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Molecular Neurobiology

, Volume 54, Issue 6, pp 4764–4770 | Cite as

Dodecafluoropentane Improves Neurological Function Following Anterior Ischemic Stroke

  • M. Christine Arthur
  • Aliza Brown
  • Kristen Carlson
  • John Lowery
  • Robert D. Skinner
  • William C. Culp
Article

Abstract

Dodecafluoropentane emulsion (DDFPe), an advanced oxygen transport drug, given IV at 90-min intervals maintains viability in the penumbra during cerebral ischemia in the standard rabbit anterior stroke model (STND). This study investigated shortened dosage schedules of DDFPe in nonstandard posterior (NSTND) strokes following occlusions of the posterior cerebral arteries. DDFPe given at shortened schedules of 30 or 60-min injection intervals will reduce neurological deficits, percent stroke volume (%SV), and serum glutamate levels in NSTND ischemic strokes. New Zealand White rabbits (N = 26) were randomly placed into three groups: A (n = 9) controls given saline injections every 60 min, B (n = 9) 2 % DDFPe given IV every 30 min, and C (n = 8) DDFPe every 60 min. Injections began 1 h after embolization. Groups were subdivided into STND and NSTND based on angiographically verified embolization of the cerebral arteries. Neurological assessments and blood samples were done at 0.5–1-h intervals. Rabbits were euthanized at 7 h following embolization. Stained brain slices were measured for %SV. The 30 and 60-min subgroups did not differ and were combined as DDFPe-STND or DDFPe-NSTND groups. In the DDFPe-STND stroke group, the %SV, neurological assessment scores (NAS), and serum glutamate were decreased vs. STND controls (p = 0.0016, 0.008, and 0.016, respectively). In the DDFPe-NSTND stroke group, %SV, NAS, and serum glutamate did not differ statistically compared to NSTND controls (p = 0.82, 0.097, and 0.06, respectively). More frequent dosage schedules provided no additional improvement. In anterior strokes, DDFPe improves recovery but not in the more severe NSTND strokes.

Keywords

Stroke DDFPe Rabbit Ischemia Tissue plasminogen activator Neurological assessment score 

Notes

Acknowledgments

Author Contributions Statement

AB conceived the study and designed the data collection. AB obtained research funding. MCA, JL, KC, and AB collected the data. MCA, RDS, WCC, and AB provided statistical advice on study design and analyzed the data. MCA, KC, WCC, and AB drafted the manuscript, and all authors contributed to its revision.

Compliance with Ethical Standards

All animal procedures were approved by the Institutional Care and Use Committee.

Sources of Funding

This project was supported by the Fund to Cure Stroke, a grant fund of the University of Arkansas for Medical Sciences Foundation (to author AB) and by the NIGMS IDeA Award P30 GM110702 (sponsoring author AB).

Conflict of Interest

A patent has been applied for the use of dodecafluoropentane for stroke therapy by authors WCC and RDS.

References

  1. 1.
    del Zoppo G, Saver J, EC J, et al. (2009) Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator. A science advisory from the American Heart Association/American Stroke Association. Stroke 40:2945–2948. doi: 10.1161/STROKEAHA.109.192535 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Mozaffarian D, Benjamin EJ, Go AS, et al. (2015) Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circ 131:e29–322. doi: 10.1161/CIR.0000000000000152 CrossRefGoogle Scholar
  3. 3.
    Woods SD, Skinner RD, Ricca AM, Brown AT, et al. (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 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Culp WC, Woods SD, Skinner RD, Brown AT, 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 CrossRefPubMedGoogle Scholar
  5. 5.
    Johnson JL, Dolezal MC, Kerschen A, Matsunaga TO, et al. (2009) In vitro comparison of dodecafluoropentane (DDFP) perfluorodecalin (PFD), and perfluoroctylbromide (PFOB) in the facilitation of oxygen exchange. Artif Cell Blood 37:156–162. doi: 10.1080/10731190903043192 CrossRefGoogle Scholar
  6. 6.
    Culp WC, Flores R, Brown AT, Lowery JD, 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 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Brown AT, Skinner RD, Flores R, Hennings L, et al. (2010) Stroke location and brain function in an embolic rabbit stroke model. JVIR 21:903–909. doi: 10.1016/j.jvir.2010.02.023 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Flores R, Lowery J, Skinner RD, Roberson PK, et al. (2011) Transcutaneous therapeutic ultrasound reduces infarct size in a rabbit model of acute insoluble ischemic stroke. J Exp Stroke Transl Med 4:1–7 SFES 1939-067X/10CrossRefGoogle Scholar
  9. 9.
    Brown AT, Flores R, Hamilton E, Roberson PK, et al. (2011) Microbubbles improve sonothrombolysis in vitro and decrease hemorrhage in vivo in a rabbit stroke model. Investig Radiol 46:202–207. doi: 10.1097/RLI.0b013e318200757a CrossRefGoogle Scholar
  10. 10.
    Flores R, Hennings LJ, Lowery JD, Brown AT, et al. (2011) Microbubble-augmented ultrasound sonothrombolysis decreases intracranial hemorrhage in a rabbit model of acute ischemic stroke. Investig Radiol 46:419–424. doi: 10.1097/RLI.0b013e31820e143a CrossRefGoogle Scholar
  11. 11.
    Culp WC, Woods SD, Brown AT, Lowery JD, et al. (2012) Three variations in rabbit angiographic stroke models. J Neurosci Methods 212:322–328. doi: 10.1016/j.jneumeth.2012.10.017 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Brown A, Woods S, Skinner R, Hatton J, et al. (2013) Neurological assessment scores in rabbit embolic stroke models. Open Neurol J 7:38–43CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Zhao BQ, Suzuki Y, Kondo K, Kawano K, et al. (2001) Cerebral hemorrhage due to heparin limits its neuroprotective effects: studies in a rabbit model of photothrombotic middle cerebral artery occlusion. Brain Res 902:30–39CrossRefPubMedGoogle Scholar
  14. 14.
    Zhao BQ, Suzuki Y, Kondo K, Kawano K, et al. (2002) A novel MCA occlusion model of photothrombotic ischemia with cyclic flow reductions: development of cerebral hemorrhage induced by heparin. Brain Res Protocol 9:85–92CrossRefGoogle Scholar
  15. 15.
    Zhao BQ, Suzuki Y, Kondo K, Ikeda Y, et al. (2001) Combination of a free radical scavenger and heparin reduces cerebral hemorrhage after heparin treatment in a rabbit middle cerebral artery occlusion model. Stroke 32:2157–2163CrossRefPubMedGoogle Scholar
  16. 16.
    Chen ZZ, Jiang XD, Zhang LL, Shang JH, et al. (2008) Beneficial effect of autologous transplantation of bone marrow stromal cells and endothelial progenitor cells on cerebral ischemia in rabbits. Neurosci Lett 445:36–41CrossRefPubMedGoogle Scholar
  17. 17.
    Mehndiratta M, Pandey S, Nayak R, Alam A (2012) Posterior circulation ischemic stroke—clinical characteristics, risk factors, and subtypes in a north Indian population—a prospective study. Neurohospitalist 2:46–50. doi: 10.1177/1941874412438902 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Dorňák T, Kral M, Hazlinger M, Herzog R, et al. (2015) Posterior vs. anterior circulation infarction: demography, outcomes, and frequency of hemorrhage after thrombolysis. Int J of Stroke 10:1224–1228. doi: 10.1111/ijs.12626 Google Scholar
  19. 19.
    Boulos AS, Deshaies EM, Dalfino JC, Feustel PJ, et al. (2011) Tamoxifen as an effective neuroprotectant in an endovascular canine model of stroke. J Neurosurg 114:1117–1126. doi: 10.3171/2010.8.JNS09352 CrossRefPubMedGoogle Scholar
  20. 20.
    Ohishi H, Nishijima M, Ogawa A, Yoshimoto T, et al. (1984) Protective effect of mannitol in cerebral infarction—CT findings and physiological observation in experimental cerebral infarction in dogs. No Shinkei Geka 12:153–158PubMedGoogle Scholar
  21. 21.
    Saver JL, Starkman S, Eckstein M, Stratton SJ, et al. (2015) Prehospital use of magnesium sulfate as neuroprotection in acute stroke. N Engl J Med 372:528–536. doi: 10.1056/NEJMoa1408827 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Culp WC, Brown AT, Lowery JD, Arthur MC, et al. (2015) Dodecafluoropentane emulsion extends window for tPA therapy in a rabbit stroke model. Mol Neurobiol 52:979–984. doi: 10.1007/s12035-015-9243-x CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Aliprandi A, Longoni M, Stanzani L, Tremolizzo L, et al. (2005) Increased plasma glutamate in stroke patients might be linked to altered platelet release and uptake. J Cereb Blood Flow Metab 25:513–519CrossRefPubMedGoogle Scholar
  24. 24.
    Godino M, Lizasoain I, Sanchez-Prieto J (2013) Amelioration of ischemic brain damage by peritoneal dialysis. J Clin Invest 123:4359–4363. doi: 10.1172/JCI67284 CrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Department of RadiologyUniversity of Arkansas for Medical SciencesLittle RockUSA
  2. 2.College of Medicine, Medical SchoolUniversity of Arkansas for Medical SciencesLittle RockUSA
  3. 3.Department of Laboratory Animal MedicineUniversity of Arkansas for Medical SciencesLittle RockUSA
  4. 4.Department of Neurobiology and Developmental Sciences and Center for Translational NeuroscienceUniversity of Arkansas for Medical SciencesLittle RockUSA

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