Skip to main content
SpringerLink
Log in

FTY720 is Neuroprotective and Improves Functional Outcomes After Intracerebral Hemorrhage in Mice

  • Chapter
  • First Online:
Intracerebral Hemorrhage Research

Part of the book series: Acta Neurochirurgica Supplementum ((NEUROCHIRURGICA,volume 111))

Abstract

Intracerebral hemorrhage (ICH) accounts for 20% of all strokes and is the most devastating form across all stroke types. Lymphocytes have been shown to potentiate cerebral inflammation and brain injury after stroke. FTY720 (Fingolimod) is an immune-modulating drug that prevents the egress of peripheral lymphocytes from peripheral stores. We hypothesized that FTY720 would reduce peripheral circulating lymphocytes, resulting in reduced brain injury and improved functional outcomes. CD-1 mice were anesthetized and then injected with collagenase into the right basal ganglia. Animals were divided into three groups: sham, ICH + Vehicle, and ICH + FTY720, by the intra-peritoneal route at 1 h after ICH induction. Brain water content was measured at 24 and 72 h. Neurobehavioral tests included corner test, forelimb use asymmetry, paw placement, wire-hang test, beam balance test, and a Neuroscore. FTY720 significantly reduced brain edema and improved neurological function at all time points tested. Lymphocyte modulation with FTY720 is an effective neuroprotective strategy to reduce brain injury and promote functional recovery after ICH.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Dennis MS, Burn JP, Sandercock PA, Bamford JM, Wade DT, Warlow CP (1993) Long-term survival after first-ever stroke: the Oxfordshire Community Stroke Project. Stroke 24:796–800

    PubMed  CAS  Google Scholar 

  2. James ML, Warner DS, Laskowitz DT (2008) Preclinical models of intracerebral hemorrhage: a translational perspective. Neurocrit Care 9:139–152

    Article  PubMed  Google Scholar 

  3. Wang J, Dore S (2007) Inflammation after intracerebral hemorrhage. J Cereb Blood Flow Metab 27:894–908

    Article  PubMed  CAS  Google Scholar 

  4. Hickenbottom SL, Grotta JC, Strong R, Denner LA, Aronowski J (1999) Nuclear factor-kappaB and cell death after experimental intracerebral hemorrhage in rats. Stroke 30:2472–2477, discussion 2477–2478

    PubMed  CAS  Google Scholar 

  5. Brochard V, Combadiere B, Prigent A, Laouar Y, Perrin A, Beray-Berthat V, Bonduelle O, Alvarez-Fischer D, Callebert J, Launay JM, Duyckaerts C, Flavell RA, Hirsch EC, Hunot S (2009) Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J Clin Invest 119:182–192

    PubMed  CAS  Google Scholar 

  6. Smith D (2009) Interferon-beta therapy for multiple sclerosis–is the injection site the relevant action site? J Neuroimmunol 215:117–121

    Article  PubMed  CAS  Google Scholar 

  7. Togo T, Akiyama H, Iseki E, Kondo H, Ikeda K, Kato M, Oda T, Tsuchiya K, Kosaka K (2002) Occurrence of T cells in the brain of Alzheimer’s disease and other neurological diseases. J Neuroimmunol 124:83–92

    Article  PubMed  CAS  Google Scholar 

  8. Shichita T, Sugiyama Y, Ooboshi H, Sugimori H, Nakagawa R, Takada I, Iwaki T, Okada Y, Iida M, Cua DJ, Iwakura Y, Yoshimura A (2009) Pivotal role of cerebral interleukin-17-producing gammadeltaT cells in the delayed phase of ischemic brain injury. Nat Med 15:946–950

    Article  PubMed  CAS  Google Scholar 

  9. Campanella M, Sciorati C, Tarozzo G, Beltramo M (2002) Flow cytometric analysis of inflammatory cells in ischemic rat brain. Stroke 33:586–592

    Article  Google Scholar 

  10. Brinkmann V, Davis MD, Heise CE, Albert R, Cottens S, Hof R, Bruns C, Prieschl E, Baumruker T, Hiestand P, Foster CA, Zollinger M, Lynch KR (2002) The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem 277:21453–21457

    Article  PubMed  CAS  Google Scholar 

  11. Meno-Tetang GM, Li H, Mis S, Pyszczynski N, Heining P, Lowe P, Jusko WJ (2006) Physiologically based pharmacokinetic modeling of FTY720 (2-amino-2[2-(−4-octylphenyl)ethyl]propane-1, 3-diol hydrochloride) in rats after oral and intravenous doses. Drug Metab Dispos 34:1480–1487

    Article  PubMed  CAS  Google Scholar 

  12. Chiba K (2005) FTY720, a new class of immunomodulator, inhibits lymphocyte egress from secondary lymphoid tissues and thymus by agonistic activity at sphingosine 1-phosphate receptors. Pharmacol Ther 108:308–319

    Article  PubMed  CAS  Google Scholar 

  13. Kappos L, Radue EW, O’Connor P, Polman C, Hohlfeld R, Calabresi P, Selmaj K, Agoropoulou C, Leyk M, Zhang-Auberson L, Burtin P (2010) A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 362:387–401

    Article  PubMed  CAS  Google Scholar 

  14. O’Connor P, Comi G, Montalban X, Antel J, Radue EW, de Vera A, Pohlmann H, Kappos L (2009) Oral fingolimod (FTY720) in multiple sclerosis: two-year results of a phase II extension study. Neurology 72:73–79

    Article  PubMed  Google Scholar 

  15. Tedesco-Silva H, Mourad G, Kahan BD, Boira JG, Weimar W, Mulgaonkar S, Nashan B, Madsen S, Charpentier B, Pellet P, Vanrenterghem Y (2004) FTY720, a novel immunomodulator: efficacy and safety results from the first phase 2A study in de novo renal transplantation. Transplantation 77:1826–1833

    PubMed  CAS  Google Scholar 

  16. Hasegawa Y, Suzuki H, Sozen T, Rolland W, Zhang JH (2010) Activation of sphingosine 1-phosphate receptor-1 by FTY720 is neuroprotective after ischemic stroke in rats. Stroke 41:368–374

    Article  PubMed  CAS  Google Scholar 

  17. Rosenberg GA, Mun-Bryce S, Wesley M, Kornfeld M (1990) Collagenase-induced intracerebral hemorrhage in rats. Stroke 21:801–807

    PubMed  CAS  Google Scholar 

  18. Tang J, Liu J, Zhou C, Alexander JS, Nanda A, Granger DN, Zhang JH (2004) Mmp-9 deficiency enhances collagenase-induced intracerebral hemorrhage and brain injury in mutant mice. J Cereb Blood Flow Metab 24:1133–1145

    Article  PubMed  Google Scholar 

  19. Garcia JH, Wagner S, Liu KF, Hu XJ (1995) Neurological deficit and extent of neuronal necrosis attributable to middle cerebral artery occlusion in rats. Statistical validation. Stroke 26:627–634, discussion 635

    PubMed  CAS  Google Scholar 

  20. Hartman R, Lekic T, Rojas H, Tang J, Zhang JH (2009) Assessing functional outcomes following intracerebral hemorrhage in rats. Brain Res 1280:148–157

    Article  PubMed  CAS  Google Scholar 

  21. Peeling J, Yan HJ, Corbett D, Xue M, Del Bigio MR (2001) Effect of FK-506 on inflammation and behavioral outcome following intracerebral hemorrhage in rat. Exp Neurol 167:341–347

    Article  PubMed  CAS  Google Scholar 

  22. Titova E, Ostrowski RP, Kevil CG, Tong W, Rojas H, Sowers LC, Zhang JH, Tang J (2008) Reduced brain injury in CD18-deficient mice after experimental intracerebral hemorrhage. J Neurosci Res 86:3240–3245

    Article  PubMed  CAS  Google Scholar 

  23. Chiba K, Yanagawa Y, Masubuchi Y, Kataoka H, Kawaguchi T, Ohtsuki M, Hoshino Y (1998) FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats. I. FTY720 selectively decreases the number of circulating mature lymphocytes by acceleration of lymphocyte homing. J Immunol 160:5037–5044

    PubMed  CAS  Google Scholar 

  24. Sanchez T, Estrada-Hernandez T, Paik JH, Wu MT, Venkataraman K, Brinkmann V, Claffey K, Hla T (2003) Phosphorylation and action of the immunomodulator FTY720 inhibits vascular endothelial cell growth factor-induced vascular permeability. J Biol Chem 278:47281–47290

    Article  PubMed  CAS  Google Scholar 

  25. Brinkmann V, Cyster JG, Hla T (2004) FTY720: sphingosine 1-phosphate receptor-1 in the control of lymphocyte egress and endothelial barrier function. Am J Transplant 4:1019–1025

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgement

This study is partially supported by NIH NS053407 to J.H. Zhang and NS060936 to J. Tang.

Conflict of interest statement We declare that we have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Physiology, Loma Linda University, School of Medicine, Loma Linda, CA, USA

    William B. Rolland II, Anatol Manaenko, Tim Lekic, Yu Hasegawa, Robert Ostrowski, Jiping Tang & John H. Zhang

  2. Department of Neurosurgery, Loma Linda University, School of Medicine, Loma Linda, CA, USA

    John H. Zhang

  3. Department of Physiology and Pharmacology, Loma Linda University, School of Medicine, Risley Hall, Room 219, Loma Linda, CA, 92350, USA

    John H. Zhang

  4. Department of Anesthesiology, Loma Linda University, School of Medicine, Loma Linda, CA, USA

    John H. Zhang

Authors
  1. William B. Rolland II
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anatol Manaenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tim Lekic
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yu Hasegawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Robert Ostrowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jiping Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. John H. Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John H. Zhang .

Editor information

Editors and Affiliations

  1. , Neurosurgery, Physiology, Loma Linda University, Campus Street 11041, Loma Linda, 92530, USA

    John Zhang

  2. School of Medicine, Dept. Neurosurgery, Loma Linda University, Anderson St. 11234, Loma Linda, 92354, California, USA

    Austin Colohan

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer-Verlag/Wien

About this chapter

Cite this chapter

Rolland, W.B. et al. (2011). FTY720 is Neuroprotective and Improves Functional Outcomes After Intracerebral Hemorrhage in Mice. In: Zhang, J., Colohan, A. (eds) Intracerebral Hemorrhage Research. Acta Neurochirurgica Supplementum, vol 111. Springer, Vienna. https://doi.org/10.1007/978-3-7091-0693-8_36

Download citation

  • DOI: https://doi.org/10.1007/978-3-7091-0693-8_36

  • Published:

  • Publisher Name: Springer, Vienna

  • Print ISBN: 978-3-7091-0692-1

  • Online ISBN: 978-3-7091-0693-8

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation