Advertisement

Thromboembolic Model of Cerebral Ischemia and Reperfusion in Mice

  • Ali Alawieh
  • Wenxue Wang
  • Aarti Narang
  • Stephen TomlinsonEmail author
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1462)

Abstract

Ischemic stroke is the fourth leading cause of death in the USA and a prominent cause of death globally. Besides thrombolytic therapy used in a small subset of patients, no alternative therapeutic strategy has been shown to improve the outcome of stroke patients. Preclinical models of ischemic stroke are an essential tool for investigating pathogenic processes that happen after the ischemic insult, as well as to screen for candidate therapeutic interventions. There are several models of rodent ischemic stroke including mechanical occlusion, thromboembolic stroke, and photothrombotic stroke. However, models that permit studying stroke in the context of thrombolytic therapy, such as thromboembolic models, are becoming of increasing interest to the research community. In this chapter, we describe a thromboembolic model of ischemic stroke with and without tissue-plasminogen activator-induced reperfusion. We describe protocols for microemboli preparation, surgical procedure, and post-stroke assessment of animals.

Key words

Cerebral ischemia reperfusion Stroke Thromboembolic stroke Microemboli Thrombolytic therapy Tissue-plasminogen activator 

Notes

Acknowledgements

This work is funded by a Department of Veterans Affairs Merit Award (RX00114) and the NIH (P20GM109040) to S.T. and an American Heart Association Pre-doctoral Fellowship Award (15PRE25250009) to A.A.

References

  1. 1.
    Naghavi M, Wang H, Lozano R, Davis A, Liang X, Zhou M, Vollset SE, Ozgoren AA, Abdalla S, Abd-Allah F (2015) Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 385:117–171CrossRefGoogle Scholar
  2. 2.
    Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, de Ferranti S, Despres JP, Fullerton HJ, Howard VJ, Huffman MD, Judd SE, Kissela BM, Lackland DT, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Matchar DB, McGuire DK, Mohler ER III, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Willey JZ, Woo D, Yeh RW, Turner MB, American Heart Association Statistics C, Stroke Statistics S (2015) Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation 131:29–322Google Scholar
  3. 3.
    Wardlaw JM, Koumellis P, Liu M (2013) Thrombolysis (different doses, routes of administration and agents) for acute ischaemic stroke. Cochrane Database System Rev 5, CD000514Google Scholar
  4. 4.
    Broderick JP, Palesch YY, Demchuk AM, Yeatts SD, Khatri P, Hill MD, Jauch EC, Jovin TG, Yan B, Silver FL, von Kummer R, Molina CA, Demaerschalk BM, Budzik R, Clark WM, Zaidat OO, Malisch TW, Goyal M, Schonewille WJ, Mazighi M, Engelter ST, Anderson C, Spilker J, Carrozzella J, Ryckborst KJ, Janis LS, Martin RH, Foster LD, Tomsick TA, Interventional Management of Stroke IIII (2013) Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med 368:893–903CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Hacke W, Donnan G, Fieschi C, Kaste M, von Kummer R, Broderick JP, Brott T, Frankel M, Grotta JC, Haley EC Jr, Kwiatkowski T, Levine SR, Lewandowski C, Lu M, Lyden P, Marler JR, Patel S, Tilley BC, Albers G, Bluhmki E, Wilhelm M, Hamilton S, Investigators AT, Investigators ET, Investigators Nr-PSG (2004) Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 363:768–774CrossRefPubMedGoogle Scholar
  6. 6.
    Alawieh A, Elvington A, Tomlinson S (2015) Complement in the homeostatic and ischemic brain. Front Immunol 6:417CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Chamorro A, Meisel A, Planas AM, Urra X, van de Beek D, Veltkamp R (2012) The immunology of acute stroke. Nat Rev Neurol 8:401–410CrossRefPubMedGoogle Scholar
  8. 8.
    Alawieh A, Sabra Z, Sabra M, Tomlinson S, Zaraket FA (2015) A rich-club organization in brain ischemia protein interaction network. Sci Rep 5:13513CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Hata R, Mies G, Wiessner C, Fritze K, Hesselbarth D, Brinker G, Hossmann KA (1998) A reproducible model of middle cerebral artery occlusion in mice: hemodynamic, biochemical, and magnetic resonance imaging. J Cereb Blood Flow Metab 18:367–375CrossRefPubMedGoogle Scholar
  10. 10.
    Longa EZ, Weinstein PR, Carlson S, Cummins R (1989) Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20:84–91CrossRefPubMedGoogle Scholar
  11. 11.
    Chen S, Hsu C, Hogan E, Maricq H, Balentine J (1986) A model of focal ischemic stroke in the rat: reproducible extensive cortical infarction. Stroke 17:738–743CrossRefPubMedGoogle Scholar
  12. 12.
    Atochin DN, Murciano JC, Gursoy-Ozdemir Y, Krasik T, Noda F, Ayata C, Dunn AK, Moskowitz MA, Huang PL, Muzykantov VR (2004) Mouse model of microembolic stroke and reperfusion. Stroke 35:2177–2182CrossRefPubMedGoogle Scholar
  13. 13.
    Fuxe K, Cintra A, Andbjer B, Änggärds E, Goldstein M, Agnati J (1989) Centrally administered endothelin‐1 produces lesions in the brain of the male rat. Acta Physiol Scand 137:155–156CrossRefPubMedGoogle Scholar
  14. 14.
    Horie N, Maag A-L, Hamilton SA, Shichinohe H, Bliss TM, Steinberg GK (2008) Mouse model of focal cerebral ischemia using endothelin-1. J Neurosci Methods 173:286–290CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    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
  16. 16.
    Albers GW, Goldstein LB, Hess DC, Wechsler LR, Furie KL, Gorelick PB, Hurn P, Liebeskind DS, Nogueira RG, Saver JL (2011) Stroke Treatment Academic Industry Roundtable (STAIR) recommendations for maximizing the use of intravenous thrombolytics and expanding treatment options with intra-arterial and neuroprotective therapies. Stroke 42:2645–2650CrossRefPubMedGoogle Scholar
  17. 17.
    Brinker G, Franke C, Hoehn M, Uhlenkuken U, Hossmann KA (1999) Thrombolysis of cerebral clot embolism in rat: effect of treatment delay. Neuroreport 10:3269–3272CrossRefPubMedGoogle Scholar
  18. 18.
    Overgaard K, Sereghy T, Pedersen H, Boysen G (1994) Effect of delayed thrombolysis with rt-PA in a rat embolic stroke model. J Cereb Blood Flow Metab 14:472–477CrossRefPubMedGoogle Scholar
  19. 19.
    Jiang Q, Zhang RL, Zhang ZG, Ewing JR, Divine GW, Chopp M (1998) Diffusion-, T2-, and perfusion-weighted nuclear magnetic resonance imaging of middle cerebral artery embolic stroke and recombinant tissue plasminogen activator intervention in the rat. J Cereb Blood Flow Metab 18:758–767CrossRefPubMedGoogle Scholar
  20. 20.
    Busch E, Kruger K, Allegrini PR, Kerskens CM, Gyngell ML, Hoehn-Berlage M, Hossmann KA (1998) Reperfusion after thrombolytic therapy of embolic stroke in the rat: magnetic resonance and biochemical imaging. J Cereb Blood Flow Metab 18:407–418CrossRefPubMedGoogle Scholar
  21. 21.
    Elvington A, Atkinson C, Kulik L, Zhu H, Yu J, Kindy MS, Holers VM, Tomlinson S (2012) Pathogenic natural antibodies propagate cerebral injury following ischemic stroke in mice. J Immunol 188:1460–1468CrossRefPubMedGoogle Scholar
  22. 22.
    Zhang L, Schallert T, Zhang ZG, Jiang Q, Arniego P, Li Q, Lu M, Chopp M (2002) A test for detecting long-term sensorimotor dysfunction in the mouse after focal cerebral ischemia. J Neurosci Methods 117:207–214CrossRefPubMedGoogle Scholar
  23. 23.
    Hunter AJ, Hatcher J, Virley D, Nelson P, Irving E, Hadingham SJ, Parsons AA (2000) Functional assessments in mice and rats after focal stroke. Neuropharmacology 39:806–816CrossRefPubMedGoogle Scholar
  24. 24.
    Bouet V, Boulouard M, Toutain J, Divoux D, Bernaudin M, Schumann-Bard P, Freret T (2009) The adhesive removal test: a sensitive method to assess sensorimotor deficits in mice. Nat Protoc 4:1560–1564CrossRefPubMedGoogle Scholar
  25. 25.
    Tennant KA, Asay AL, Allred RP, Ozburn AR, Kleim JA, Jones TA (2010) The vermicelli and capellini handling tests: simple quantitative measures of dexterous forepaw function in rats and mice. J Vis Exp (41):pii: 2076Google Scholar
  26. 26.
    Rosenfeld CS, Ferguson SA (2014) Barnes maze testing strategies with small and large rodent models. J Vis Exp (84):e51194Google Scholar
  27. 27.
    Borlongan CV, Cahill DW, Sanberg PR (1995) Locomotor and passive avoidance deficits following occlusion of the middle cerebral artery. Physiol Behav 58:909–917CrossRefPubMedGoogle Scholar
  28. 28.
    Bromley-Brits K, Deng Y, Song W (2011) Morris water maze test for learning and memory deficits in Alzheimer’s disease model mice. J Vis Exp (53):pii: 2920Google Scholar
  29. 29.
    Murciano J-C, Harshaw D, Neschis DG, Koniaris L, Bdeir K, Medinilla S, Fisher AB, Golden MA, Cines DB, Nakada MT (2002) Platelets inhibit the lysis of pulmonary microemboli. Am J Physiol Lung Cell Mol Physiol 282:L529–L539CrossRefPubMedGoogle Scholar
  30. 30.
    Bdeir K, Murciano J-C, Tomaszewski J, Koniaris L, Martinez J, Cines DB, Muzykantov VR, Higazi AA-R (2000) Urokinase mediates fibrinolysis in the pulmonary microvasculature. Blood 96:1820–1826PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Ali Alawieh
    • 1
    • 2
  • Wenxue Wang
    • 1
    • 2
  • Aarti Narang
    • 1
    • 2
  • Stephen Tomlinson
    • 2
    • 3
    • 4
    Email author
  1. 1.Department of Microbiology and ImmunologyMedical University of South CarolinaCharlestonUSA
  2. 2.Neuroscience InstituteMedical University of South CarolinaCharlestonUSA
  3. 3.Department of Microbiology and ImmunologyMedical University of South CarolinaCharlestonUSA
  4. 4.Ralph H. Johnson Veteran Affairs Medical CenterCharlestonUSA

Personalised recommendations