37
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Bone Fracture Pre-Ischemic Stroke Exacerbates Ischemic Cerebral Injury in Mice

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Ischemic stroke is a devastating complication of bone fracture. Bone fracture shortly after stroke enhances stroke injury by augmenting inflammation. We hypothesize that bone fracture shortly before ischemic stroke also exacerbates ischemic cerebral injury. Tibia fracture was performed 6 or 24 hours before permanent middle cerebral artery occlusion (pMCAO) on C57BL/6J mice or Ccr2 RFP/+Cx3cr1 GFP/+ mice that have the RFP gene knocked into one allele of Ccr2 gene and GFP gene knocked into one allele of Cx3cr1 gene. Behavior was tested 3 days after pMCAO. Infarct volume, the number of CD68 + cells, apoptotic neurons, bone marrow-derived macrophages (RFP +), and microgila (GFP +) in the peri-infarct region were quantified. Compared to mice subjected to pMCAO only, bone fracture 6 or 24 hours before pMCAO increased behavioral deficits, the infarct volume, and the number of CD68 + cells and apoptotic neurons in the peri-infarct area. Both bone marrow-derived macrophages (CCR2 +) and microglia (CX3CR1 +) increased in the peri-infarct regions of mice subjected to bone fracture before pMCAO compared to stroke-only mice. The mice subjected to bone fracture 6 hours before pMCAO had more severe injury than mice that had bone fracture 24 hours before pMCAO. Our data showed that bone fracture shortly before stroke also increases neuroinflammation and exacerbates ischemic cerebral injury. Our findings suggest that inhibition of neuroinflammation or management of stroke risk factors before major bone surgery would be beneficial for patients who are likely to suffer from stroke.

          Related collections

          Most cited references27

          • Record: found
          • Abstract: found
          • Article: not found

          Control of synaptic strength by glial TNFalpha.

          Activity-dependent modulation of synaptic efficacy in the brain contributes to neural circuit development and experience-dependent plasticity. Although glia are affected by activity and ensheathe synapses, their influence on synaptic strength has largely been ignored. Here, we show that a protein produced by glia, tumor necrosis factor alpha (TNFalpha), enhances synaptic efficacy by increasing surface expression of AMPA receptors. Preventing the actions of endogenous TNFalpha has the opposite effects. Thus, the continual presence of TNFalpha is required for preservation of synaptic strength at excitatory synapses. Through its effects on AMPA receptor trafficking, TNFalpha may play roles in synaptic plasticity and modulating responses to neural injury.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: found
            Is Open Access

            Inflammatory mechanisms in ischemic stroke: therapeutic approaches

            Acute ischemic stroke is the third leading cause of death in industrialized countries and the most frequent cause of permanent disability in adults worldwide. Despite advances in the understanding of the pathophysiology of cerebral ischemia, therapeutic options remain limited. Only recombinant tissue-plasminogen activator (rt-PA) for thrombolysis is currently approved for use in the treatment of this devastating disease. However, its use is limited by its short therapeutic window (three hours), complications derived essentially from the risk of hemorrhage, and the potential damage from reperfusion/ischemic injury. Two important pathophysiological mechanisms involved during ischemic stroke are oxidative stress and inflammation. Brain tissue is not well equipped with antioxidant defenses, so reactive oxygen species and other free radicals/oxidants, released by inflammatory cells, threaten tissue viability in the vicinity of the ischemic core. This review will discuss the molecular aspects of oxidative stress and inflammation in ischemic stroke and potential therapeutic strategies that target neuroinflammation and the innate immune system. Currently, little is known about endogenous counterregulatory immune mechanisms. However, recent studies showing that regulatory T cells are major cerebroprotective immunomodulators after stroke suggest that targeting the endogenous adaptive immune response may offer novel promising neuroprotectant therapies.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Role of interleukin-1beta in postoperative cognitive dysfunction.

              Although postoperative cognitive dysfunction (POCD) often complicates recovery from major surgery, the pathogenic mechanisms remain unknown. We explored whether systemic inflammation, in response to surgical trauma, triggers hippocampal inflammation and subsequent memory impairment, in a mouse model of orthopedic surgery. C57BL/6J, knock out (lacking interleukin [IL]-1 receptor, IL-1R(-/-)) and wild type mice underwent surgery of the tibia under general anesthesia. Separate cohorts of animals were tested for memory function with fear conditioning tests, or euthanized at different times to assess levels of systemic and hippocampal cytokines and microglial activation; the effects of interventions, designed to interrupt inflammation (specifically and nonspecifically), were also assessed. Surgery caused hippocampal-dependent memory impairment that was associated with increased plasma cytokines, as well as reactive microgliosis and IL-1beta transcription and expression in the hippocampus. Nonspecific attenuation of innate immunity with minocycline prevented surgery-induced changes. Functional inhibition of IL-1beta, both in mice pretreated with IL-1 receptor antagonist and in IL-1R(-/-) mice, mitigated the neuroinflammatory effects of surgery and memory dysfunction. A peripheral surgery-induced innate immune response triggers an IL-1beta-mediated inflammatory process in the hippocampus that underlies memory impairment. This may represent a viable target to interrupt the pathogenesis of postoperative cognitive dysfunction.
                Bookmark

                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                18 April 2016
                2016
                : 11
                : 4
                : e0153835
                Affiliations
                [1 ]Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California San Francisco, San Francisco, California, United States of America
                [2 ]Department of Neurosurgery, Tianjin Fifth Center Hospital, Tianjin, China
                [3 ]Department of Neurosurgery, Beijing Tiantan Hospital, Beijing, China
                [4 ]Department of Neurology, Shanghai Ninth People’s Hospital, Shanghai, China
                Indian Institute of Integrative Medicine, INDIA
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: HS LW. Performed the experiments: LW SK LZ ZL WZ. Analyzed the data: LW SK DZ HS. Wrote the paper: LW HS.

                Article
                PONE-D-15-50233
                10.1371/journal.pone.0153835
                4835054
                27089041
                fdbe39a5-cb2c-41d6-97b3-f9318a34a104
                © 2016 Wang et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 17 November 2015
                : 2 April 2016
                Page count
                Figures: 7, Tables: 1, Pages: 14
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: R01 NS027713
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: R01 HL122774
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: R21 NS083788
                Award Recipient :
                Funded by: Michael Ryan Zodda Foundation
                Award Recipient :
                Funded by: UCSF Research Evaluation and Allocation Committee (REAC)
                Award Recipient :
                This work was supported by National Institutes of Health R01 NS027713, R01 HL122774 and R21 NS083788 (to HS); Michael Ryan Zodda Foundation (to HS); and UCSF Research Evaluation and Allocation Committee (REAC) (to HS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Critical Care and Emergency Medicine
                Trauma Medicine
                Traumatic Injury
                Bone Fracture
                Biology and Life Sciences
                Anatomy
                Musculoskeletal System
                Skeleton
                Tibia
                Medicine and Health Sciences
                Anatomy
                Musculoskeletal System
                Skeleton
                Tibia
                Medicine and Health Sciences
                Neurology
                Cerebrovascular Diseases
                Stroke
                Ischemic Stroke
                Medicine and Health Sciences
                Vascular Medicine
                Stroke
                Ischemic Stroke
                Medicine and Health Sciences
                Neurology
                Cerebrovascular Diseases
                Stroke
                Medicine and Health Sciences
                Vascular Medicine
                Stroke
                Biology and Life Sciences
                Organisms
                Animals
                Vertebrates
                Amniotes
                Mammals
                Rodents
                Mice
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Blood Cells
                White Blood Cells
                Macrophages
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Immune Cells
                White Blood Cells
                Macrophages
                Biology and Life Sciences
                Immunology
                Immune Cells
                White Blood Cells
                Macrophages
                Medicine and Health Sciences
                Immunology
                Immune Cells
                White Blood Cells
                Macrophages
                Medicine and Health Sciences
                Neurology
                Brain Damage
                Medicine and Health Sciences
                Critical Care and Emergency Medicine
                Trauma Medicine
                Brain Damage
                Biology and Life Sciences
                Immunology
                Immune Response
                Inflammation
                Medicine and Health Sciences
                Immunology
                Immune Response
                Inflammation
                Medicine and Health Sciences
                Diagnostic Medicine
                Signs and Symptoms
                Inflammation
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Signs and Symptoms
                Inflammation
                Custom metadata
                All relevant data are available from the Harvard Dataverse ( https://dataverse.harvard.edu/dataverse/Wang-2016).

                Uncategorized
                Uncategorized

                Comments

                Comment on this article