Skip to main content
SpringerLink
Log in

A Clinically Relevant Rabbit Embolic Stroke Model for Acute Ischemic Stroke Therapy Development: Mechanisms and Targets

  • Chapter
  • First Online:
Translational Stroke Research

Part of the book series: Springer Series in Translational Stroke Research ((SSTSR))

Abstract

Alteplase (tissue plasminogen activator, tPA) is currently the only ­FDA-approved treatment that can be given to acute ischemic stroke (AIS) patients, if patients present within 3 h of an ischemic stroke. Recent clinical trial evidence now suggests that the therapeutic treatment window for tPA can be expanded 4.5 h, but this is not formally approved by the FDA. Even though there remains a significant risk of intracerebral hemorrhage (ICH) associated with alteplase administration, there is an increased chance of favorable outcome with tPA treatment.

Over the last 30 years, significant progress in the understanding of mechanisms involved in stroke damage have resulted from the sue of a series of in vivo stroke models. The use of preclinical models has also assisted with the identification of new treatments strategies, but the new strategies have not been easily translated from the laboratory animal into the stroke patient. Current research trends emphasize the development of new and potentially useful thrombolytics, neuroprotective agents and devices, which are also being tested for efficacy in preclinical and clinical trials. We have used the rabbit small clot embolic stroke model (RSCEM) to optimize treatment strategies prior to the development of clinical trials. Originally, the RSCEM was used to develop tPA for efficacy, and it remains the only preclinical model used to gain FDA approval of a therapeutic agent for stroke. This chapter will focus on recent studies of new therapeutic approaches developed using the RSCEM. Analysis from existing preclinical and clinical trials indicates that the RSCEM can be used as an effective translational tool to gauge the clinical potential of new treatments.

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. Lapchak PA. Development of thrombolytic therapy for stroke: a perspective. Expert Opin Investig Drugs. 2002;11(11):1623–32.

    Article  CAS  PubMed  Google Scholar 

  2. Schellinger PD, Fiebach JB, Mohr A, Ringleb PA, Jansen O, Hacke W. Thrombolytic therapy for ischemic stroke—a review. Part II—Intra-arterial thrombolysis, vertebrobasilar stroke, phase IV trials, and stroke imaging. Crit Care Med. 2001;29(9):1819–25.

    Article  CAS  PubMed  Google Scholar 

  3. Schellinger PD, Fiebach JB, Mohr A, Ringleb PA, Jansen O, Hacke W. Thrombolytic therapy for ischemic stroke—a review. Part I—intravenous thrombolysis. Crit Care Med. 2001;29(9):1812–8.

    Article  CAS  PubMed  Google Scholar 

  4. Verstraete M. Newer thrombolytic agents. Ann Acad Med Singapore. 1999;28(3):424–33.

    CAS  PubMed  Google Scholar 

  5. Hacke W, Kaste M, Bluhmki E, Brozman M, Davalos A, Guidetti D, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359(13):1317–29.

    Article  CAS  PubMed  Google Scholar 

  6. Lansberg MG, Bluhmki E, Thijs VN. Efficacy and safety of tissue plasminogen activator 3 to 4.5 hours after acute ischemic stroke: a metaanalysis. Stroke. 2009;40(7):2438–41.

    Article  CAS  PubMed  Google Scholar 

  7. Chernyshev OY, Martin-Schild S, Albright KC, Barreto A, Misra V, Acosta I, et al. Safety of tPA in stroke mimics and neuroimaging-negative cerebral ischemia. Neurology. 2010;74(17):1340–5.

    Article  CAS  PubMed  Google Scholar 

  8. Lees KR, Bluhmki E, von Kummer R, Brott TG, Toni D, Grotta JC, et al. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet. 2010;375(9727):1695–703.

    Article  CAS  PubMed  Google Scholar 

  9. Lapchak PA. Translational stroke research using a rabbit embolic stroke model: a correlative analysis hypothesis for novel therapy development. Transl Stroke Res. 2010;1(2):96–107.

    Article  PubMed  Google Scholar 

  10. Saver JL, Albers GW, Dunn B, Johnston KC, Fisher M. Stroke Therapy Academic Industry Roundtable (STAIR) recommendations for extended window acute stroke therapy trials. Stroke. 2009;40(7):2594–600.

    Article  PubMed  Google Scholar 

  11. NINDS. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995;333(24):1581–7.

    Article  Google Scholar 

  12. Petty GW, Brown Jr RD, Whisnant JP, Sicks JD, O’Fallon WM, Wiebers DO. Ischemic stroke subtypes: a population-based study of functional outcome, survival, and recurrence. Stroke. 2000;31(5):1062–8.

    Article  CAS  PubMed  Google Scholar 

  13. Petty GW, Brown Jr RD, Whisnant JP, Sicks JD, O’Fallon WM, Wiebers DO. Ischemic stroke subtypes: a population-based study of incidence and risk factors. Stroke. 1999;30(12):2513–6.

    Article  CAS  PubMed  Google Scholar 

  14. Lapchak PA, Araujo DM. Advances in ischemic stroke treatment: neuroprotective and combination therapies. Expert Opin Emerg Drugs. 2007;12(1):97–112.

    Article  CAS  PubMed  Google Scholar 

  15. Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci. 1999;22(9):391–7.

    Article  CAS  PubMed  Google Scholar 

  16. Moskowitz MA, Lo EH, Iadecola C. The science of stroke: mechanisms in search of treatments. Neuron. 2010;67(2):181–98.

    Article  CAS  PubMed  Google Scholar 

  17. Lipton P. Ischemic cell death in brain neurons. Physiol Rev. 1999;79(4):1431–568.

    CAS  PubMed  Google Scholar 

  18. Michel P, Bogousslavsky J. Penumbra is brain: no excuse not to perfuse. Ann Neurol. 2005;58(5):661–3.

    Article  PubMed  Google Scholar 

  19. Moustafa RR, Baron JC. Imaging the penumbra in acute stroke. Curr Atheroscler Rep. 2006;8(4):281–9.

    Article  PubMed  Google Scholar 

  20. Fisher M. The ischemic penumbra: identification, evolution and treatment concepts. Cerebrovasc Dis. 2004;17:1–6.

    Article  PubMed  Google Scholar 

  21. Muir KW. Heterogeneity of stroke pathophysiology and neuroprotective clinical trial design. Stroke. 2002;33(6):1545–50.

    Article  PubMed  Google Scholar 

  22. Lapchak PA. Emerging therapies: pleiotropic multi-target drugs to treat stroke victims. Transl Stroke Res. 2011;2(2):129–35.

    Article  PubMed  Google Scholar 

  23. White BC, Sullivan JM, DeGracia DJ, O’Neil BJ, Neumar RW, Grossman LI, et al. Brain ischemia and reperfusion: molecular mechanisms of neuronal injury. J Neurol Sci. 2000;179(S 1–2):1–33.

    Article  CAS  PubMed  Google Scholar 

  24. Lapchak PA. A critical assessment of edaravone acute ischemic stroke efficacy trials: is edaravone an effective neuroprotective therapy? Expert Opin Pharmacother. 2010;11(10):1753–63.

    Article  CAS  PubMed  Google Scholar 

  25. Lapchak PA. Neuroprotective and neurotrophic curcuminoids to treat stroke: a translational perspective. Expert Opin Investig Drugs. 2011;20(1):13–22.

    Article  CAS  PubMed  Google Scholar 

  26. Ginsberg MD. Neuroprotection for ischemic stroke: past, present and future. Neuropharmacology. 2008;55(3):363–89.

    Article  CAS  PubMed  Google Scholar 

  27. Fisher M. New approaches to neuroprotective drug development. Stroke. 2011;42(1 Suppl):S24–7.

    Article  PubMed  Google Scholar 

  28. Woodruff TM, Thundyil J, Tang SC, Sobey CG, Taylor SM, Arumugam TV. Pathophysiology, treatment, and animal and cellular models of human ischemic stroke. Mol Neurodegener. 2011;6(1):11.

    Article  PubMed  Google Scholar 

  29. Tuttolomondo A, Di Sciacca R, Di Raimondo D, Arnao V, Renda C, Pinto A, et al. Neuron protection as a therapeutic target in acute ischemic stroke. Curr Top Med Chem. 2009;9(14):1317–34.

    Article  CAS  PubMed  Google Scholar 

  30. Scott PA, Frederiksen SM, Kalbfleisch JD, Xu Z, Meurer WJ, Caveney AF, et al. Safety of intravenous thrombolytic use in four emergency departments without acute stroke teams. Acad Emerg Med. 2010;17(10):1062–71.

    Article  PubMed  Google Scholar 

  31. Ferguson KN, Kidwell CS, Starkman S, Saver JL. Hyperacute treatment initiation in neuroprotective agent stroke trials. J Stroke Cerebrovasc Dis. 2004;13(3):109–12.

    Article  PubMed  Google Scholar 

  32. Lapchak PA, Schubert DR, Maher PA. Delayed treatment with a novel neurotrophic compound reduces behavioral deficits in rabbit ischemic stroke. J Neurochem. 2011;116(1):122–31.

    Article  CAS  PubMed  Google Scholar 

  33. STAIR. Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke. 1999;30(12):2752–8.

    Article  Google Scholar 

  34. Hacke W, Brott T, Caplan L, Meier D, Fieschi C, von Kummer R, et al. Thrombolysis in acute ischemic stroke: controlled trials and clinical experience. Neurology. 1999;53(7):S3–14.

    CAS  PubMed  Google Scholar 

  35. Hsia AW, Sachdev HS, Tomlinson J, Hamilton SA, Tong DC. Efficacy of IV tissue plasminogen activator in acute stroke: does stroke subtype really matter? Neurology. 2003;61(1):71–5.

    Article  CAS  PubMed  Google Scholar 

  36. Lyden P, Lu M, Jackson C, Marler J, Kothari R, Brott T, et al. Underlying Structure of the National Institutes of Health Stroke Scale: results of a factor analysis. Stroke. 1999;30:2347.

    Article  CAS  PubMed  Google Scholar 

  37. Lyden P, Raman R, Liu L, Grotta J, Broderick J, Olson S, et al. NIHSS training and certification using a new digital video disk is reliable. Stroke. 2005;36(11):2446–9.

    Article  PubMed  Google Scholar 

  38. Sulter G, Steen C, De Keyser J. Use of the Barthel Index and modified Rankin Scale in acute stroke trials. Stroke. 1999;30:1538.

    Article  CAS  PubMed  Google Scholar 

  39. Wilson JT, Hareendran A, Grant M, Baird T, Schultz UGR, Muir KW, et al. Improving the assessment of outcomes in strokes. Stroke. 2002;33:2243.

    Article  PubMed  Google Scholar 

  40. Young FB, Lees KR, Weir CJ. Strengthening acute stroke trials through optimal use of disability end points. Stroke. 2003;34(11):2676–80.

    Article  PubMed  Google Scholar 

  41. Ginsberg MD. The validity of rodent brain-ischemia models is self-evident. Arch Neurol. 1996;53(10):1065–7; discussion 70.

    Google Scholar 

  42. Ginsberg MD. Life after cerovive: a personal perspective on ischemic neuroprotection in the post-NXY-059 era. Stroke. 2007;38(6):1967–72.

    Article  PubMed  Google Scholar 

  43. Hoyte L, Kaur J, Buchan AM. Lost in translation: taking neuroprotection from animal models to clinical trials. Exp Neurol. 2004;188(2):200–4.

    Article  CAS  PubMed  Google Scholar 

  44. Turner R, Jickling G, Sharp F. Are underlying assumptions of current animal models of human stroke correct: from STAIRS to high hurdles? Transl Stroke Res. 2011;2(2):138–43.

    Article  PubMed  Google Scholar 

  45. Zivin JA, Fisher M, DeGirolami U, Hemenway CC, Stashak JA. Tissue plasminogen activator reduces neurological damage after cerebral embolism. Science. 1985;230(4731):1289.

    Article  CAS  PubMed  Google Scholar 

  46. Lapchak PA. Effect of internal carotid artery reperfusion in combination with Tenecteplase on clinical scores and hemorrhage in a rabbit embolic stroke model. Brain Res. 2009;1294:211–7.

    Article  CAS  PubMed  Google Scholar 

  47. Lapchak PA, De Taboada L. Transcranial near infrared laser treatment (NILT) increases cortical adenosine-5′-triphosphate (ATP) content following embolic strokes in rabbits. Brain Res. 2010;1306:100–5.

    Article  CAS  PubMed  Google Scholar 

  48. Lapchak PA, Streeter J, DeTaboada L. Transcranial near infrared laser therapy (NILT) to treat acute ischemic stroke: a review of efficacy, safety and possible mechanism of action derived from rabbit embolic stroke studies SPIE Proceedings. 7552R:7552–31.

    Google Scholar 

  49. Kawaguchi M, Furuya H, Patel PM. Neuroprotective effects of anesthetic agents. J Anesth. 2005;19(2):150–6.

    Article  PubMed  Google Scholar 

  50. Koerner IP, Brambrink AM. Brain protection by anesthetic agents. Curr Opin Anaesthesiol. 2006;19(5):481–6.

    Article  PubMed  Google Scholar 

  51. Matchett GA, Allard MW, Martin RD, Zhang JH. Neuroprotective effect of volatile anesthetic agents: molecular mechanisms. Neurol Res. 2009;31(2):128–34.

    Article  CAS  PubMed  Google Scholar 

  52. Nishikawa K, MacIver MB. Excitatory synaptic transmission mediated by NMDA receptors is more sensitive to isoflurane than are non-NMDA receptor-mediated responses. Anesthesiology. 2000;92(1):228–36.

    Article  CAS  PubMed  Google Scholar 

  53. Lapchak PA, Zivin JA. The lipophilic multifunctional antioxidant edaravone (radicut) improves behavior following embolic strokes in rabbits: a combination therapy study with tissue plasminogen activator. Exp Neurol. 2009;215(1):95–100.

    Article  CAS  PubMed  Google Scholar 

  54. Waud DR. On biological assays involving quantal responses. J Pharmacol Exp Ther. 1972;183:577–607.

    CAS  PubMed  Google Scholar 

  55. Lapchak PA. Translational stroke research using a rabbit embolic stroke model: a correlative analysis hypothesis for novel therapy development. Trans Stroke Res. 2010;1:96–107.

    Article  Google Scholar 

  56. Kasner SE. Clinical interpretation and use of stroke scales. Lancet Neurol. 2006;5(7):603–12.

    Article  PubMed  Google Scholar 

  57. Lindsell CJ, Alwell K, Moomaw CJ, Kleindorfer DO, Woo D, Flaherty ML, et al. Validity of a retrospective National Institutes of Health Stroke Scale scoring methodology in patients with severe stroke. J Stroke Cerebrovasc Dis. 2005;14(6):281–3.

    Article  PubMed  Google Scholar 

  58. Lyden P, Brott T, Tilley B, Welch KM, Mascha EJ, Levine S, et al. Improved reliability of the NIH Stroke Scale using video training. NINDS TPA Stroke Study Group. Stroke. 1994;25(11):2220–6.

    Article  CAS  PubMed  Google Scholar 

  59. Lyden P, Lu M, Jackson C, Marler J, Kothari R, Brott T, et al. Underlying structure of the National Institutes of Health Stroke Scale: results of a factor analysis. NINDS tPA Stroke Trial Investigators. Stroke. 1999;30(11):2347–54.

    Article  CAS  PubMed  Google Scholar 

  60. Waud DR. On biological assays involving quantal responses. J Pharmacol Exp Ther. 1972;183(3):577–607.

    CAS  PubMed  Google Scholar 

  61. Lapchak PA, Zhang JH. Resolving the negative data publication dilemma in translational stroke research. Transl Stroke Res. 2011;2(1):1–6.

    Article  PubMed  Google Scholar 

  62. Lapchak PA, Araujo DM, Zivin JA. Comparison of tenecteplase with alteplase on clinical rating scores following small clot embolic strokes in rabbits. Exp Neurol. 2004;185(1):154–9.

    Article  CAS  PubMed  Google Scholar 

  63. Lapchak PA, Salgado KF, Chao CH, Zivin JA. Transcranial near-infrared light therapy improves motor function following embolic strokes in rabbits: an extended therapeutic window study using continuous and pulse frequency delivery modes. Neuroscience. 2007;148(4):907–14.

    Article  CAS  PubMed  Google Scholar 

  64. Lapchak PA, Wei J, Zivin JA. Transcranial infrared laser therapy improves clinical rating scores after embolic strokes in rabbits. Stroke. 2004;35(8):1985–8.

    Article  PubMed  Google Scholar 

  65. Lapchak PA, Araujo DM, Song D, Wei J, Purdy R, Zivin JA. Effects of the spin trap agent disodium-[(tert-butylimino)methyl]benzene-1,3-disulfonate N-oxide (generic NXY-059) on intracerebral hemorrhage in a rabbit large clot embolic stroke model: combination studies with tissue plasminogen activator. Stroke. 2002;33(6):1665–70.

    Article  CAS  PubMed  Google Scholar 

  66. Silver JH, Lapchak PA. Continuous monitoring of changes in plasma nitrite following cerebral ischemia in a rabbit embolic stroke model. Transl Stroke Res. 2011;2(2):218–26.

    Article  PubMed  Google Scholar 

  67. Bederson JB, Pitts LH, Germano SM, Nishimura MC, Davis RL, Bartkowski HM. Evaluation of 2,3,5-triphenyltetrazolium chloride as a stain for detection and quantification of experimental cerebral infarction in rats. Stroke. 1986;17(6):1304–8.

    Article  CAS  PubMed  Google Scholar 

  68. Guluma KZ, Lapchak PA. Comparison of the post-embolization effects of tissue-plasminogen activator and simvastatin on neurological outcome in a clinically relevant rat model of acute ischemic stroke. Brain Res. 2010;1354:206–16.

    Article  CAS  PubMed  Google Scholar 

  69. Kricka LJ. Clinical and biochemical applications of luciferases and luciferins. Anal Biochem. 1988;175:14–21.

    Article  CAS  PubMed  Google Scholar 

  70. Fisher RL, Gandolfi AJ, Brendel K. Human liver quality is a dominant factor in the outcome of in vitro studies. Cell Biol Toxicol. 2001;17(3):179–89.

    Article  CAS  PubMed  Google Scholar 

  71. Eide FF, Lowenstein DH, Reichardt LF. Neurotrophins and their receptors–current concepts and implications for neurologic disease. Exp Neurol. 1993;121(2):200–14.

    Article  CAS  PubMed  Google Scholar 

  72. Olson L, Backman L, Ebendal T, Eriksdotter-Jonhagen M, Hoffer B, Humpel C, et al. Role of growth factors in degeneration and regeneration in the central nervous system; clinical experiences with NGF in Parkinson’s and Alzheimer’s diseases. J Neurol. 1994;242(1 Suppl 1):S12–5.

    Article  CAS  PubMed  Google Scholar 

  73. Patapoutian A, Reichardt LF. Trk receptors: mediators of neurotrophin action. Curr Opin Neurobiol. 2001;11(3):272–80.

    Article  CAS  PubMed  Google Scholar 

  74. Reichardt LF. Neurotrophin-regulated signalling pathways. Philos Trans R Soc Lond B Biol Sci. 2006;361(1473):1545–64.

    Article  CAS  PubMed  Google Scholar 

  75. Wu D. Neuroprotection in experimental stroke with targeted neurotrophins. NeuroRx. 2005;2(1):120–8.

    Article  PubMed  Google Scholar 

  76. Yano H, Chao MV. Neurotrophin receptor structure and interactions. Pharm Acta Helv. 2000;74(2–3):253–60.

    Article  CAS  PubMed  Google Scholar 

  77. Rossler OG, Giehl KM, Thiel G. Neuroprotection of immortalized hippocampal neurons by brain-derived neurotrophic factor and Raf-1 protein kinase: role of extracellular signal-regulated protein kinase and phosphatidylinositol 3-kinase. J Neurochem. 2004;88(5):1240–52.

    Article  PubMed  CAS  Google Scholar 

  78. Schratt GM, Nigh EA, Chen WG, Hu L, Greenberg ME. BDNF regulates the translation of a select group of mRNAs by a mammalian target of rapamycin-phosphatidylinositol 3-kinase-dependent pathway during neuronal development. J Neurosci. 2004;24(33):7366–77.

    Article  CAS  PubMed  Google Scholar 

  79. Tamatani M, Matsuyama T, Yamaguchi A, Mitsuda N, Tsukamoto Y, Taniguchi M, et al. ORP150 protects against hypoxia/ischemia-induced neuronal death. Nat Med. 2001;7(3):317–23.

    Article  CAS  PubMed  Google Scholar 

  80. Ying SW, Futter M, Rosenblum K, Webber MJ, Hunt SP, Bliss TV, et al. Brain-derived neurotrophic factor induces long-term potentiation in intact adult hippocampus: requirement for ERK activation coupled to CREB and upregulation of Arc synthesis. J Neurosci. 2002;22(5):1532–40.

    CAS  PubMed  Google Scholar 

  81. Yin Y, Edelman GM, Vanderklish PW. The brain-derived neurotrophic factor enhances synthesis of Arc in synaptoneurosomes. Proc Natl Acad Sci U S A. 2002;99(4):2368–73.

    Article  CAS  PubMed  Google Scholar 

  82. Mehta SL, Manhas N, Raghubir R. Molecular targets in cerebral ischemia for developing novel therapeutics. Brain Res Rev. 2007;54(1):34–66.

    Article  CAS  PubMed  Google Scholar 

  83. Zhao H, Sapolsky RM, Steinberg GK. Phosphoinositide-3-kinase/akt survival signal pathways are implicated in neuronal survival after stroke. Mol Neurobiol. 2006;34(3):249–70.

    Article  CAS  PubMed  Google Scholar 

  84. Liu C, Wu J, Xu K, Cai F, Gu J, Ma L, et al. Neuroprotection by baicalein in ischemic brain injury involves PTEN/AKT pathway. J Neurochem. 2010;112:1500–12.

    Article  CAS  PubMed  Google Scholar 

  85. Lapchak PA, Araujo DM, Song D, Wei J, Zivin JA. Neuroprotective effects of the spin trap agent disodium-[(tert-butylimino)methyl]benzene-1,3-disulfonate N-oxide (generic NXY-059) in a rabbit small clot embolic stroke model: combination studies with the thrombolytic tissue plasminogen activator. Stroke. 2002;33(5):1411–5.

    Article  CAS  PubMed  Google Scholar 

  86. Zivin JA, Lyden PD, DeGirolami U, Kochhar A, Mazzarella V, Hemenway CC, et al. Tissue plasminogen activator. Reduction of neurologic damage after experimental embolic stroke. Arch Neurol. 1988;45(4):387–91.

    Article  CAS  PubMed  Google Scholar 

  87. Albers GW, Bates VE, Clark WM, Bell R, Verro P, Hamilton SA. Intravenous tissue-type plasminogen activator for treatment of acute stroke: the Standard Treatment with Alteplase to Reverse Stroke (STARS) study. JAMA. 2000;283(9):1145–50.

    Article  CAS  PubMed  Google Scholar 

  88. Alberts MJ. tPA in acute ischemic stroke: United States experience and issues for the future. Neurology. 1998;51(3 Suppl 3):S53–5.

    Article  CAS  PubMed  Google Scholar 

  89. Christou I, Alexandrov AV, Burgin WS, Wojner AW, Felberg RA, Malkoff M, et al. Timing of recanalization after tissue plasminogen activator therapy determined by transcranial Doppler correlates with clinical recovery from ischemic stroke. Stroke. 2000;31(8):1812–6.

    Article  CAS  PubMed  Google Scholar 

  90. Clark WM, Albers GW, Madden KP, Hamilton S. The rtPA (alteplase) 0- to 6-hour acute stroke trial, part A (A0276g): results of a double-blind, placebo-controlled, multicenter study. Thrombolytic therapy in acute ischemic stroke study investigators. Stroke. 2000;31(4):811–6.

    Article  CAS  PubMed  Google Scholar 

  91. Grotta JC, Alexandrov AV. tPA-associated reperfusion after acute stroke demonstrated by SPECT. Stroke. 1998;29(2):429–32.

    Article  CAS  PubMed  Google Scholar 

  92. Grotta JC, Burgin WS, El-Mitwalli A, Long M, Campbell M, Morgenstern LB, et al. Intravenous tissue-type plasminogen activator therapy for ischemic stroke: Houston experience 1996 to 2000. Arch Neurol. 2001;58(12):2009–13.

    Article  CAS  PubMed  Google Scholar 

  93. Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA. 1995;274(13):1017–25.

    Article  CAS  PubMed  Google Scholar 

  94. Reeves MJ, Arora S, Broderick JP, Frankel M, Heinrich JP, Hickenbottom S, et al. Acute stroke care in the US: results from 4 pilot prototypes of the Paul Coverdell National Acute Stroke Registry. Stroke. 2005;36(6):1232–40.

    Article  PubMed  Google Scholar 

  95. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333(24):1581–7.

    Article  Google Scholar 

  96. Zunker P, Schick A, Padro T, Kienast J, Phillips A, Ringelstein EB. Tissue plasminogen activator and plasminogen activator inhibitor in patients with acute ischemic stroke: relation to stroke etiology. Neurol Res. 1999;21(8):727–32.

    CAS  PubMed  Google Scholar 

  97. del Zoppo G. Thrombolytic therapy in cerebrovascular disease. Curr Concepts Cerebrovasc Dis. 1988;23:7.

    Google Scholar 

  98. Bowes MP, Zivin JA, Rothlein R. Monoclonal antibody to the ICAM-1 adhesion site reduces neurological damage in a rabbit cerebral embolism stroke model. Exp Neurol. 1993;119(2):215–9.

    Article  CAS  PubMed  Google Scholar 

  99. Bowes MP, Rothlein R, Fagan SC, Zivin JA. Monoclonal antibodies preventing leukocyte activation reduce experimental neurologic injury and enhance efficacy of thrombolytic therapy. Neurology. 1995;45(4):815–9.

    Article  CAS  PubMed  Google Scholar 

  100. Bousova I, Martin J, Jahodar L, Dusek J, Palicka V, Drsata J. Evaluation of in vitro effects of natural substances of plant origin using a model of protein glycoxidation. J Pharm Biomed Anal. 2005;37(5):957–62.

    Article  CAS  PubMed  Google Scholar 

  101. Martin J, Dusek J. The Baikal scullcap (Scutellaria baicalensis Georgi)—a potential source of new drugs. Ceska Slov Farm. 2002;51(6):277–83.

    CAS  PubMed  Google Scholar 

  102. Roy MK, Nakahara K, Na TV, Trakoontivakorn G, Takenaka M, Isobe S, et al. Baicalein, a flavonoid extracted from a methanolic extract of Oroxylum indicum inhibits proliferation of a cancer cell line in vitro via induction of apoptosis. Die Pharmazie. 2007;62(2):149–53.

    CAS  PubMed  Google Scholar 

  103. Huang Y, Tsang SY, Yao X, Chen ZY. Biological properties of baicalein in cardiovascular system. Curr Drug Targets. 2005;5(2):177–84.

    CAS  Google Scholar 

  104. Huang WH, Lee AR, Chien PY, Chou TC. Synthesis of baicalein derivatives as potential anti-aggregatory and anti-inflammatory agents. J Pharm Pharmacol. 2005;57(2):219–25.

    Article  CAS  PubMed  Google Scholar 

  105. Ma Z, Otsuyama K, Liu S, Abroun S, Ishikawa H, Tsuyama N, et al. Baicalein, a component of Scutellaria radix from Huang-Lian-Jie-Du-Tang (HLJDT), leads to suppression of proliferation and induction of apoptosis in human myeloma cells. Blood. 2005;105(8):3312–8.

    Article  CAS  PubMed  Google Scholar 

  106. Lapchak PA, Maher P, Schubert D, Zivin JA. Baicalein, an antioxidant 12/15 lipoxygenase inhibitor improves clinical rating scores following multiple infarct embolic strokes. Neuroscience. 2007;150(3):585–91.

    Article  CAS  PubMed  Google Scholar 

  107. Goldfinger TM. Beyond the French paradox: the impact of moderate beverage alcohol and wine consumption in the prevention of cardiovascular disease. Cardiol Clin. 2003;21(3):449–57.

    Article  PubMed  Google Scholar 

  108. Kar P, Laight D, Shaw KM, Cummings MH. Flavonoid-rich grapeseed extracts: a new approach in high cardiovascular risk patients? Int J Clin Pract. 2006;60(11):1484–92.

    Article  CAS  PubMed  Google Scholar 

  109. Nijveldt RJ, van Nood E, van Hoorn DE, Boelens PG, van Norren K, van Leeuwen PA. Flavonoids: a review of probable mechanisms of action and potential applications. Am J Clin Nutr. 2001;74(4):418–25.

    CAS  PubMed  Google Scholar 

  110. Renaud S, Ruf JC. The French paradox: vegetables or wine. Circulation. 1994;90(6):3118–9.

    Article  CAS  PubMed  Google Scholar 

  111. Manach C, Scalbert A, Morand C, Remesy C, Jimenez L. Polyphenols: food sources and bioavailability. Am J Clin Nutr. 2004;79(5):727–47.

    CAS  PubMed  Google Scholar 

  112. Scalbert A, Manach C, Morand C, Remesy C, Jimenez L. Dietary polyphenols and the prevention of diseases. Crit Rev Food Sci Nutr. 2005;45(4):287–306.

    Article  CAS  PubMed  Google Scholar 

  113. Chassevent F. Chlorogenic acid, physiological and pharmacological activity. Ann Nutr Aliment. 1969;23 Suppl 1:1–14.

    PubMed  Google Scholar 

  114. Jung HA, Park JC, Chung HY, Kim J, Choi JS. Antioxidant flavonoids and chlorogenic acid from the leaves of Eriobotrya japonica. Arch Pharm Res. 1999;22(2):213–8.

    Article  CAS  PubMed  Google Scholar 

  115. dos Santos MD, Almeida MC, Lopes NP, de Souza GE. Evaluation of the anti-inflammatory, analgesic and antipyretic activities of the natural polyphenol chlorogenic acid. Biol Pharm Bull. 2006;29(11):2236–40.

    Article  PubMed  Google Scholar 

  116. Jin UH, Lee JY, Kang SK, Kim JK, Park WH, Kim JG, et al. A phenolic compound, 5-caffeoylquinic acid (chlorogenic acid), is a new type and strong matrix metalloproteinase-9 inhibitor: isolation and identification from methanol extract of Euonymus alatus. Life Sci. 2005;77(22):2760–9.

    Article  CAS  PubMed  Google Scholar 

  117. Lapchak PA. The phenylpropanoid micronutrient chlorogenic acid improves clinical rating scores in rabbits following multiple infarct ischemic strokes: synergism with tissue plasminogen activator. Exp Neurol. 2007;205(2):407–13.

    Article  CAS  PubMed  Google Scholar 

  118. Parnham M, Sies H. Ebselen: prospective therapy for cerebral ischaemia. Expert Opin Investig Drugs. 2000;9(3):607–19.

    Article  CAS  PubMed  Google Scholar 

  119. Lapchak PA, Zivin JA. Ebselen, a seleno-organic antioxidant, is neuroprotective after embolic strokes in rabbits: synergism with low-dose tissue plasminogen activator. Stroke. 2003;34(8):2013–8.

    Article  CAS  PubMed  Google Scholar 

  120. Seo JY, Lee CH, Cho JH, Choi JH, Yoo KY, Kim DW, et al. Neuroprotection of ebselen against ischemia/reperfusion injury involves GABA shunt enzymes. J Neurol Sci. 2009;285(1–2):88–94.

    Article  CAS  PubMed  Google Scholar 

  121. Yamagata K, Ichinose S, Miyashita A, Tagami M. Protective effects of ebselen, a seleno-organic antioxidant on neurodegeneration induced by hypoxia and reperfusion in stroke-prone spontaneously hypertensive rat. Neuroscience. 2008;153(2):428–35.

    Article  CAS  PubMed  Google Scholar 

  122. Dajas F, Rivera-Megret F, Blasina F, Arredondo F, Abin-Carriquiry JA, Costa G, et al. Neuroprotection by flavonoids. Braz J Med Biol Res. 2003;36(12):1613–20.

    Article  CAS  PubMed  Google Scholar 

  123. Maher P. A comparison of the neurotrophic activities of the flavonoid fisetin and some of its derivatives. Free Radic Res. 2006;40(10):1105–11.

    Article  CAS  PubMed  Google Scholar 

  124. Maher P. The flavonoid fisetin promotes nerve cell survival from trophic factor withdrawal by enhancement of proteasome activity. Arch Biochem Biophys. 2008;476(2):139–44.

    Article  CAS  PubMed  Google Scholar 

  125. Rivera F, Urbanavicius J, Gervaz E, Morquio A, Dajas F. Some aspects of the in vivo neuroprotective capacity of flavonoids: bioavailability and structure-activity relationship. Neurotox Res. 2004;6(7–8):543–53.

    Article  PubMed  Google Scholar 

  126. Maher P, Salgado KF, Zivin JA, Lapchak PA. A novel approach to screening for new neuroprotective compounds for the treatment of stroke. Brain Res. 2007;1173:117–25.

    Article  CAS  PubMed  Google Scholar 

  127. Kuroda S, Tsuchidate R, Smith ML, Maples KR, Siesjo BK. Neuroprotective effects of a novel nitrone, NXY-059, after transient focal cerebral ischemia in the rat. J Cereb Blood Flow Metab. 1999;19(7):778–87.

    Article  CAS  PubMed  Google Scholar 

  128. Green AR, Lanbeck-Vallen K, Ashwood T, Lundquist S, Lindstrom Boo E, Jonasson H, et al. Brain penetration of the novel free radical trapping neuroprotectant NXY-059 in rats subjected to permanent focal ischemia. Brain Res. 2006;1072(1):224–6.

    Article  CAS  PubMed  Google Scholar 

  129. Lapchak PA, Song D, Wei J, Zivin JA. Coadministration of NXY-059 and tenecteplase six hours following embolic strokes in rabbits improves clinical rating scores. Exp Neurol. 2004;188(2):279–85.

    Article  CAS  PubMed  Google Scholar 

  130. Lees KR, Zivin JA, Ashwood T, Davalos A, Davis SM, Diener HC, et al. NXY-059 for acute ischemic stroke. N Engl J Med. 2006;354(6):588–600.

    Article  CAS  PubMed  Google Scholar 

  131. Shuaib A, Lees KR, Lyden P, Grotta J, Davalos A, Davis SM, et al. NXY-059 for the treatment of acute ischemic stroke. N Engl J Med. 2007;357(6):562–71.

    Article  CAS  PubMed  Google Scholar 

  132. Bath PM, Gray LJ, Bath AJ, Buchan A, Miyata T, Green AR. Effects of NXY-059 in experimental stroke: an individual animal meta-analysis. Br J Pharmacol. 2009;157(7):1157–71.

    Article  CAS  PubMed  Google Scholar 

  133. Watanabe T, Tahara M, Todo S. The novel antioxidant edaravone: from bench to bedside. Cardiovasc Ther. 2008;26(2):101–14.

    Article  CAS  PubMed  Google Scholar 

  134. Yoshida H, Yanai H, Namiki Y, Fukatsu-Sasaki K, Furutani N, Tada N. Neuroprotective effects of edaravone: a novel free radical scavenger in cerebrovascular injury. CNS Drug Rev. 2006;12(1):9–20.

    Article  CAS  PubMed  Google Scholar 

  135. Lapchak PA. Taking a light approach to treating acute ischemic stroke patients: transcranial near-infrared laser therapy translational science. Ann Med. 2010;42(8):576–86.

    Article  PubMed  Google Scholar 

  136. Detaboada L, Ilic S, Leichliter-Martha S, Oron U, Oron A, Streeter J. Transcranial application of low-energy laser irradiation improves neurological deficits in rats following acute stroke. Lasers Surg Med. 2006;38(1):70–3.

    Article  PubMed  Google Scholar 

  137. Ilic S, Leichliter S, Streeter J, Oron A, DeTaboada L, Oron U. Effects of power densities, continuous and pulse frequencies, and number of sessions of low-level laser therapy on intact rat brain. Photomed Laser Surg. 2006;24(4):458–66.

    Article  PubMed  Google Scholar 

  138. Oron A, Oron U, Chen J, Eilam A, Zhang C, Sadeh M, et al. Low-level laser therapy applied transcranially to rats after induction of stroke significantly reduces long-term neurological deficits. Stroke. 2006;37(10):2620–4.

    Article  PubMed  Google Scholar 

  139. Lampl Y, Zivin JA, Fisher M, Lew R, Welin L, Dahlof B, Andersson B, Perez J, Caparo C, Ilic S, Oron U. Infrared laser therapy for ischemic stroke—a new treatment strategy: results of the neuorthera effectiveness and safety Trial-1 (NEST-1). Stroke. 2007;38(6):1843–9.

    Article  PubMed  Google Scholar 

  140. Zivin JA, Albers GW, Bornstein N, Chippendale T, Dahlof B, Devlin T, et al. Effectiveness and safety of transcranial laser therapy for acute ischemic stroke. Stroke. 2009;40(4):1359–64.

    Article  PubMed  Google Scholar 

  141. NEST-3. http://clinicaltrials.gov/ct2/show/NCT01120301; 2012. Accessed Jan 11, 2012.

  142. Aronowski J, Strong R, Shirzadi A, Grotta JC. Ethanol plus caffeine (caffeinol) for treatment of ischemic stroke: preclinical experience. Stroke. 2003;34(5):1246–51.

    Article  CAS  PubMed  Google Scholar 

  143. Belayev L, Khoutorova L, Zhang Y, Belayev A, Zhao W, Busto R, et al. Caffeinol confers cortical but not subcortical neuroprotection after transient focal cerebral ischemia in rats. Brain Res. 2004;1008(2):278–83.

    Article  CAS  PubMed  Google Scholar 

  144. Lapchak PA, Song D, Wei J, Zivin JA. Pharmacology of caffeinol in embolized rabbits: clinical rating scores and intracerebral hemorrhage incidence. Exp Neurol. 2004;188(2):286–91.

    Article  CAS  PubMed  Google Scholar 

  145. Gainer JL. Trans-sodium crocetinate for treating hypoxia/ischemia. Expert Opin Investig Drugs. 2008;17(6):917–24.

    Article  CAS  PubMed  Google Scholar 

  146. Okonkwo DO, Wagner J, Melon DE, Alden T, Stone JR, Helm GA, et al. Trans-sodium crocetinate increases oxygen delivery to brain parenchyma in rats on oxygen supplementation. Neurosci Lett. 2003;352(2):97–100.

    Article  CAS  PubMed  Google Scholar 

  147. Giaccio M. Crocetin from saffron: an active component of an ancient spice. Crit Rev Food Sci Nutr. 2004;44(3):155–72.

    Article  CAS  PubMed  Google Scholar 

  148. Stennett AK, Gainer JL. TSC for hemorrhagic shock: effects on cytokines and blood pressure. Shock. 2004;22(6):569–74.

    Article  CAS  PubMed  Google Scholar 

  149. Lapchak PA. Efficacy and safety profile of the carotenoid trans sodium crocetinate administered to rabbits following multiple infarct ischemic strokes: a combination therapy study with tissue plasminogen activator. Brain Res. 2010;1309:136–45.

    Article  CAS  PubMed  Google Scholar 

  150. Mellon SH, Griffin LD. Neurosteroids: biochemistry and clinical significance. Trends Endocrinol Metab. 2002;13(1):35.

    Article  CAS  PubMed  Google Scholar 

  151. Lapchak PA, Araujo DM. Preclinical development of neurosteroids as neuroprotective agents for the treatment of neurodegenerative diseases. Int Rev Neurobiol. 2001;46:379–97.

    Article  CAS  PubMed  Google Scholar 

  152. Jiang N, Chopp M, Stein D, Feit H. Progesterone is neuroprotective after transient middle cerebral artery occlusion in male rats. Brain Res. 1996;735(1):101–7.

    Article  CAS  PubMed  Google Scholar 

  153. Chen J, Chopp M, Li Y. Neuroprotective effects of progesterone after transient middle cerebral artery occlusion in rat. J Neurol Sci. 1999;171(1):24–30.

    Article  CAS  PubMed  Google Scholar 

  154. Lapchak PA. The neuroactive steroid 3-alpha-ol-5-beta-pregnan-20-one hemisuccinate, a selective NMDA receptor antagonist improves behavioral performance following spinal cord ischemia. Brain Res. 2004;997:152–8.

    Article  CAS  PubMed  Google Scholar 

  155. Weaver Jr CE, Marek P, Park-Chung M, Tam SW, Farb DH. Neuroprotective activity of a new class of steroidal inhibitors of the N-methyl-D-aspartate receptor. Proc Natl Acad Sci U S A. 1997;94(19):10450–4.

    Article  CAS  PubMed  Google Scholar 

  156. Malayev A, Gibbs TT, Farb DH. Inhibition of the NMDA response by pregnenolone sulphate reveals subtype selective modulation of NMDA receptors by sulphated steroids. Br J Pharmacol. 2002;135(4):901.

    Article  CAS  PubMed  Google Scholar 

  157. Lapchak PA. 3alpha-OL-5-beta-pregnan-20-one hemisuccinate, a steroidal low-affinity NMDA receptor antagonist improves clinical rating scores in a rabbit multiple infarct ischemia model: synergism with tissue plasminogen activator. Exp Neurol. 2006;197(2):531–7.

    Article  CAS  PubMed  Google Scholar 

  158. Chen HS, Lipton SA. Pharmacological implications of two distinct mechanisms of interaction of memantine with N-methyl-D-aspartate-gated channels. J Pharmacol Exp Ther. 2005;314(3):961–71.

    Article  CAS  PubMed  Google Scholar 

  159. Lipton SA. Pathologically-activated therapeutics for neuroprotection: mechanism of NMDA receptor block by memantine and S-nitrosylation. Curr Drug Targets. 2007;8(5):621–32.

    Article  CAS  PubMed  Google Scholar 

  160. Lipton SA, Chen HS. Paradigm shift in neuroprotective drug development: clinically tolerated NMDA receptor inhibition by memantine. Cell Death Differ. 2004;11(1):18–20.

    Article  CAS  PubMed  Google Scholar 

  161. Xia P, Chen HS, Zhang D, Lipton SA. Memantine preferentially blocks extrasynaptic over synaptic NMDA receptor currents in hippocampal autapses. J Neurosci. 2010;30(33):11246–50.

    Article  CAS  PubMed  Google Scholar 

  162. Lipton SA. Failures and successes of NMDA receptor antagonists: molecular basis for the use of open-channel blockers like memantine in the treatment of acute and chronic neurologic insults. NeuroRx. 2004;1(1):101–10.

    Article  PubMed  Google Scholar 

  163. Chen HS, Pellegrini JW, Aggarwal SK, Lei SZ, Warach S, Jensen FE, et al. Open-channel block of N-methyl-D-aspartate (NMDA) responses by memantine: therapeutic advantage against NMDA receptor-mediated neurotoxicity. J Neurosci. 1992;12(11):4427–36.

    CAS  PubMed  Google Scholar 

  164. Lapchak PA. Memantine, an uncompetitive low affinity NMDA open-channel antagonist improves clinical rating scores in a multiple infarct embolic stroke model in rabbits. Brain Res. 2006;1088(1):141–7.

    Article  CAS  PubMed  Google Scholar 

  165. Poulton KR, Rossi ML. Peripheral nerve protein glycation and muscle fructolysis: evidence of abnormal carbohydrate metabolism in ALS. Funct Neurol. 1993;8(1):33–42.

    CAS  PubMed  Google Scholar 

  166. Winegrad AI, Morrison AD, Clements Jr RS. Polyol pathway activity in aorta. Adv Metab Disord. 1973;2 Suppl 2:117–27.

    CAS  PubMed  Google Scholar 

  167. Kaneko M, Bucciarelli L, Hwang YC, Lee L, Yan SF, Schmidt AM, et al. Aldose reductase and AGE-RAGE pathways: key players in myocardial ischemic injury. Ann N Y Acad Sci. 2005;1043:702–9.

    Article  CAS  PubMed  Google Scholar 

  168. Hwang YC, Shaw S, Kaneko M, Redd H, Marrero MB, Ramasamy R. Aldose reductase pathway mediates JAK-STAT signaling: a novel axis in myocardial ischemic injury. FASEB J. 2005;19(7):795–7.

    CAS  PubMed  Google Scholar 

  169. Iwata K, Matsuno K, Nishinaka T, Persson C, Yabe-Nishimura C. Aldose reductase inhibitors improve myocardial reperfusion injury in mice by a dual mechanism. J Pharmacol Sci. 2006;102(1):37–46.

    Article  CAS  PubMed  Google Scholar 

  170. Ramasamy R. Aldose reductase: a novel target for cardioprotective interventions. Curr Drug Targets. 2003;4(8):625–32.

    Article  CAS  PubMed  Google Scholar 

  171. Dan Q, Wong R, Chung SK, Chung SS, Lam KS. Interaction between the polyol pathway and non-enzymatic glycation on aortic smooth muscle cell migration and monocyte adhesion. Life Sci. 2004;76(4):445–59.

    Article  CAS  PubMed  Google Scholar 

  172. Wirasathien L, Pengsuparp T, Suttisri R, Ueda H, Moriyasu M, Kawanishi K. Inhibitors of aldose reductase and advanced glycation end-products formation from the leaves of Stelechocarpus cauliflorus R.E. Fr. Phytomedicine. 2006;14(7–8):546–50.

    PubMed  Google Scholar 

  173. Leist M, Ghezzi P, Grasso G, Bianchi R, Villa P, Fratelli M, et al. Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science. 2004;305(5681):239–42.

    Article  CAS  PubMed  Google Scholar 

  174. Lapchak PA. Erythropoietin molecules to treat acute ischemic stroke: a translational dilemma! Expert opinion investigational. Drugs. 2010;19(10):1179–86.

    CAS  Google Scholar 

  175. Lapchak PA. Carbamylated erythropoietin to treat neuronal injury: new development strategies. Expert Opin Investig Drugs. 2008;17(8):1175–86.

    Article  CAS  PubMed  Google Scholar 

  176. Lapchak PA. The many faces of erythropoietin: from erythropoiesis to a rational neuroprotective strategy—correspondence. Expert Opin Investig Drugs. 2008;17(10):1615–6.

    Article  CAS  PubMed  Google Scholar 

  177. Lapchak PA, Kirkeby A, Zivin JA, Sager TN. Therapeutic window for nonerythropoietic carbamylated-erythropoietin to improve motor function following multiple infarct ischemic strokes in New Zealand white rabbits. Brain Res. 2008;1238:208–14.

    Article  CAS  PubMed  Google Scholar 

  178. Ehrenreich H, Weissenborn K, Prange H, Schneider D, Weimar C, Wartenberg K, et al. Recombinant human erythropoietin in the treatment of acute ischemic stroke. Stroke. 2009;40(12):e647–56.

    Article  CAS  PubMed  Google Scholar 

  179. Liu Y, Dargusch R, Maher P, Schubert D. A broadly neuroprotective derivative of curcumin. J Neurochem. 2008;105(4):1336–45.

    Article  CAS  PubMed  Google Scholar 

  180. Wu A, Ying Z, Schubert D, Gomez-Pinilla F. Brain and spinal cord interaction: a dietary curcumin derivative counteracts locomotor and cognitive deficits after brain trauma. Neurorehabil Neural Repair. 2011;25(4):332–42.

    Article  PubMed  Google Scholar 

  181. Delanty N, Vaughan CJ. Vascular effects of statins in stroke. Stroke. 1997;28(11):2315–20.

    Article  CAS  PubMed  Google Scholar 

  182. Hebert PR, Gaziano JM, Chan KS, Hennekens CH. Cholesterol lowering with statin drugs, risk of stroke, and total mortality. An overview of randomized trials. JAMA. 1997;278(4):313–21.

    Article  CAS  PubMed  Google Scholar 

  183. Kashyap ML. Cholesterol and atherosclerosis: a contemporary perspective. Ann Acad Med Singapore. 1997;26(4):517–23.

    CAS  PubMed  Google Scholar 

  184. Laufs U, Gertz K, Dirnagl U, Bohm M, Nickenig G, Endres M. Rosuvastatin, a new HMG-CoA reductase inhibitor, upregulates endothelial nitric oxide synthase and protects from ischemic stroke in mice. Brain Res. 2002;942(1–2):23–30.

    Article  CAS  PubMed  Google Scholar 

  185. Seyfried D, Han Y, Lu D, Chen J, Bydon A, Chopp M. Improvement in neurological outcome after administration of atorvastatin following experimental intracerebral hemorrhage in rats. J Neurosurg. 2004;101(1):104–7.

    Article  CAS  PubMed  Google Scholar 

  186. Prinz V, Laufs U, Gertz K, Kronenberg G, Balkaya M, Leithner C, et al. Intravenous rosuvastatin for acute stroke treatment: an animal study. Stroke. 2008;39(2):433–8.

    Article  CAS  PubMed  Google Scholar 

  187. Shimamura M, Sato N, Sata M, Kurinami H, Takeuchi D, Wakayama K, et al. Delayed postischemic treatment with fluvastatin improved cognitive impairment after stroke in rats. Stroke. 2007;38(12):3251–8.

    Article  CAS  PubMed  Google Scholar 

  188. Wang S, Lee SR, Guo SZ, Kim WJ, Montaner J, Wang X, et al. Reduction of tissue plasminogen activator-induced matrix metalloproteinase-9 by simvastatin in astrocytes. Stroke. 2006;37(7):1910–2.

    Article  CAS  PubMed  Google Scholar 

  189. Ma T, Zhao Y, Kwak YD, Yang Z, Thompson R, Luo Z, et al. Statin’s excitoprotection is mediated by sAPP and the subsequent attenuation of calpain-induced truncation events, likely via rho-ROCK signaling. J Neurosci. 2009;29(36):11226–36.

    Article  CAS  PubMed  Google Scholar 

  190. Sugawara T, Jadhav V, Ayer R, Zhang J. Simvastatin attenuates cerebral vasospasm and improves outcomes by upregulation of PI3K/Akt pathway in a rat model of subarachnoid hemorrhage. Acta Neurochir Suppl. 2008;102:391–4.

    Article  PubMed  Google Scholar 

  191. Wu L, Zhao L, Zheng Q, Shang F, Wang X, Wang L, et al. Simvastatin attenuates hypertrophic responses induced by cardiotrophin-1 via JAK-STAT pathway in cultured cardiomyocytes. Mol Cell Biochem. 2006;284(1–2):65–71.

    Article  CAS  PubMed  Google Scholar 

  192. Lapchak PA, Han MK. Simvastatin improves clinical scores in a rabbit multiple infarct ischemic stroke model: synergism with a rock inhibitor, but not the thrombolytic tissue plasminogen activator. Brain Res. 2010;18(1344):217–25.

    Article  CAS  Google Scholar 

  193. MICROPLASMIN. http://www.strokecenter.org/trials/TrialDetail.aspx?tid=523; 2008. Accessed Jan 11, 2012.

  194. Haley Jr EC, Thompson JL, Grotta JC, Lyden PD, Hemmen TG, Brown DL, et al. Phase IIB/III trial of tenecteplase in acute ischemic stroke: results of a prematurely terminated randomized clinical trial. Stroke. 2010;41(4):707–11.

    Article  CAS  PubMed  Google Scholar 

  195. Davydov L, Cheng JW. Tenecteplase: a review. Clin Ther. 2001;23(7):982–97. discussion 1.

    Article  CAS  PubMed  Google Scholar 

  196. Melandri G, Vagnarelli F, Calabrese D, Semprini F, Nanni S, Branzi A. Review of tenecteplase (TNKase) in the treatment of acute myocardial infarction. Vasc Health Risk Manag. 2009;5(1):249–56.

    Article  CAS  PubMed  Google Scholar 

  197. Hefer DV, Munir A, Khouli H. Low-dose tenecteplase during cardiopulmonary resuscitation due to massive pulmonary embolism: a case report and review of previously reported cases. Blood Coagul Fibrinolysis. 2007;18(7):691–4.

    Article  PubMed  Google Scholar 

  198. Dunn CJ, Goa KL. Tenecteplase: a review of its pharmacology and therapeutic efficacy in patients with acute myocardial infarction. Am J Cardiovasc Drugs. 2001;1(1):51–66.

    Article  CAS  PubMed  Google Scholar 

  199. Chapman DF, Lyden P, Lapchak PA, Nunez S, Thibodeaux H, Zivin J. Comparison of TNK with wild-type tissue plasminogen activator in a rabbit embolic stroke model. Stroke. 2001;32(3):748–52.

    Article  CAS  PubMed  Google Scholar 

  200. Nagai N, Demarsin E, Van Hoef B, Wouters S, Cingolani D, Laroche Y, et al. Recombinant human microplasmin: production and potential therapeutic properties. J Thromb Haemost. 2003;1(2):307–13.

    Article  CAS  PubMed  Google Scholar 

  201. Wu HL, Shi GY, Wohl RC, Bender ML. Structure and formation of microplasmin. Proc Natl Acad Sci U S A. 1987;84(24):8793–5.

    Article  CAS  PubMed  Google Scholar 

  202. Wu HL, Shi GY, Bender ML. Preparation and purification of microplasmin. Proc Natl Acad Sci U S A. 1987;84(23):8292–5.

    Article  CAS  PubMed  Google Scholar 

  203. Collen D. Revival of plasmin as a therapeutic agent? Thromb Haemost. 2001;86(3):731–2.

    CAS  PubMed  Google Scholar 

  204. Lapchak PA, Araujo DM, Pakola S, Song D, Wei J, Zivin JA. Microplasmin: a novel thrombolytic that improves behavioral outcome after embolic strokes in rabbits. Stroke. 2002;33(9):2279–84.

    Article  CAS  PubMed  Google Scholar 

  205. Lapchak PA, Chapman DF, Zivin JA. Metalloproteinase inhibition reduces thrombolytic ­(tissue plasminogen activator)-induced hemorrhage after thromboembolic stroke. Stroke. 2000;31(12):3034–40.

    Article  CAS  PubMed  Google Scholar 

  206. EAISG. Effect of a novel free radical scavenger, edaravone (MCI-186), on acute brain infarction. Randomized, placebo-controlled, double-blind study at multicenters. Cerebrovasc Dis. 2003;15(3):222–9.

    Article  CAS  Google Scholar 

  207. Inatomi Y, Takita T, Yonehara T, Fujioka S, Hashimoto Y, Hirano T, et al. Efficacy of edaravone in cardioembolic stroke. Intern Med. 2006;45(5):253–7.

    Article  PubMed  Google Scholar 

  208. Kitagawa Y. Edaravone in acute ischemic stroke. Intern Med. 2006;45(5):225–6.

    Article  PubMed  Google Scholar 

  209. Sinha M, Anuradha H, Juyal R, Shukla R, Garg R, Kar A. Edaravone in acute ischemic stroke, an Indian experience. Neurology Asia. 2009;14:7–10.

    Google Scholar 

  210. Lapchak PA, Maher P, Schubert D, Zivin JA. Baicalein, an antioxidant 12/15 lipoxygenase inhibitor improves clinical rating scores following multiple infarct embolic strokes. Neuroscience. 2007;150(3):585–91.

    Article  CAS  PubMed  Google Scholar 

  211. Caffeinol. http://www.strokecenter.org/trials/InterventionDetail.aspx?tid=249; 2008. Accessed Jan 11, 2012.

  212. Ebselen. http://www.strokecenter.org/trials/TrialDetail.aspx?tid=298; 2011. Accessed Jan 11, 2012.

Download references

Acknowledgments

This article was supported by an NINDS Translational Research grant U01 NS60685 and NIH American Recovery and Reinvestment Act R01 grant NS060864.

Author information

Authors and Affiliations

  1. Department of Neurology, Cedars-Sinai Medical Center, Davis Research Building, D-2091, 110 N. George Burns Road, Los Angeles, CA, 90048, USA

    Paul A. Lapchak PhD, FAHA

Authors
  1. Paul A. Lapchak PhD, FAHA
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paul A. Lapchak PhD, FAHA .

Editor information

Editors and Affiliations

  1. , Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, 90048, California, USA

    Paul A. Lapchak

  2. Loma Linda University, 11234 Anderson Street, Room 2562B, Loma Linda, 92354, California, USA

    John H. Zhang

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Lapchak, P.A. (2012). A Clinically Relevant Rabbit Embolic Stroke Model for Acute Ischemic Stroke Therapy Development: Mechanisms and Targets. In: Lapchak, P., Zhang, J. (eds) Translational Stroke Research. Springer Series in Translational Stroke Research. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-9530-8_27

Download citation

Publish with us

Policies and ethics

Search

Navigation