Molecular Neurobiology

, Volume 52, Issue 2, pp 979–984 | Cite as

Dodecafluoropentane Emulsion Extends Window for tPA Therapy in a Rabbit Stroke Model

  • W. C. Culp
  • A. T. Brown
  • J. D. Lowery
  • M. C. Arthur
  • P. K. Roberson
  • R. D. Skinner
Article

Abstract

Dodecafluoropentane emulsion (DDFPe) nanodroplets are exceptional oxygen transporters and can protect ischemic brain in stroke models 24 h without reperfusion. Current stroke therapy usually fails to reach patients because of delays following stroke onset. We tested using DDFPe to extend the time window for tissue plasminogen activator (tPA). Longer treatment windows will allow more patients more complete stroke recovery. We test DDFPe to safely extend the time window for tPA thrombolysis to 9 h after stroke. With IACUC approval, randomized New Zealand white rabbits (3.4–4.7 kg, n = 30) received angiography and 4-mm blood clot in the internal carotid artery for flow-directed middle cerebral artery occlusion. Seven failed and were discarded. Groups were IV tPA (n = 11), DDFPe + tPA (n = 7), and no therapy controls (n = 5). DDFPe (0.3 ml/kg, 2 % emulsion) IV dosing began at 1 h and continued at 90 min intervals for 6 doses in one test group; the other received saline injections. Both got standard IV tPA (0.9 mg/kg) therapy starting 9 h post stroke. At 24 h, neurological assessment scores (NAS, 0–18) were determined. Following brain removal percent stroke volume (%SV) was measured. Outcomes were compared with Kruskal-Wallis analysis. For NAS, DDFPe + tPA was improved overall, p = 0.0015, and vs. tPA alone, p = 0.0052. For %SV, DDFPe + tPA was improved overall, p = 0.0003 and vs. tPA alone, p = 0.0018. NAS controls and tPA alone were not different but %SV was, p = 0.0078. With delayed reperfusion, DDFPe + tPA was more effective than tPA alone in preserving functioning brain after stroke. DDFPe significantly extends the time window for tPA therapy.

Keywords

Stroke Animal model Dodecafluoropentane emulsion (DDFPe) Tissue plasminogen activator (tPA) 

References

  1. 1.
    Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ et al (2014) Heart disease and stroke statistics—2014 update: a report from the American Heart Association. Circulation 129:e28–e292. doi:10.1161/01.cir.0000441139.02102.80 CrossRefPubMedGoogle Scholar
  2. 2.
    Savers JL (2014) The field administration of stroke therapy—magnesium (FAST-MAG) Phase 3: Primary Results “Golden Hour” stroke trial. International Stroke Conference (ISC) 2014. Abstract 214. Presented February 13, 2014Google Scholar
  3. 3.
    Culp WC, Woods SD, Skinner RD, Brown AT, Lowery JD, Johnson JLH, Unger EC, Hennings LJ et al (2012) Dodecafluoropentane emulsion decreases infarct volume in a rabbit ischemic stroke model. JVIR 23:116–121. doi:10.1016/j.jvir.2011.10.001 PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Woods SD, Skinner RD, Ricca AM, Brown AT, Lowery JD, Borrelli MJ, Lay JO, Culp WC (2013) Progress in dodecafluoropentane emulsion as a neuroprotective agent in a rabbit stroke model. Mol Neurobiol 48:363–367. doi:10.1007/s12035-013-8495-6 PubMedCentralCrossRefPubMedGoogle Scholar
  5. 5.
    Culp WC, Woods SD, Brown AT, Lowery JD, Hennings LJ, Skinner RD, Borrelli MJ, Roberson PK (2012) Three variations in rabbit angiographic stroke models. J Neurosci Methods 212(2):322–328. doi:10.1016/j.jneumeth.2012.10.017 PubMedCentralCrossRefPubMedGoogle Scholar
  6. 6.
    Culp WC, Flores R, Lowery JD, Brown AT, Hennings LJ, Roberson PK, Woods SD, Hatton JH et al (2011) Successful microbubble sonothrombolysis without tissue plasminogen activator in a rabbit model of acute ischemic stroke. Stroke 42:2280–2285. doi:10.1161/STROKEAHA.110.607150 PubMedCentralCrossRefPubMedGoogle Scholar
  7. 7.
    Zivin JA, Fisher M, DeGirolami U, Hemenway CC, Stashak JA (1985) Tissue plasminogen activator reduces neurological damage after cerebral embolism. Science 230:1289–1292CrossRefPubMedGoogle Scholar
  8. 8.
    Brown AT, Flores R, Hamilton E, Roberson PK, Borrelli MJ, Culp WC (2011) Microbubbles improve sonothrombolysis in vitro and decrease hemorrhage in vivo in a rabbit stroke model. Investig Radiol 46(3):202–207. doi:10.1097/RLI.0b013e318200757a CrossRefGoogle Scholar
  9. 9.
    Brown AT, Arthur MC, Nix JS, Montgomery JA, Skinner RD, Roberson PK, Borrelli M, Culp WC (2014) Dodecafluoropentane emulsion (DDFPe) decreases stroke size and improves neurological scores in a permanent occlusion rat stroke model. Open Neurol J 8(1):27–33. doi:10.2174/1874205x01408010027
  10. 10.
    Brown AT, Skinner RD, Flores R, Hennings L, Borrelli MJ, Lowery J, Culp W (2010) Stroke location and brain function in an embolic rabbit stroke model. J Vasc Interv Radiol 21:903–909. doi:10.1016/j.jvir.2010.02.023 PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Ren Y, Hashimoto M, Pulsinelli WA, Nowak TS Jr (2004) Hypothermic protection in rat focal ischemia models: strain differences and relevance to “reperfusion injury”. J Cereb Blood Flow Metab 24:42–53. doi:10.1097/01.WCB.0000095802.98378.91 CrossRefPubMedGoogle Scholar
  12. 12.
    Fitzgerald RT, Ou X, Nix JS, Arthur MC, Brown AT, Skinner RD, Borrelli MJ, Culp WC. (2015) Dodecafluoropentane emulsion delays and reduces MRI markers of infarction in a rat stroke model. Magn Reson Imaging, Magn Reson Imaging 33(2):236–239. doi:10.1016/j.mri.2014.10.012
  13. 13.
    The European Agency for the Evaluation of Medicinal Products Human Medicines Evaluation Unit, 27 July 1998, CPMP/1342/98Google Scholar
  14. 14.
    The European Agency for the Evaluation of Medicinal Products Human Medicines Evaluation Unit, London, 22 May 2001, Doc. Ref: EMEA/37043/00Google Scholar
  15. 15.
    Johnson JL, Dolezal MC, Kerschen A, Matsunaga TO, Unger EC (2009) In vitro comparison of dodecafluoropentane (DDFP), perfluorodecalin (PFD), and perfluoroctylbromide (PFOB) in the facilitation of oxygen exchange. Artif Cells Blood Substit Immobil Biotechnol 37(4):156–162. doi:10.1080/10731190903043192 CrossRefPubMedGoogle Scholar
  16. 16.
    Correas JM, Quay SC (1996) EchoGen emulsion: a new ultrasound contrast agent based on phase shift colloids. Clin Radiol 51(S1):11–14PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • W. C. Culp
    • 1
  • A. T. Brown
    • 1
  • J. D. Lowery
    • 2
  • M. C. Arthur
    • 1
  • P. K. Roberson
    • 3
  • R. D. Skinner
    • 1
    • 4
  1. 1.Department of RadiologyUniversity of Arkansas for Medical SciencesLittle RockUSA
  2. 2.Laboratory Animal MedicineUniversity of Arkansas for Medical SciencesLittle RockUSA
  3. 3.Department of BiostatisticsUniversity of Arkansas for Medical SciencesLittle RockUSA
  4. 4.Neurobiology and Developmental Sciences and Center for Translational NeuroscienceUniversity of Arkansas for Medical SciencesLittle RockUSA

Personalised recommendations