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Advances in Translational Medicine 2010

2011; Lippincott Williams & Wilkins; Volume: 42; Issue: 2 Linguagem: Inglês

10.1161/strokeaha.110.605055

1524-4628

Anna M. Planas, Richard J. Traystman,

Acute Ischemic Stroke Management

HomeStrokeVol. 42, No. 2Advances in Translational Medicine 2010 Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplementary MaterialsFree AccessResearch ArticlePDF/EPUBAdvances in Translational Medicine 2010 Anna M. Planas, PhD and Richard J. Traystman, PhD Anna M. PlanasAnna M. Planas From the Department of Brain Ischemia and Neurodegeneration (A.M.P.), IIBB-CSIC, IDIBAPS, Barcelona, Spain; and the Departments of Anesthesiology, Emergency Medicine, Neurology, and Pharmacology (R.J.T.), University of Colorado Denver, Aurora, CO. and Richard J. TraystmanRichard J. Traystman From the Department of Brain Ischemia and Neurodegeneration (A.M.P.), IIBB-CSIC, IDIBAPS, Barcelona, Spain; and the Departments of Anesthesiology, Emergency Medicine, Neurology, and Pharmacology (R.J.T.), University of Colorado Denver, Aurora, CO. Originally published13 Jan 2011https://doi.org/10.1161/STROKEAHA.110.605055Stroke. 2011;42:283–284Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2011: Previous Version 1 Translation from bench to bedside is a tremendous challenge for stroke researchers. Effective neuroprotection from ischemia in humans is elusive despite a number of encouraging results in the laboratory. However, the lessons obtained so far might pave the way to better research strategies and more fruitful translational results. Rapid reperfusion within ischemic brain is essential to prevent further neuronal cell death. What else can be done to minimize brain damage once blood flow is re-established? Various interventions and drugs can prevent further cell death after reperfusion in animals. However, the challenge remains to be beneficial in humans. Adequate selection of patients is critical and there have been advances in identification of biomarkers, including gene expression signatures1 that may assist to identify stroke subtypes in patients. Several ongoing stroke clinical trials (www.strokecenter.org/) are the results of translation to the clinics of experimental findings. Hypothermia has provided strong preclinical evidence and several clinical trials are ongoing worldwide (Controlled Hypothermia in Large Infarction [CHILI], CHIL, COAST-II, HAIS-SE, and Mild Hypothermia in Acute Ischemic Stroke trial). Clinical trials are also assessing molecules that may decrease hemorrhagic complications and toxicity of recombinant tissue plasminogen activator (Desmoteplase in Acute Ischemic Stroke Trial [DIAS]-3, DIAS-4, TNKilas) and experimental research is ongoing on this subject.2 Other clinical trials are focused on therapies that have shown benefits in animals such as albumin (Alias-2), citicoline (ICTUS), or oxygen (SO2S). Combination therapies of tissue plasminogen activator and antioxidants (edaravone–citicoline; deferoxamine; uric acid) are based on beneficial effects obtained in preclinical studies with antioxidants in reperfused animals. However, reperfusion injury is not always apparent and treatments targeting reperfusion injury are not beneficial to all reperfused animals.3 Therefore, identification of patients with early signs of reperfusion injury by noninvasive imaging and biomarkers may be crucial to bring these treatments into successful randomized controlled clinical trials.Improvements in animal studies have been made by studying aged individuals4,5 and animals with stroke risk factors or genetic predisposition to hypertension, diabetes, hyperlipidemia, obesity,6 atherosclerosis, inflammation and infection.7 Also, increasing awareness is given to the effects of gender and sex hormones on the risk and outcome of stroke.8,9Progress has been made on the concept that not only must neurons be protected, but also the functionality of the neurovascular unit must be preserved.10 The prominent function of matrix metalloproteinases in acute brain injury and the activator effects that tissue plasminogen activator can exert on matrix metalloproteinases is now recognized. Furthermore, activated matrix metalloproteinase-9 appears to be a good biomarker that correlates with imaging markers of blood–brain barrier disruption.11 Ongoing stroke clinical trials with statins (NeuSTART II, Neu START, and STARS07) are in part based on the concept of vascular protection and matrix metalloproteinase inhibition.Advances in understanding communication between the brain and periphery are also relevant to stroke research. It is believed that stroke triggers immunodepression that renders ischemic animals and patients with stroke more prone to infection. Infection or strong inflammatory processes before ischemia exacerbate brain damage in animals,7 and several drugs that attenuate inflammation12 appear promising in preclinical studies. The ongoing clinical trial with minocycline (Minocycline to Improve Neurologic Outcome in Stroke [MINOS]) is mainly based on the anti-inflammatory effects that this drug has shown in experimental animal models of stroke. Targeting certain proinflammatory molecules and innate immune receptors such as interleukin-1b, CCL5,7 HMGB1,13 CD36,14 lipid mediators, complement activation pathways,15 and factors involved in the coagulation cascade16 are undergoing intense preclinical and clinical research. The role that alterations in the microcirculation play in brain damage need to be better explored. How inflammatory mediators released by brain cells, endothelium, leukocytes, and platelets17 create procoagulant events in the microvasculature, after recanalization of large vessel occlusion, is under investigation. The classical view that infiltrating leukocytes are deleterious is challenged by identification of anti-inflammatory subtypes of monocytes in patients with stroke, benefits of regulatory T-cells in ischemic animals, and by evidence suggesting that leukocyte infiltration is essential to modify potentially destructive local inflammation after brain damage.18 The leukocyte responses to brain ischemia are dynamic and have a specific time course involving phases of initiation, phagocytosis, and resolution of inflammation that paves the way for regenerative processes. Although we must increase our understanding of the molecular determinants of these steps, the growing view is that inflammation will have to be modulated but not fully suppressed.Experimental findings support functional recovery after stroke through plasticity phenomena, which can be promoted with drugs, interventions inducing brain stimulation (eg, enriched environment), and stem cells, even in aged rats that still have regenerative capacity.4 There is an increasing awareness about the possible relevance of endogenous circulating stem cells in patients with stroke19,20 and stronger evidence to support the idea that neurogenesis is activated after stroke in the human brain.21,22 Animal studies show that subventricular zone-derived neural progenitor cells migrate along blood vessels toward ischemic injury sites,23 but we are far from knowing whether these cells become new neurons integrating into the network. The available evidence supports the idea that stem cells favor recovery by promoting an environment that facilitates axonal regeneration, neurite outgrowth, functional reorganization, and neurogenesis. Results from the first studies in humans support beneficial effects of stem cell transplantation,24 and the need for large trials has been advised after a recent meta-analysis of current data available in patients with stroke.25 Several cell therapies are now being used in ongoing stroke trials (eg, Autologous Cell Therapy, SIVMAS, STEMS2) and are important to determine whether the experimental findings will be translatable to humans.26 Finally, additional studies are needed to evaluate whether interventions such as electric, electromagnetic, optical, or other forms of brain stimulation might be beneficial after stroke. It is likely that the results of ongoing stroke trials focusing on recovery (eg, Intravenous Thrombolysis Plus Hypothermia for Acute Treatment of Ischemic Stroke [ICTUS], ImpACT-24, MACSI, MAG111539, Motor Imagery for Gait Rehabilitation, Transcranial Direct Current Stimulation, TRAGAT, Virtual Reality Training Program) will bring some light to this issue in the near future.DisclosuresA.M.P. receives funding from the Spanish Ministry of Science and Innovation (SAF2008-04515-C01) and by the European Community (FP7/2007-2013; grant agreement number 201024). R.J.T. acknowledges funding from NIH/NINDSR01 NS046072.FootnotesCorrespondence to Anna M. Planas, PhD, Research Scientist, IIBB-CSIC, IDIBAPS, Department of Brain Ischemia and Neurodegeneration, Rossello 161, planta 6, Barcelona, E-08036, Spain. E-mail: [email protected]csic.es.References1. 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Stem cells in human neurodegenerative disorders—time for clinical translation?J Clin Invest. 2010; 120:29–40.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Onetti Y, Dantas A, Pérez B, Cugota R, Chamorro A, Planas A, Vila E and Jiménez-Altayó F (2015) Middle cerebral artery remodeling following transient brain ischemia is linked to early postischemic hyperemia: A target of uric acid treatment, American Journal of Physiology-Heart and Circulatory Physiology, 10.1152/ajpheart.00001.2015, 308:8, (H862-H874), Online publication date: 15-Apr-2015. Marinescu M, Chauveau F, Durand A, Riou A, Cho T, Dencausse A, Ballet S, Nighoghossian N, Berthezène Y and Wiart M (2012) Monitoring therapeutic effects in experimental stroke by serial USPIO-enhanced MRI, European Radiology, 10.1007/s00330-012-2567-2, 23:1, (37-47), Online publication date: 1-Jan-2013. He X, Sandhu H, Yang Y, Hua F, Belser N, Kim D and Xia Y (2012) Neuroprotection against hypoxia/ischemia: δ-opioid receptor-mediated cellular/molecular events, Cellular and Molecular Life Sciences, 10.1007/s00018-012-1167-2, 70:13, (2291-2303), Online publication date: 1-Jul-2013. Zhou L, Li Y, Bosworth H, Ehiri J and Luo C (2013) Challenges facing translational research organizations in China: a qualitative multiple case study, Journal of Translational Medicine, 10.1186/1479-5876-11-256, 11:1, Online publication date: 1-Dec-2013. Gliem M, Hermsen D, van Rooijen N, Hartung H and Jander S (2012) Secondary Intracerebral Hemorrhage Due to Early Initiation of Oral Anticoagulation After Ischemic Stroke, Stroke, 43:12, (3352-3357), Online publication date: 1-Dec-2012. Kummer R, Albers G and Mori E (2012) The Desmoteplase in Acute Ischemic Stroke (DIAS) Clinical Trial Program, International Journal of Stroke, 10.1111/j.1747-4949.2012.00910.x, 7:7, (589-596), Online publication date: 1-Oct-2012. Gliem M, Mausberg A, Lee J, Simiantonakis I, van Rooijen N, Hartung H and Jander S (2012) Macrophages prevent hemorrhagic infarct transformation in murine stroke models, Annals of Neurology, 10.1002/ana.23529, 71:6, (743-752), Online publication date: 1-Jun-2012. February 2011Vol 42, Issue 2 Advertisement Article InformationMetrics © 2011 American Heart Association, Inc.https://doi.org/10.1161/STROKEAHA.110.605055PMID: 21233466 Manuscript receivedDecember 2, 2010Manuscript acceptedDecember 7, 2010Originally publishedJanuary 13, 2011 KeywordsstroketranslationexperimentalclinicaltreatmentPDF download Advertisement SubjectsTreatment