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      Multimodal imaging reveals temporal and spatial microglia and matrix metalloproteinase activity after experimental stroke

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          Abstract

          Stroke is the most common cause of death and disability from neurologic disease in humans. Activation of microglia and matrix metalloproteinases (MMPs) is involved in positively and negatively affecting stroke outcome. Novel, noninvasive, multimodal imaging methods visualizing microglial and MMP alterations were employed. The spatio-temporal dynamics of these parameters were studied in relation to blood flow changes. Micro positron emission tomography ( μPET) using [ 18F]BR-351 showed MMP activity within the first days after transient middle cerebral artery occlusion (tMCAo), followed by increased [ 18F]DPA-714 uptake as a marker for microglia activation with a maximum at 14 days after tMCAo. The inflammatory response was spatially located in the infarct core and in adjacent (penumbral) tissue. For the first time, multimodal imaging based on PET, single photon emission computed tomography, and magnetic resonance imaging revealed insight into the spatio-temporal distribution of critical parameters of poststroke inflammation. This allows further evaluation of novel treatment paradigms targeting the postischemic inflammation.

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          In vivo imaging of tumors with protease-activated near-infrared fluorescent probes.

          R Weissleder, C. H. Tung, U Mahmood … (1999)
          We have developed a method to image tumor-associated lysosomal protease activity in a xenograft mouse model in vivo using autoquenched near-infrared fluorescence (NIRF) probes. NIRF probes were bound to a long circulating graft copolymer consisting of poly-L-lysine and methoxypolyethylene glycol succinate. Following intravenous injection, the NIRF probe carrier accumulated in solid tumors due to its long circulation time and leakage through tumor neovasculature. Intratumoral NIRF signal was generated by lysosomal proteases in tumor cells that cleave the macromolecule, thereby releasing previously quenched fluorochrome. In vivo imaging showed a 12-fold increase in NIRF signal, allowing the detection of tumors with submillimeter-sized diameters. This strategy can be used to detect such early stage tumors in vivo and to probe for specific enzyme activity.
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            Role of matrix metalloproteinases in delayed cortical responses after stroke.

            Bing-Qiao Zhao, Sophia Wang, Hahn-Young Kim … (2006)
            Matrix metalloproteinases (MMPs) are zinc-endopeptidases with multifactorial actions in central nervous system (CNS) physiology and pathology. Accumulating data suggest that MMPs have a deleterious role in stroke. By degrading neurovascular matrix, MMPs promote injury of the blood-brain barrier, edema and hemorrhage. By disrupting cell-matrix signaling and homeostasis, MMPs trigger brain cell death. Hence, there is a movement toward the development of MMP inhibitors for acute stroke therapy. But MMPs may have a different role during delayed phases after stroke. Because MMPs modulate brain matrix, they may mediate beneficial plasticity and remodeling during stroke recovery. Here, we show that MMPs participate in delayed cortical responses after focal cerebral ischemia in rats. MMP-9 is upregulated in peri-infarct cortex at 7-14 days after stroke and is colocalized with markers of neurovascular remodeling. Treatment with MMP inhibitors at 7 days after stroke suppresses neurovascular remodeling, increases ischemic brain injury and impairs functional recovery at 14 days. MMP processing of bioavailable VEGF may be involved because inhibition of MMPs reduces endogenous VEGF signals, whereas additional treatment with exogenous VEGF prevents MMP inhibitor-induced worsening of infarction. These data suggest that, contrary to MMP inhibitor therapies for acute stroke, strategies that modulate MMPs may be needed for promoting stroke recovery.
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              Reactive astrocytes overexpress TSPO and are detected by TSPO positron emission tomography imaging.

              Sonia Lavisse, Martine Guillermier, Anne-Sophie Hérard … (2012)
              Astrocytes and microglia become reactive under most brain pathological conditions, making this neuroinflammation process a surrogate marker of neuronal dysfunction. Neuroinflammation is associated with increased levels of translocator protein 18 kDa (TSPO) and binding sites for TSPO ligands. Positron emission tomography (PET) imaging of TSPO is thus commonly used to monitor neuroinflammation in preclinical and clinical studies. It is widely considered that TSPO PET signal reveals reactive microglia, although a few studies suggested a potential contribution of reactive astrocytes. Because astrocytes and microglia play very different roles, it is crucial to determine whether reactive astrocytes can also overexpress TSPO and yield to a detectable TSPO PET signal in vivo. We used a model of selective astrocyte activation through lentiviral gene transfer of the cytokine ciliary neurotrophic factor (CNTF) into the rat striatum, in the absence of neurodegeneration. CNTF induced an extensive activation of astrocytes, which overexpressed GFAP and become hypertrophic, whereas microglia displayed minimal increase in reactive markers. Two TSPO radioligands, [(18)F]DPA-714 [N,N-diethyl-2-(2-(4-(2-[(18)F]fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide] and [(11)C]SSR180575 (7-chloro-N,N-dimethyl-5-[(11)C]methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide), showed a significant binding in the lenti-CNTF-injected striatum that was saturated and displaced by PK11195 [N-methyl-N-(1-methylpropyl)-1-(2-chlorophenyl)-isoquinoline-3-carboxamide]. The volume of radioligand binding matched the GFAP immunopositive volume. TSPO mRNA levels were significantly increased, and TSPO protein was overexpressed by CNTF-activated astrocytes. We show that reactive astrocytes overexpress TSPO, yielding to a significant and selective binding of TSPO radioligands. Therefore, caution must be used when interpreting TSPO PET imaging in animals or patients because reactive astrocytes can contribute to the signal in addition to reactive microglia.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Cereb Blood Flow Metab
                Journal ID (iso-abbrev): J. Cereb. Blood Flow Metab
                Title: Journal of Cerebral Blood Flow & Metabolism
                Publisher: Nature Publishing Group
                ISSN (Print): 0271-678X
                ISSN (Electronic): 1559-7016
                Publication date (Print): November 2015
                Publication date (Electronic): 01 July 2015
                Publication date PMC-release: 1 November 2015
                Volume: 35
                Issue: 11
                Pages: 1711-1721
                Affiliations
                [1 ]European Institute for Molecular Imaging (EIMI), Westfälische Wilhelms University Münster , Münster, Germany
                [2 ]Paris Centre de Recherche Cardiovasculaire (PARC) , Paris, France
                [3 ]Department of Clinical Radiology of the University Hospital, Westfälische Wilhelms University Münster , Münster, Germany
                [4 ]Department of Nuclear Medicine of the University Hospital, Westfälische Wilhelms University Münster , Münster, Germany
                [5 ]Cells-in-Motion Cluster of Excellence (EXC 1003—CiM), Westfälische Wilhelms University Münster , Münster, Germany
                [6 ]Service Hospitalier Frédéric Joliot, Institut d'Imagerie BioMédicale, CEA, Orsay, France
                [7 ]Institute of Biostructure and Bioimaging, CNR , Naples, Italy
                [8 ]Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (CSIC), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) , Barcelona, Spain
                [9 ]Institute of Physiological Chemistry and Pathobiochemistry, Westfälische Wilhelms University Münster , Münster, Germany
                [10 ]Department of Geriatrics, Johanniter Hospital, Evangelische Kliniken , Bonn, Germany
                Author notes
                [* ]European Institute for Molecular Imaging (EIMI), University of Münster , Waldeyerstrasse 15, Münster 48149, Germany. E-mail: ahjacobs@ 123456uni-muenster.de
                [11]

                Current address: Radiopharmaceutical Chemistry, German Cancer Research Center (dkfz), Heidelberg, Germany.

                Article
                Publisher Item ID: jcbfm2015149
                DOI: 10.1038/jcbfm.2015.149
                PMC ID: 4635244
                PubMed ID: 26126867
                SO-VID: aa8afcfa-d1a0-4781-bbee-57f2e0d6ad9d
                Copyright © Copyright © 2015 International Society for Cerebral Blood Flow & Metabolism, Inc.
                License:

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/

                History
                Date received : 10 December 2014
                Date revision received : 11 May 2015
                Date accepted : 15 May 2015
                Categories
                Subject: Original Article

                ScienceOpen disciplines: Neurosciences
                Keywords: microglia,matrix metalloproteases,perfusion,positron emission tomography,stroke
                Data availability:
                ScienceOpen disciplines: Neurosciences
                Keywords: microglia, matrix metalloproteases, perfusion, positron emission tomography, stroke

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