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      Thinking Outside the Ischemia Box: Advancements in the Use of Multiple Sclerosis Drugs in Ischemic Stroke

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          Abstract

          Ischemic stroke (IS) is a major cause of death and disability, despite early intervention. Thrombo-inflammation, the inflammatory process triggered by ischemia, is a concept that ties IS with multiple sclerosis (MS), under the wider ‘umbrella’ of neuroinflammation, i.e., the inflammation of the nervous tissue. Drawing from this, numerous studies have explored the potential of MS disease-modifying drugs in the setting of IS. In this review, we present the available studies and discuss their potential in ameliorating IS outcomes. Based on our search, the vast majority of the studies have been conducted on animals, yielding mostly positive results. Two clinical trials involving natalizumab showed that it does not confer any benefits, but four human studies regarding fingolimod have showcased its potential in improving recovery prospects. However, concerns on safety and other issues are raised, and basic questions still need to be answered.

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          Heart Disease and Stroke Statistics—2018 Update: A Report From the American Heart Association

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            Inflammation and Stroke: An Overview.

            The immune response to acute cerebral ischemia is a major factor in stroke pathobiology and outcome. While the immune response starts locally in occluded and hypoperfused vessels and the ischemic brain parenchyma, inflammatory mediators generated in situ propagate through the organism as a whole. This "spillover" leads to a systemic inflammatory response first, followed by immunosuppression aimed at dampening the potentially harmful proinflammatory milieu. In this overview we will outline the inflammatory cascade from its starting point in the vasculature of the ischemic brain to the systemic immune response elicited by brain ischemia. Potential immunomodulatory therapeutic approaches, including preconditioning and immune cell therapy will also be discussed.
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              Lost in translation: the valley of death across preclinical and clinical divide – identification of problems and overcoming obstacles

              A rift that has opened up between basic research (bench) and clinical research and patients (bed) who need their new treatments, diagnostics and prevention, and this rift is widening and getting deeper. The crisis involving the “translation” of basic scientific findings in a laboratory setting into human applications and potential treatments or biomarkers for a disease is widely recognized both in academia and industry. Despite the attempts that have been made both in academic and industry settings to mitigate this problem, the high attrition rates of drug development and the problem with reproducibility and translatability of preclinical findings to human applications remain a fact and the return on the investment has been limited in terms of clinical impact. Here I provide an overview of the challenges facing the drug development, and translational discordance with specific focus on a number of “culprits” in translational research including poor hypothesis, irreproducible data, ambiguous preclinical models, statistical errors, the influence of organizational structures, lack of incentives in the academic setting, governmental funding mechanisms, the clinical relevance of basic research, insufficient transparency, and lack of data sharing in research. I further provide some suggestions and new strategies that include some new aspects on open innovation models, entrepreneurship, transparency, and decision making to overcome each of the many problems during the drug discovery and development process and to more dynamically adjust for innovation challenges with broader scientific feedback.
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                Author and article information

                Contributors
                Role: Academic Editor
                Role: Academic Editor
                Journal
                J Clin Med
                J Clin Med
                jcm
                Journal of Clinical Medicine
                MDPI
                2077-0383
                07 February 2021
                February 2021
                : 10
                : 4
                : 630
                Affiliations
                [1 ]Department of Neurology, University Hospital of Larissa, Faculty of Medicine, School of Health Sciences, University of Thessaly, 41110 Larissa, Greece; aaloizou@ 123456med.uth.gr (A.-M.A.); vsiokas@ 123456med.uth.gr (V.S.); georginapat08@ 123456gmail.com (G.P.); liampasioannes@ 123456gmail.com (I.L.); zitsouri@ 123456med.uth.gr (Z.T.)
                [2 ]Multiple Sclerosis Center, B’ Department of Neurology, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; bakirtzischristos@ 123456yahoo.gr
                [3 ]Department of Cardiothoracic Surgery, University General Hospital of Heraklion, Medical School, University of Crete, 71003 Heraklion, Greece; lazopoulosg@ 123456ath.forthnet.gr
                [4 ]Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; calinadaniela@ 123456gmail.com
                [5 ]Department of Toxicology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; daoana00@ 123456gmail.com
                [6 ]Laboratory of Toxicology, School of Medicine, University of Crete, 71003 Heraklion, Greece; tsatsaka@ 123456uoc.gr
                [7 ]Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, 41110 Larissa, Greece; bogdanos@ 123456uth.gr
                Author notes
                [* ]Correspondence: ebsdar@ 123456gmail.com
                Author information
                https://orcid.org/0000-0001-9354-774X
                https://orcid.org/0000-0002-2958-5220
                https://orcid.org/0000-0002-4737-3707
                https://orcid.org/0000-0002-1523-9116
                https://orcid.org/0000-0002-8162-5955
                https://orcid.org/0000-0003-3824-2462
                https://orcid.org/0000-0003-2957-641X
                Article
                jcm-10-00630
                10.3390/jcm10040630
                7914575
                33562264
                681b39f5-5bb5-4ec9-aa3a-dcbde04de391
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 20 December 2020
                : 03 February 2021
                Categories
                Review

                ischemic stroke,multiple sclerosis,natalizumab,fingolimod

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