18
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      The heme and radical scavenger α 1-microglobulin (A1M) confers early protection of the immature brain following preterm intraventricular hemorrhage

      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

          Background

          Germinal matrix intraventricular hemorrhage (GM-IVH) is associated with cerebro-cerebellar damage in very preterm infants, leading to neurodevelopmental impairment. Penetration, from the intraventricular space, of extravasated red blood cells and extracellular hemoglobin (Hb), to the periventricular parenchyma and the cerebellum has been shown to be causal in the development of brain injury following GM-IVH. Furthermore, the damage has been described to be associated with the cytotoxic nature of extracellular Hb-metabolites. To date, there is no therapy available to prevent infants from developing either hydrocephalus or serious neurological disability. Mechanisms previously described to cause brain damage following GM-IVH, i.e., oxidative stress and Hb-metabolite toxicity, suggest that the free radical and heme scavenger α 1-microglobulin (A1M) may constitute a potential neuroprotective intervention.

          Methods

          Using a preterm rabbit pup model of IVH, where IVH was induced shortly after birth in pups delivered by cesarean section at E29 (3 days prior to term), we investigated the brain distribution of recombinant A1M (rA1M) following intracerebroventricular (i.c.v.) administration at 24 h post-IVH induction. Further, short-term functional protection of i.c.v.-administered human A1M (hA1M) following IVH in the preterm rabbit pup model was evaluated.

          Results

          Following i.c.v. administration, rA1M was distributed in periventricular white matter regions, throughout the fore- and midbrain and extending to the cerebellum. The regional distribution of rA1M was accompanied by a high co-existence of positive staining for extracellular Hb.

          Administration of i.c.v.-injected hA1M was associated with decreased structural tissue and mitochondrial damage and with reduced mRNA expression for proinflammatory and inflammatory signaling-related genes induced by IVH in periventricular brain tissue.

          Conclusions

          The results of this study indicate that rA1M/hA1M is a potential candidate for neuroprotective treatment following preterm IVH.

          Electronic supplementary material

          The online version of this article (10.1186/s12974-019-1486-4) contains supplementary material, which is available to authorized users.

          Related collections

          Most cited references64

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

          Pathogenesis of cerebral white matter injury of prematurity.

          Cerebral white matter injury, characterised by loss of premyelinating oligodendrocytes (pre-OLs), is the most common form of injury to the preterm brain and is associated with a high risk of neurodevelopmental impairment. The unique cerebrovascular anatomy and physiology of the premature baby underlies the exquisite sensitivity of white matter to the abnormal milieu of preterm extrauterine life, in particular ischaemia and inflammation. These two upstream mechanisms can coexist and amplify their effects, leading to activation of two principal downstream mechanisms: excitotoxicity and free radical attack. Upstream mechanisms trigger generation of reactive oxygen and nitrogen species. The pre-OL is intrinsically vulnerable to free radical attack due to immaturity of antioxidant enzyme systems and iron accumulation. Ischaemia and inflammation trigger glutamate receptor-mediated injury leading to maturation-dependent cell death and loss of cellular processes. This review looks at recent evidence for pathogenetic mechanisms in white matter injury with emphasis on targets for prevention and treatment of injury.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Early detection of regional cerebral ischemia in cats: comparison of diffusion- and T2-weighted MRI and spectroscopy.

            Diffusion-weighted MR images were compared with T2-weighted MR images and correlated with 1H spin-echo and 31P MR spectroscopy for 6-8 h following a unilateral middle cerebral and bilateral carotid artery occlusion in eight cats. Diffusion-weighted images using strong gradient strengths (b values of 1413 s/mm2) displayed a significant relative hyperintensity in ischemic regions as early as 45 min after onset of ischemia whereas T2-weighted spin-echo images failed to clearly demonstrate brain injury up to 2-3 h postocclusion. Signal intensity ratios (SIR) of ischemic to normal tissues were greater in the diffusion-weighted images at all times than in either TE 80 or TE 160 ms T2-weighted MR images. Diffusion- and T2-weighted SIR did not correlate for the first 1-2 h postocclusion. Good correlation was found between diffusion-weighted SIR and ischemic disturbances of energy metabolism as detected by 31P and 1H MR spectroscopy. Diffusion-weighted hyperintensity in ischemic tissues may be temperature-related, due to rapid accumulation of diffusion-restricted water in the intracellular space (cytotoxic edema) resulting from the breakdown of the transmembrane pump and/or to microscopic brain pulsations.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Semaphorins command cells to move.

              Semaphorins are secreted or transmembrane proteins that regulate cell motility and attachment in axon guidance, vascular growth, immune cell regulation and tumour progression. The main receptors for semaphorins are plexins, which have established roles in regulating Rho-family GTPases. Recent work shows that plexins can also influence R-Ras, which, in turn, can regulate integrins. Such regulation is probably a common feature of semaphorin signalling and contributes substantially to our understanding of semaphorin biology.
                Bookmark

                Author and article information

                Contributors
                olga.romantsik@med.lu.se
                alex_adusei.agyemang@med.lu.se
                snjolaug.sveinsdottir@gmail.com
                sillarutar@gmail.com
                bo@imagene.se
                magnus.cinthio@elmat.lth.se
                matthias@colzyx.com
                sywrysyneck@gmail.com
                hk@a1m.se
                stefan.hansson@med.lu.se
                bo.akerstrom@med.lu.se
                david.ley@med.lu.se
                +46-(0)709 378 638 , magnus.gram@med.lu.se
                Journal
                J Neuroinflammation
                J Neuroinflammation
                Journal of Neuroinflammation
                BioMed Central (London )
                1742-2094
                7 June 2019
                7 June 2019
                2019
                : 16
                : 122
                Affiliations
                [1 ]ISNI 0000 0001 0930 2361, GRID grid.4514.4, Pediatrics, Department of Clinical Sciences Lund, , Lund University, ; Lund, Sweden
                [2 ]ISNI 0000 0001 0930 2361, GRID grid.4514.4, Infection Medicine, Department of Clinical Sciences Lund, , Lund University, ; Lund, Sweden
                [3 ]ISNI 0000 0004 5897 0093, GRID grid.500491.9, ImaGene-iT AB, , Medicon Village, ; Lund, Sweden
                [4 ]ISNI 0000 0001 0930 2361, GRID grid.4514.4, Department of Electrical Measurements, , Lund University, ; Lund, Sweden
                [5 ]ISNI 0000 0004 1937 0247, GRID grid.5841.8, Fetal i+D Fetal Medicine Research Center, BCNatal Barcelona Center for Maternal-Fetal and Neonatal Medicine, , University of Barcelona, ; Barcelona, Spain
                [6 ]A1M Pharma AB, Lund, Sweden
                [7 ]ISNI 0000 0001 0930 2361, GRID grid.4514.4, Obstetrics and Gynecology, Department of Clinical Sciences Lund, , Lund University, ; Lund, Sweden
                Article
                1486
                10.1186/s12974-019-1486-4
                6554963
                31174551
                71da0361-4968-4074-a3cb-193da067553e
                © The Author(s). 2019

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 27 November 2018
                : 25 April 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100004359, Vetenskapsrådet;
                Categories
                Research
                Custom metadata
                © The Author(s) 2019

                Neurosciences
                intraventricular hemorrhage,hemoglobin,α1-microglobulin,oxidative stress,damage to the immature brain

                Comments

                Comment on this article