Advertisement

Histological and Elemental Changes in Ischemic Stroke

  • M. Jake Pushie
  • Vedashree R. Meher
  • Nicole J. Sylvain
  • Huishu Hou
  • Annalise T. Kudryk
  • Michael E. Kelly
  • Roland N. Auer
Chapter

Abstract

Stroke is a leading cause of serious long-term disability in adults and a leading cause of death in developed nations. Following an ischemic stroke the metabolic profile of the affected tissue is significantly altered, with the infarct representing the most severely affected tissue, and the surrounding penumbra, or peri-infarct zone (PIZ), containing a gradient of metabolic states progressing from severely impacted toward an otherwise healthy profile. The penumbra contains potentially salvageable tissue and is the focus in many stroke treatments. In this chapter, we employ the photothrombotic stroke model (a widely used animal model for studying focal ischemia) to study the histopathological and bioelemental changes that occur post-stroke. Synchrotron-based X-ray fluorescence imaging allows simultaneous measurement of multiple elements in situ within biological tissues, as their naturally-occurring concentrations. Images of elemental distributions are compared to conventional histopathological changes in the infarct and penumbra. Understanding the bioelemental changes associated with the post-stroke brain provides opportunities to expand our understanding of the underlying cellular and tissue changes associated with ischemic stroke and can ultimately be used to guide development of future treatment methods targeting the penumbra.

Keywords

Ischemic stroke Penumbra Photothrombotic stroke Excitotoxicity X-ray fluorescence imaging Elemental mapping 

Notes

Acknowledgements

AK was a recipient of the College of Medicine Dean’s summer research award. MEBK is the Saskatchewan Clinical Stroke Research Chair and is supported by grants from the Canadian Institutes of Health research (CIHR), the Saskatchewan Health Research Foundation, the Heart and Stroke Foundation, Saskatchewan, and the University of Saskatchewan, College of Medicine. Research described in this chapter was performed in part at the Canadian Light Source, which is supported by the Natural Sciences and Engineering Research Council of Canada, the National Research Council Canada, CIHR, and Province of Saskatchewan, Western Economic Diversification Canada, and the University of Saskatchewan. In addition, the Stanford Synchrotron Radiation Lightsource (SSRL), SLAC National Accelerator Laboratory, was used for this research and is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the National Institutes of Health, National Institute of General Medical Sciences (including P41GM103393). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH.

References

  1. Aichler M, Walch A (2015) MALDI Imaging mass spectrometry: current frontiers and perspectives in pathology research and practice. Lab Investig 95:422–431CrossRefPubMedPubMedCentralGoogle Scholar
  2. Auer RN, Siesjö BK (1988) Biological differences between ischemia, hypoglycemia, and epilepsy. Ann Neurol 24:699–707CrossRefPubMedGoogle Scholar
  3. Bandera E, Botteri M, Minelli C, Sutton A, Abrams KR, Latronico N (2006) Cerebral blood flow threshold of ischemic penumbra and infarct core in acute ischemic stroke: a systematic review. Stroke 37:1334–1339CrossRefPubMedGoogle Scholar
  4. Benveniste H (1991) The excitotoxin hypothesis in relation to cerebral ischemia. Cerebrovasc Brain Metab Rev 3:213–245PubMedGoogle Scholar
  5. Birben E, Sahiner UM, Sackesen C, Erzurum S, Kalayci O (2012) Oxidative stress and antioxidant defense. World Allergy Organ J 5:9–19CrossRefPubMedPubMedCentralGoogle Scholar
  6. Bitanihirwe BK, Cunningham MG (2009) Zinc: the brain’s dark horse. Synapse 63:1029–1049CrossRefPubMedGoogle Scholar
  7. Brini M, Calì T, Ottolini D, Carafoli E (2014) Neuronal calcium signaling: function and dysfunction. Cell Mol Life Sci 71:2787–2814CrossRefPubMedGoogle Scholar
  8. Caine S, Hackett MJ, Hou H, Kumar S, Maley J, Ivanishvili Z, Suen B, Szmigielski A, Jiang Z, Sylvain NJ, Nichol H, Kelly ME (2016) A novel multi-modal platform to image molecular and elemental alterations in ischemic stroke. Neurobiol Dis 91:132–142CrossRefPubMedGoogle Scholar
  9. Carmichael ST (2005) Rodent models of focal stroke: size, mechanism, and purpose. NeuroRx 2:396–409CrossRefPubMedPubMedCentralGoogle Scholar
  10. Crawford AM (2015) Mblank computer program. Methodologies in XRF Cytometry (Thesis). University of Michigan, MichiganGoogle Scholar
  11. Debonnel G, Beauschesne L, de Montigny C (1989) Domoic acid, the alleged “mussel toxin”, might produce its neurotoxic effect through kainate receptor activation: an electrophysiological study in the rat dorsal hippocampus. Can J Physiol Pharmacol 67:29–33CrossRefPubMedGoogle Scholar
  12. Del Bigio MR (2002) Glial linings of the brain. In: Walz W (ed) The neuronal environment: brain homeostasis in health and disease. Humana Press, Totowa, NJ.Google Scholar
  13. Egger AE, Theiner S, Kornauth C, Heffeter P, Berger W, Keppler BK, Hartinger CG (2014) Quantitative bioimaging by LA-ICP-MS: a methodological study on the distribution of Pt and Ru in viscera originating from cisplatin- and KP1339-treated mice. Metallomics 6:1616–1625CrossRefPubMedGoogle Scholar
  14. Feigin VL, Lawes CM, Bennett DA, Barker-Collo SL, Parag V (2009) Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol 8:355–369CrossRefPubMedGoogle Scholar
  15. Fisher M (1997) Characterizing the target of acute stroke therapy. Stroke 28:866–872CrossRefPubMedGoogle Scholar
  16. Fluri F, Schuhmann MK, Kleinschnitz C (2015) Animal models of ischemic stroke and their application in clinical research. Drug Des Devel Ther 9:3445–3454PubMedPubMedCentralGoogle Scholar
  17. Hackett MJ, McQuillan JA, El-Assaad F, Aitken JB, Levina A, Cohen DD, Siegele R, Carter EA, Grau GE, Hunt NH, Lay PA (2011) Chemical alterations to murine brain tissue induced by formalin fixation: implications for biospectroscopic imaging and mapping studies of disease pathogenesis. Analyst 136:2941–2952CrossRefPubMedGoogle Scholar
  18. Hackett MJ, Smith SE, Paterson PG, Nichol H, Pickering IJ, George GN (2012) X-ray absorption spectroscopy at the sulfur K-edge: a new tool to investigate the biochemical mechanisms of neurodegeneration. ACS Chem Neurosci 3:178–185CrossRefPubMedPubMedCentralGoogle Scholar
  19. Hackett MJ, Britz CJ, Paterson PG, Nichol H, Pickering IJ, George GN (2015) In situ biospectroscopic investigation of rapid ischemic and postmortem induced biochemical alterations in the rat brain. ACS Chem Neurosci 6:226–238CrossRefPubMedGoogle Scholar
  20. Hackett MJ, Sylvain NJ, Hou H, Caine S, Alaverdashvili M, Pushie MJ, Kelly ME (2016) Concurrent glycogen and lactate imaging with FTIR spectroscopy to spatially localize metabolic parameters of the glial response following brain ischemia. Anal Chem 88:10949–10956CrossRefPubMedGoogle Scholar
  21. Hansen AJ, Olsen CE (1980) Brain extracellular space during spreading depression and ischemia. Acta Physiol Scand 108:355–365CrossRefPubMedGoogle Scholar
  22. Harris HH, Vogt S, Eastgate H, Legnini DG, Hornberger B, Cai Z, Lai B, Lay PA (2008) Migration of mercury from dental amalgam through human teeth. J Synchrotron Radiat 15:123–128CrossRefPubMedGoogle Scholar
  23. Heiss WD (1992) Experimental evidence of ischemic thresholds and functional recovery. Stroke 23:1668–1672CrossRefPubMedGoogle Scholar
  24. Hossmann K-A (1994) Viability thresholds and the penumbra of focal ischemia. Ann Neurol 36:557–565CrossRefPubMedGoogle Scholar
  25. Jensen AN, Jenson LT (2014) Manganese transport, trafficking and function in invertebrates. Manganese in health and disease. RSC Publishing, London, pp 1–33CrossRefGoogle Scholar
  26. Kalimo H, Rehncrona S, Söderfeldt H, Olsson Y, Siesjö B (1981) Brain lactic acidosis and ischemic cell damage. 2. Histopathology. J Cereb Blood Flow Metab 1:313–327CrossRefPubMedGoogle Scholar
  27. Kalogeris T, Baines CP, Krenz M, Korthuis RJ (2012) Cell biology of ischemia/reperfusion injury. Int Rev Cell Mol Biol 298:229–317CrossRefPubMedPubMedCentralGoogle Scholar
  28. Kaplan B, Brint S, Tanabe J, Jacewicz M, Wang XJ, Pulsinelli W (1991) Temporal thresholds for neocortical infarction in rats subjected to reversible focal cerebral ischemia. Stroke 22:1032–1039CrossRefPubMedGoogle Scholar
  29. Karim MR, Petering DH (2016) Newport Green, a fluorescent sensor of weakly bound cellular Zn(2+): competition with proteome for Zn(2). Metallomics 8:201–210CrossRefPubMedPubMedCentralGoogle Scholar
  30. Kim GW, Sugawara T, Chan PH (2000) Involvement of oxidative stress and caspase-3 in cortical infarction after photothrombotic ischemia in mice. J Cereb Blood Flow Metab 20:1690–1701CrossRefPubMedGoogle Scholar
  31. Kitamura Y, Iida Y, Abe J, Ueda M, Mifune M, Kasuya F, Ohta M, Igarashi K, Saito Y, Saji H (2006) Protective effect of zinc against ischemic neuronal injury in a middle cerebral artery occlusion model. J Pharmacol Sci 100:142–148CrossRefPubMedGoogle Scholar
  32. Labat-gest V, Tomasi S (2013) Photothrombotic ischemia: a minimally invasive and reproducible photochemical cortical lesion model for mouse stroke studies. J Vis Exp. https://doi.org/10.3791/50370
  33. Latchaw RE, Yonas H, Hunter GJ, Yuh WT, Ueda T, Sorensen AG, Sunshine JL, Biller J, Wechsler L, Higashida R, Hademenos G, Council on Cardiovascular Radiology of the American Heart Association (2003) Guidelines and recommendations for perfusion imaging in cerebral ischemia: a scientific statement for healthcare professionals by the writing group on perfusion imaging, from the Council on Cardiovascular Radiology of the American Heart Association. Stroke 34:1084–1104CrossRefPubMedGoogle Scholar
  34. Lee JM, Grabb MC, Zipfel GJ, Choi DW (2000) Brain tissue responses to ischemia. J Clin Invest 106:723–731CrossRefPubMedPubMedCentralGoogle Scholar
  35. Lin X, Miao P, Wang J, Yuan F, Guan Y, Tang Y, He X, Wang Y, Yang GY (2013) Surgery-related thrombosis critically affects the brain infarct volume in mice following transient middle cerebral artery occlusion. PLoS ONE 8:e75561CrossRefPubMedPubMedCentralGoogle Scholar
  36. Lindahl PA, Moore MJ (2016) Labile low-molecular-mass metal complexes in mitochondria: trials and tribulations of a burgeoning field. Biochemistry 55:4140–4153CrossRefPubMedPubMedCentralGoogle Scholar
  37. Lins BR, Pushie JM, Jones M, Howard DL, Howland JG, Hackett MJ (2016) Mapping alterations to the endogenous elemental distribution within the lateral ventricles and choroid plexus in brain disorders using X-ray fluorescence imaging. PLoS ONE 11:e0158152CrossRefPubMedPubMedCentralGoogle Scholar
  38. Liu F, McCullough LD (2011) Middle cerebral artery occlusion model in rodents: methods and potential pitfalls. J Biomed Biotechnol 2011:464701PubMedPubMedCentralGoogle Scholar
  39. Menzie J, Prentice H, Wu JY (2013) Neuroprotective mechanisms of taurine against ischemic stroke. Brain Sci 3:877–907CrossRefPubMedPubMedCentralGoogle Scholar
  40. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Després JP, Fullerton HJ, Howard VJ, Huffman MD, Isasi CR, Jiménez MC, Judd SE, Kissela BM, Lichtman JH, Lisabeth LD, Writing Group Members (2016) Heart disease and stroke statistics-2016 update: a report from the American Heart Association. Circulation 133:e38–e360CrossRefGoogle Scholar
  41. Nicholson C, Kamali-Zare P, Tao L (2011) Brain extracellular space as a diffusion barrier. Comput Vis Sci 14:309–325CrossRefPubMedPubMedCentralGoogle Scholar
  42. Nowak TS Jr, Jacewicz M (1994) The heat shock/stress response in focal cerebral ischemia. Brain Pathol 4:67–76CrossRefPubMedGoogle Scholar
  43. Paschen W (1996) Glutamate excitotoxicity in transient global cerebral ischemia. Acta Neurobiol Exp (Wars) 56:313–322Google Scholar
  44. Popescu BF, Frischer JM, Webb SM, Tham M, Adiele RC, Robinson CA, Fitz-Gibbon PD, Weigand SD, Metz I, Nehzati S, George GN, Pickering IJ, Brück W, Hametner S, Lassmann H, Parisi JE, Yong G, Lucchinetti CF (2017) Pathogenic implications of distinct patterns of iron and zinc in chronic MS lesions. Acta Neuropathol 134:45–64CrossRefPubMedPubMedCentralGoogle Scholar
  45. Puljak L, Kilic G (2006) Emerging roles of chloride channels in human diseases. Biochim Biophys Acta 1762:404–413CrossRefPubMedGoogle Scholar
  46. Pushie MJ, Pickering IJ, Martin GR, Tsutsui S, Jirik FR, George GN (2011) Prion protein expression level alters regional copper, iron and zinc content in the mouse brain. Metallomics 3:206–214CrossRefPubMedGoogle Scholar
  47. Pushie MJ, Pickering IJ, Korbas M, Hackett MJ, George GN (2014) Elemental and chemically specific X-ray fluorescence imaging of biological systems. Chem Rev 114:8499–8541CrossRefPubMedPubMedCentralGoogle Scholar
  48. Rae TD, Schmidt PJ, Pufahl RA, Culotta VC, O'Halloran TV (1999) Undetectable intracellular free copper: the requirement of a copper chaperone for superoxide dismutase. Science 284:805–808CrossRefPubMedGoogle Scholar
  49. Robison G, Zakharova T, Fu S, Jiang W, Fulper R, Barrea R, Marcus MA, Zheng W, Pushkar Y (2012) X-ray fluorescence imaging: a new tool for studying manganese neurotoxicity. PLoS ONE 7:e48899CrossRefPubMedPubMedCentralGoogle Scholar
  50. Selim MH, Ratan RR (2004) The role of iron neurotoxicity in ischemic stroke. Ageing Res Rev 3:345–353CrossRefPubMedGoogle Scholar
  51. Siesjö BK, Katsura K, Kristián T (1996) Acidosis-related damage. Adv Neurol 71:209–233PubMedGoogle Scholar
  52. Smith ML, Auer RN, Siesjö BK (1984) The density and distribution of ischemic brain injury in the rat following 2-10 min of forebrain ischemia. Acta Neuropathol 64:319–332CrossRefPubMedGoogle Scholar
  53. Song J, Park J, Oh Y, Lee JE (2015) Glutathione suppresses cerebral infarct volume and cell death after ischemic injury: involvement of FOXO3 inactivation and Bcl2 expression. Oxidative Med Cell Longev 2015:426069Google Scholar
  54. Spasojevic I, Mojovic M, Stevic Z, Spasic SD, Jones DR, Morina A, Spasic MB (2010) Bioavailability and catalytic properties of copper and iron for Fenton chemistry in human cerebrospinal fluid. Redox Rep 15:29–35CrossRefPubMedGoogle Scholar
  55. Sullivan B, Robison G, Osborn J, Kay M, Thompson P, Davis K, Zakharova T, Antipova O, Pushkar Y (2017) On the nature of the Cu-rich aggregates in brain astrocytes. Redox Biol 11:231–239CrossRefPubMedGoogle Scholar
  56. Thrift AG, Thayabaranathan T, Howard G, Howard VJ, Rothwell PM, Feigin VL, Norrving B, Donnan GA, Cadilhac DA (2017) Global stroke statistics. Int J Stroke 12:13–32CrossRefPubMedGoogle Scholar
  57. Tombaugh GC, Sapolsky RM (1993) Evolving concepts about the role of acidosis in ischemic neuropathology. J Neurochem 61:793–803CrossRefPubMedGoogle Scholar
  58. Ward J, Marvin R, O'Halloran T, Jacobsen C, Vogt S (2013) Rapid and accurate analysis of an X-ray fluorescence microscopy data set through gaussian mixture-based soft clustering methods. Microsc Microanal 19:1281–1289CrossRefPubMedGoogle Scholar
  59. Watson BD, Dietrich WD, Busto R, Wachtel MS, Ginsberg MD (1985) Induction of reproducible brain infarction by photochemically initiated thrombosis. Ann Neurol 17:497–504CrossRefPubMedGoogle Scholar
  60. West AE, Chen WG, Dalva MB, Dolmetsch RE, Kornhauser JM, Shaywitz AJ, Takasu MA, Tao X, Greenberg ME (2001) Calcium regulation of neuronal gene expression. Proc Natl Acad Sci U S A 98:11024–11031CrossRefPubMedPubMedCentralGoogle Scholar
  61. Winship IR, Murphy TH (2008) In vivo calcium imaging reveals functional rewiring of single somatosensory neurons after stroke. J Neurosci 28:6592–6606CrossRefPubMedGoogle Scholar
  62. Woodruff TM, Thundyil J, Tang SC, Sobey CG, Taylor SM, Arumugam TV (2011) Pathophysiology, treatment, and animal and cellular models of human ischemic stroke. Mol Neurodegener 6:11CrossRefPubMedPubMedCentralGoogle Scholar
  63. Zhang M, Peng G, Sun D, Xie Y, Xia J, Long H, Hu K, Xiao B (2014) Synchrotron radiation imaging is a powerful tool to image brain microvasculature. Med Phys 41:031907CrossRefPubMedGoogle Scholar
  64. Zille M, Farr TD, Przesdzing I, Müller J, Sommer C, Dirnagl U, Wunder A (2012) Visualizing cell death in experimental focal cerebral ischemia: promises, problems, and perspectives. J Cereb Blood Flow Metab 32:213–231CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • M. Jake Pushie
    • 1
  • Vedashree R. Meher
    • 2
  • Nicole J. Sylvain
    • 1
  • Huishu Hou
    • 1
  • Annalise T. Kudryk
    • 3
  • Michael E. Kelly
    • 1
  • Roland N. Auer
    • 4
    • 5
  1. 1.Division of Neurosurgery, Department of SurgeryCollege of Medicine, University of SaskatchewanSaskatoonCanada
  2. 2.Department of Health SciencesCollege of Medicine, University of SaskatchewanSaskatoonCanada
  3. 3.College of Medicine, University of SaskatchewanSaskatoonCanada
  4. 4.Department of Pathology and Laboratory MedicineCollege of Medicine, University of SaskatchewanSaskatoonCanada
  5. 5.Department of PathologyRoyal University HospitalSaskatoonCanada

Personalised recommendations