 5215 patients were screened and 423 were randomly assigned, of whom 408 (201 thrombectomy alone, 207 intravenous alteplase plus thrombectomy) were included in the primary efficacy analysis. A modified Rankin scale score of 0-2 at 90 days was reached by 114 (57%) of 201 patients assigned to thrombectomy alone and 135 (65%) of 207 patients assigned to intravenous alteplase plus thrombectomy (adjusted risk difference -7 .3%, 95% CI -16.6 to 2.1, lower limit of one-sided 95% CI -15.1%, crossing the non-inferiority margin of - 12%). Symptomatic intracranial haemorrhage occurred in five (2%) of 201 patients undergoing thrombectomy alone and seven (3%) of 202 patients receiving intravenous alteplase plus thrombectomy ( risk difference -1.0%, 95% CI -4.8 to 2 .7). Successful reperfusion was less common in patients assigned to thrombectomy alone (182 [ 91%] of 201 vs 199 [96%] of 207, risk difference -5.1%, 95% CI -10.2 to 0. 0, p=0.047). Interpretation Thrombectomy alone was not shown to be non-inferior to intravenous alteplase plus thrombectomy and resulted in decreased reperfusion rates. These results do not support omitting intravenous alteplase before thrombectomy in eligible patients. Copyright (C) 2022 Elsevier Ltd. All rights reserved.

Published
2022
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3. Nogo-A antibodies enhance axonal repair and remyelination in neuro-inflammatory and demyelinating pathology

Author

Sandra Kapitza, Julia Kaiser, Nicolas Good, Patricia S. Plattner, Christiane Bleul, Michael Linnebank, Roland Martin, Marc P. Schneider, Björn Zörner, Maryam S. Seyedsadr, Benjamin V. Ineichen, and Martin E. Schwab

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Encephalomyelitis, Autoimmune, Experimental, Nogo Proteins, Biology, Antibodies, Pathology and Forensic Medicine, Lesion, 03 medical and health sciences, Cellular and Molecular Neuroscience, Myelin, 0302 clinical medicine, medicine, Animals, Remyelination, Inflammation, Multiple sclerosis, Neurodegeneration, Experimental autoimmune encephalomyelitis, Brain, Recovery of Function, medicine.disease, Spinal cord, Axons, Rats, 030104 developmental biology, medicine.anatomical_structure, Rats, Inbred Lew, Corticospinal tract, Female, Neurology (clinical), medicine.symptom, 030217 neurology & neurosurgery
Abstract

Two hallmarks of chronic multiple sclerosis lesions are the absence of significant spontaneous remyelination and primary as well as secondary neurodegeneration. Both characteristics may be influenced by the presence of inhibitory factors preventing myelin and neuronal repair. We investigated the potential of antibodies against Nogo-A, a well-known inhibitory protein for neuronal growth and plasticity, to enhance neuronal regeneration and remyelination in two animal models of multiple sclerosis. We induced a targeted experimental autoimmune encephalomyelitis (EAE) lesion in the dorsal funiculus of the cervical spinal cord of adult rats resulting in a large drop of skilled forelimb motor functions. We subsequently observed improved recovery of forelimb function after anti-Nogo-A treatment. Anterograde tracing of the corticospinal tract revealed enhanced axonal sprouting and arborisation within the spinal cord gray matter preferentially targeting pre-motor and motor spinal cord laminae on lesion level and above in the anti-Nogo-A-treated animals. An important additional effect of Nogo-A-neutralization was enhanced remyelination observed after lysolecithin-induced demyelination of spinal tracts. Whereas remyelinated fiber numbers in the lesion site were increased several fold, no effect of Nogo-A-inhibition was observed on oligodendrocyte precursor proliferation, migration, or differentiation. Enhancing remyelination and promoting axonal regeneration and plasticity represent important unmet medical needs in multiple sclerosis. Anti-Nogo-A antibodies hold promise as a potential new therapy for multiple sclerosis, in particular during the chronic phase of the disease when neurodegeneration and remyelination failure determine disability evolution.

Published
2017
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4. Intrathecal insulin-like growth factor 1 but not insulin enhances myelin repair in young and aged rats

Author

Dianne P. Figlewicz, Martin E. Schwab, Nicolas Good, Maryam S. Seyedsadr, Martin Hlavica, Aro Delparente, Andrin Good, Benjamin V. Ineichen, Patricia S. Plattner, University of Zurich, and Ineichen, Benjamin V

Subjects
Blood Glucose, 0301 basic medicine, medicine.medical_treatment, 610 Medicine & health, Cell Count, 03 medical and health sciences, Insulin-like growth factor, Myelin, 0302 clinical medicine, In vivo, Animals, Insulin, Medicine, Rats, Long-Evans, Insulin-Like Growth Factor I, Remyelination, Injections, Spinal, Myelin Sheath, 10242 Brain Research Institute, business.industry, Macrophages, General Neuroscience, Multiple sclerosis, Growth factor, 2800 General Neuroscience, Lysophosphatidylcholines, medicine.disease, Spinal cord, Rats, 030104 developmental biology, medicine.anatomical_structure, Immunology, 570 Life sciences, biology, Female, business, 030217 neurology & neurosurgery, Demyelinating Diseases
Abstract

One main pathological hallmark of multiple sclerosis (MS) is demyelination. Novel therapies which enhance myelin repair are urgently needed. Insulin and insulin-like growth factor 1 (IGF-1) have strong functional relationships. Here, we addressed the potential capacity of IGF-1 and insulin to enhance remyelination in an animal demyelination model in vivo. We found that chronic intrathecal infusion of IGF-1 enhanced remyelination after lysolecithin-induced demyelination in the spinal cord of young and aged rats. Aged rats showed a weaker innate remyelination capacity and are therefore a good model for progressive MS which is defined by chronic demyelination. In contrast to IGF-1, Insulin had no effect on remyelination in either age group. Our findings highlight the potential use of IGF-1 as remyelinating therapy for MS, particularly the progressive stage in which chronic demyelination is the hallmark.

Published
2017
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5. Nogo-A Antibodies for Progressive Multiple Sclerosis

Author

Benjamin V. Ineichen, Michael Linnebank, Martin E. Schwab, Nicolas Good, Patricia S. Plattner, and Roland Martin

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Neurology, Multiple Sclerosis, Nogo Proteins, Bioinformatics, Antibodies, 03 medical and health sciences, Myelin, 0302 clinical medicine, mental disorders, medicine, Animals, Humans, Immunologic Factors, Pharmacology (medical), Optic neuritis, Remyelination, Spinal cord injury, business.industry, Multiple sclerosis, medicine.disease, Clinical trial, Psychiatry and Mental health, 030104 developmental biology, medicine.anatomical_structure, Neurology (clinical), business, 030217 neurology & neurosurgery, Progressive disease
Abstract

Most of the current therapies, as well as many of the clinical trials, for multiple sclerosis (MS) target the inflammatory autoimmune processes, but less than 20% of all clinical trials investigate potential therapies for the chronic progressive disease stage of MS. The latter is responsible for the steadily increasing disability in many patients, and there is an urgent need for novel therapies that protect nervous system tissue and enhance axonal growth and/or remyelination. As outlined in this review, solid pre-clinical data suggest neutralization of the neurite outgrowth inhibitor Nogo-A as a potential new way to achieve both axonal and myelin repair. Several phase I clinical studies with anti-Nogo-A antibodies have been conducted in different disease paradigms including MS and spinal cord injury. Data from spinal cord injury and amyotrophic lateral sclerosis (ALS) trials accredit a good safety profile of high doses of anti-Nogo-A antibodies administered intravenously or intrathecally. An antibody against a Nogo receptor subunit, leucine rich repeat and immunoglobulin-like domain-containing protein 1 (LINGO-1), was recently shown to improve outcome in patients with acute optic neuritis in a phase II study. Nogo-A-suppressing antibodies could be novel drug candidates for the relapsing as well as the progressive MS disease stage. In this review, we summarize the available pre-clinical and clinical evidence on Nogo-A and elucidate the potential of Nogo-A-antibodies as a therapy for progressive MS.

Published
2017

6. Sudan black: a fast, easy and non-toxic method to assess myelin repair in demyelinating diseases

Author

Martin E. Schwab, Carla A. Wicki, Benjamin V. Ineichen, Elisabeth J. Rushing, Michael Linnebank, Nicolas Good, Oliver Weinmann, Patricia S. Plattner, University of Zurich, and Ineichen, Benjamin V

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Histology, 610 Medicine & health, Naphthalenes, 2722 Histology, Pathology and Forensic Medicine, 03 medical and health sciences, Myelin, 2737 Physiology (medical), 0302 clinical medicine, In vivo, Physiology (medical), Medicine, Animals, Humans, Rats, Long-Evans, Remyelination, 10242 Brain Research Institute, Staining and Labeling, business.industry, Multiple sclerosis, Neurodegeneration, medicine.disease, Spinal cord, 3. Good health, Surgery, Staining, Rats, 2734 Pathology and Forensic Medicine, 2728 Neurology (clinical), 030104 developmental biology, medicine.anatomical_structure, Neurology, Spinal Cord, 2808 Neurology, 570 Life sciences, biology, Sudan black, Female, Neurology (clinical), business, Azo Compounds, 030217 neurology & neurosurgery, Demyelinating Diseases
Abstract

Aims The search for novel drugs that enhance myelin repair in entities such as multiple sclerosis has top priority in neurological research, not least because remyelination can hinder further neurodegeneration in neuro-inflammatory conditions. Recently, several new compounds with the potential to boost remyelination have been identified using high-throughput in vitro screening methods. However, assessing their potential to enhance remyelination in vivo using plastic embedded semi-thin sections or electron microscopy, even though being the gold standard for assessing remyelination, is toxic, extremely time-consuming, and expensive. Methods We screened available myelin dyes for a staining candidate which offers a faster and easier alternative to visualize remyelination in cryo-sections. Results We identified sudan black as a candidate with excellent myelin resolution and we show that our adapted sudan black staining can demonstrate myelin repair in rodent spinal cord cryosections as reliable as in semithin sections, but much faster, easier, less toxic and less expensive. Besides that, it can resolve the small myelinated axons in the corpus callosum. The staining can yet readily be combined with immunostainings which can be challenging in semithin sections. We validated the method in human spinal cord tissue as well as in experimental demyelination of the rat spinal cord by a lysolecithin time course experiment. As proof-of-principle, we demonstrate that sudan black is able to reliably detect the remyelination enhancing properties of benztropine. Conclusion Our adapted sudan black staining can be used to rapidly and non-toxically screen for remyelinating therapies in demyelinating diseases. This article is protected by copyright. All rights reserved.

Published
2016

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