학술논문
Early Blood-Brain Barrier Impairment as a Pathological Hallmark in a Novel Model of Closed-Head Concussive Brain Injury (CBI) in Mice.
Document Type
Academic Journal
Author
Blaschke SJ; Department of Neurology, Faculty of Medicine and University Hospital, University of Cologne, 50923 Cologne, Germany.; Cognitive Neuroscience Section, Institute of Neuroscience and Medicine (INM-3), Research Centre Juelich, 52428 Juelich, Germany.; Rautenberg N; Department of Neurology, Faculty of Medicine and University Hospital, University of Cologne, 50923 Cologne, Germany.; Cognitive Neuroscience Section, Institute of Neuroscience and Medicine (INM-3), Research Centre Juelich, 52428 Juelich, Germany.; Endepols H; Institute of Radiochemistry and Experimental Molecular Imaging, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany.; Department of Nuclear Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.; Nuclear Chemistry, Institute of Neuroscience and Medicine (INM-5), Research Centre Juelich, 52428 Juelich, Germany.; Jendro A; Department of Neurology, Faculty of Medicine and University Hospital, University of Cologne, 50923 Cologne, Germany.; Konrad J; Mechanobiology, Institute of Biological Information Processing (IBI-2), Research Centre Juelich, 52425 Juelich, Germany.; Vlachakis S; Department of Neurology, Faculty of Medicine and University Hospital, University of Cologne, 50923 Cologne, Germany.; Wiedermann D; Multimodal Imaging Group, Max Planck Institute for Metabolism Research, 50931 Cologne, Germany.; Schroeter M; Department of Neurology, Faculty of Medicine and University Hospital, University of Cologne, 50923 Cologne, Germany.; Cognitive Neuroscience Section, Institute of Neuroscience and Medicine (INM-3), Research Centre Juelich, 52428 Juelich, Germany.; Hoffmann B; Mechanobiology, Institute of Biological Information Processing (IBI-2), Research Centre Juelich, 52425 Juelich, Germany.; Merkel R; Mechanobiology, Institute of Biological Information Processing (IBI-2), Research Centre Juelich, 52425 Juelich, Germany.; Marklund N; Department of Clinical Sciences Lund, Neurosurgery, Lund University, 221 85 Lund, Sweden.; Fink GR; Department of Neurology, Faculty of Medicine and University Hospital, University of Cologne, 50923 Cologne, Germany.; Cognitive Neuroscience Section, Institute of Neuroscience and Medicine (INM-3), Research Centre Juelich, 52428 Juelich, Germany.; Rueger MA; Department of Neurology, Faculty of Medicine and University Hospital, University of Cologne, 50923 Cologne, Germany.; Cognitive Neuroscience Section, Institute of Neuroscience and Medicine (INM-3), Research Centre Juelich, 52428 Juelich, Germany.
Source
Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE
Subject
Language
English
Abstract
Concussion, caused by a rotational acceleration/deceleration injury mild enough to avoid structural brain damage, is insufficiently captured in recent preclinical models, hampering the relation of pathophysiological findings on the cellular level to functional and behavioral deficits. We here describe a novel model of unrestrained, single vs. repetitive concussive brain injury (CBI) in male C56Bl/6j mice. Longitudinal behavioral assessments were conducted for up to seven days afterward, alongside the evaluation of structural cerebral integrity by in vivo magnetic resonance imaging (MRI, 9.4 T), and validated ex vivo by histology. Blood-brain barrier (BBB) integrity was analyzed by means of fluorescent dextran- as well as immunoglobulin G (IgG) extravasation, and neuroinflammatory processes were characterized both in vivo by positron emission tomography (PET) using [ 18 F]DPA-714 and ex vivo using immunohistochemistry. While a single CBI resulted in a defined, subacute neuropsychiatric phenotype, longitudinal cognitive testing revealed a marked decrease in spatial cognition, most pronounced in mice subjected to CBI at high frequency (every 48 h). Functional deficits were correlated to a parallel disruption of the BBB, (R 2 = 0.29, p < 0.01), even detectable by a significant increase in hippocampal uptake of [ 18 F]DPA-714, which was not due to activation of microglia, as confirmed immunohistochemically. Featuring a mild but widespread disruption of the BBB without evidence of macroscopic damage, this model induces a characteristic neuro-psychiatric phenotype that correlates to the degree of BBB disruption. Based on these findings, the BBB may function as both a biomarker of CBI severity and as a potential treatment target to improve recovery from concussion.