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A novel neurotherapeutic for multiple sclerosis, ischemic injury, methamphetamine addiction, and traumatic brain injury

Neurovascular, autoimmune, and traumatic injuries of the central nervous system (CNS) all have in common an initial acute inflammatory response mediated by influx across the blood-brain barrier of activated mononuclear cells followed by chronic and often progressive disability. Although some anti-in...

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Autores principales: Vandenbark, Arthur A., Meza-Romero, Roberto, Benedek, Gil, Offner, Halina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346590/
https://www.ncbi.nlm.nih.gov/pubmed/30683115
http://dx.doi.org/10.1186/s12974-018-1393-0
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author Vandenbark, Arthur A.
Meza-Romero, Roberto
Benedek, Gil
Offner, Halina
author_facet Vandenbark, Arthur A.
Meza-Romero, Roberto
Benedek, Gil
Offner, Halina
author_sort Vandenbark, Arthur A.
collection PubMed
description Neurovascular, autoimmune, and traumatic injuries of the central nervous system (CNS) all have in common an initial acute inflammatory response mediated by influx across the blood-brain barrier of activated mononuclear cells followed by chronic and often progressive disability. Although some anti-inflammatory therapies can reduce cellular infiltration into the initial lesions, there are essentially no effective treatments for the progressive phase. We here review the successful treatment of animal models for four separate neuroinflammatory and neurodegenerative CNS conditions using a single partial MHC class II construct called DRa1-hMOG-35-55 or its newest iteration, DRa1(L50Q)-hMOG-35-55 (DRhQ) that can be administered without a need for class II tissue type matching due to the conserved DRα1 moiety of the drug. These constructs antagonize the cognate TCR and bind with high affinity to their cell-bound CD74 receptor on macrophages and dendritic cells, thereby competitively inhibiting downstream signaling and pro-inflammatory effects of macrophage migration inhibitory factor (MIF) and its homolog, d-dopachrome tautomerase (D-DT=MIF-2) that bind to identical residues of CD74 leading to progressive disease. These effects suggest the existence of a common pathogenic mechanism involving a chemokine-driven influx of activated monocytes into the CNS tissue that can be reversed by parenteral injection of the DRa1-MOG-35-55 constructs that also induce anti-inflammatory macrophages and microglia within the CNS. Due to their ability to block this common pathway, these novel drugs appear to be prime candidates for therapy of a wide range of neuroinflammatory and neurodegenerative CNS conditions.
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spelling pubmed-63465902019-01-29 A novel neurotherapeutic for multiple sclerosis, ischemic injury, methamphetamine addiction, and traumatic brain injury Vandenbark, Arthur A. Meza-Romero, Roberto Benedek, Gil Offner, Halina J Neuroinflammation Review Neurovascular, autoimmune, and traumatic injuries of the central nervous system (CNS) all have in common an initial acute inflammatory response mediated by influx across the blood-brain barrier of activated mononuclear cells followed by chronic and often progressive disability. Although some anti-inflammatory therapies can reduce cellular infiltration into the initial lesions, there are essentially no effective treatments for the progressive phase. We here review the successful treatment of animal models for four separate neuroinflammatory and neurodegenerative CNS conditions using a single partial MHC class II construct called DRa1-hMOG-35-55 or its newest iteration, DRa1(L50Q)-hMOG-35-55 (DRhQ) that can be administered without a need for class II tissue type matching due to the conserved DRα1 moiety of the drug. These constructs antagonize the cognate TCR and bind with high affinity to their cell-bound CD74 receptor on macrophages and dendritic cells, thereby competitively inhibiting downstream signaling and pro-inflammatory effects of macrophage migration inhibitory factor (MIF) and its homolog, d-dopachrome tautomerase (D-DT=MIF-2) that bind to identical residues of CD74 leading to progressive disease. These effects suggest the existence of a common pathogenic mechanism involving a chemokine-driven influx of activated monocytes into the CNS tissue that can be reversed by parenteral injection of the DRa1-MOG-35-55 constructs that also induce anti-inflammatory macrophages and microglia within the CNS. Due to their ability to block this common pathway, these novel drugs appear to be prime candidates for therapy of a wide range of neuroinflammatory and neurodegenerative CNS conditions. BioMed Central 2019-01-23 /pmc/articles/PMC6346590/ /pubmed/30683115 http://dx.doi.org/10.1186/s12974-018-1393-0 Text en © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply. 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Review
Vandenbark, Arthur A.
Meza-Romero, Roberto
Benedek, Gil
Offner, Halina
A novel neurotherapeutic for multiple sclerosis, ischemic injury, methamphetamine addiction, and traumatic brain injury
title A novel neurotherapeutic for multiple sclerosis, ischemic injury, methamphetamine addiction, and traumatic brain injury
title_full A novel neurotherapeutic for multiple sclerosis, ischemic injury, methamphetamine addiction, and traumatic brain injury
title_fullStr A novel neurotherapeutic for multiple sclerosis, ischemic injury, methamphetamine addiction, and traumatic brain injury
title_full_unstemmed A novel neurotherapeutic for multiple sclerosis, ischemic injury, methamphetamine addiction, and traumatic brain injury
title_short A novel neurotherapeutic for multiple sclerosis, ischemic injury, methamphetamine addiction, and traumatic brain injury
title_sort novel neurotherapeutic for multiple sclerosis, ischemic injury, methamphetamine addiction, and traumatic brain injury
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346590/
https://www.ncbi.nlm.nih.gov/pubmed/30683115
http://dx.doi.org/10.1186/s12974-018-1393-0
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