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The March of Thrombolytic Therapy for Acute Ischemic Stroke to Clinical Trials: Pre-clinical Thrombolysis and Adjuncts to Thrombolysis Research

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Thrombolytic Therapy for Acute Stroke

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Abstract

Data from experimental and clinical cerebral ischemia studies demonstrate that acute stroke must be treated within a few hours or less to effectively reduce stroke morbidity and mortality. Time from symptom onset (presumed time of acute cerebral arterial occlusion) to treatment initiation is considered the single most important factor in the effective treatment of acute focal cerebral ischemia/infarction. Recently the time window for use of tissue plasminogin activator (rt-PA), the only approved thrombolytic pharmacotherapy for acute stroke intervention, has been extended from 3 to 4.5 h. Hemorrhagic conversion can occur and limits it use beyond this time and the efficacy drops off considerably as well.

If thrombolytic therapy is administered immediately after experimental embolic occlusion, significant reduction in neurologic damage occurs. Although microscopic intracranial hemorrhagic transformation is increased in thrombolytic-treated experimental animals, macroscopic transformation occurs more frequently with higher doses of rt-PA and with more delayed treatment times. Thus hemorrhagic transformation significantly reduces the use of thrombolysis in stroke. Newer thrombolytic agents, such as tenecteplase (TNK) and desmoteplase offered the promise of greater fibrin-selectivity, improved pharmacokinetic profiles, and safer thrombolysis that has not yet been demonstrated in definitive phase 3 randomized clinical trials. New directions in basic research are exploring adjunt with to thrombolysis therapy (i.e., “rt-PA plus” intervention) as an approach to improve the use of rt-PA and provide intervention in more patients. The objective of this “adjunct to thrombolysis” preclinical research is to improve brain protection and post-stroke outcome, to demonstrate the potential to extend the use of rt-PA to later times post-strok, to provide the data to support appropriate clinical studies that demonstrate improved intervention and to ultimately provide efficacious and safe interventions to more stroke patients.

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Abbreviations

rt-PA:

Recombinant tissue plasminogen activator

SK:

Streptokinase

UK:

Urokinase

Pro-UK:

Pro-urokinase

TNK:

Tenecteplase

MCA:

Middle cerebral artery

IU:

International units

ICH:

Intracerebral hemorrhage

PET:

Positron emission tomography

IV:

Intravenous

IA:

Intra-arterial

d::

Days

kg::

Kilograms

h:

Hours

min:

Minutes

PAI-1:

Tissue plasminogen activator inhibitor-1

U:

Units

DNA:

Deoxyribonucleic acid

DSPA:

Desmodus salivary plasminogen activator

kDa:

Kilodaltons

CBF:

Cerebral blood flow

References

  1. Meyer JS, Gilroy J, Barnhart ME, et al. Therapeutic thrombolysis in cerebral thromboembolism. In: Siekert W, Whisnant JP, editors. Cerebral vascular diseases. Grune & Stratton: Philadelphia; 1963. p. 160–75.

    Google Scholar 

  2. Del Zoppo GJ, Copeland BR, Waltz TA, et al. The beneficial effect of intracarotid urokinase on acute stroke in a baboon model. Stroke. 1986;17:638–43.

    PubMed  Google Scholar 

  3. DeLey G, Weyne I, Demeester G, et al. Streptokinase treatment versus calcium overload blockade in experimental thromboembolic stroke. Stroke. 1989;20:357–61.

    CAS  Google Scholar 

  4. Zivin JA, Fisher M, DeGirolami U, et al. Tissue plasminogen activator reduces neurological damage after cerebral embolism. Science. 1985;230:1289–92.

    CAS  PubMed  Google Scholar 

  5. del Zoppo GJ, Copeland BR, Anderchek K, Hacke W, Koziol JA. Hemorrhagic transformation following tissue plasminogen activator in experimental cerebral infarction. Stroke. 1990;21(4):596–601.

    PubMed  Google Scholar 

  6. Zivin JA, Lyden PD, DeGirolami U, et al. Tissue plasminogen activator. Reduction of neurologic damage after experimental embolic stroke. Arch Neurol. 1988;45:387–91.

    CAS  PubMed  Google Scholar 

  7. Lapchak PA. Translational stroke research using a rabbit embolic stroke model: A Correlative analysis hypothesis for novel therapy development. Transl Stroke Res. 2010;2:96–107.

    Google Scholar 

  8. Zivin JA. Acute stroke therapy with tissue plasminogen activator (tPA) since it was approved by the U.S. Food and Drug Administration (FDA). Ann Neurol. 2009;66(1):6–10.

    PubMed  Google Scholar 

  9. NINDS rt-PA Stroke Study Group. 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;333:1581–7.

    Google Scholar 

  10. Hacke W, Kaste M, Bluhmki E, Brozman M, Dávalos A, Guidetti D, Larrrue V, Lees KR, Medeghri Z, Machnig T, Schneider D, von Kummer R, Wahlgren N, Toni D, ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359:1317–29.

    CAS  PubMed  Google Scholar 

  11. Hacke W, Donnan G, Fieschi C, Kaste M, von Kummer R, Broderick JP, Brott T, Frankel M, Grotta JC, Haley Jr EC, Kwiatkowski T, Levine SR, Lewandowski C, Lu M, Lyden P, Marler JR, Patel S, Tilley BC, Albers G, Bluhmki E, Wilhelm M, Hamilton S, ATLANTIS Trials Investigators, ECASS Trials Investigators, NINDS rt-PA Study Group Investigators. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet. 2004;363:768–74.

    PubMed  Google Scholar 

  12. Slivka A, Pulsinelli W. Hemorrhagic complications of thrombolytic therapy in experimental stroke. Stroke. 1987;18:1148–56.

    CAS  PubMed  Google Scholar 

  13. Lyden PD, Zivin JA, Clark WA, et al. Tissue plasminogen activator-mediated thrombolysis of cerebral emboli and its effect on hemorrhagic infarction in rabbits. Neurology. 1989;39:703–8.

    CAS  PubMed  Google Scholar 

  14. Vaughn DF, DeClerck PJ, Mol D, et al. Recombinant plasminogen activator inhibitor-1 reverses the bleeding tendency associated with the combined administration of tissue-type plasminogen activator and aspirin in rabbits. J Clin Invest. 1989;84:586–91.

    Google Scholar 

  15. Lyden PD, Madden KP, Clark WM, et al. Incidence of cerebral hemorrhage after antifibrinolytic treatment for embolic stroke. Stroke. 1990;21:1589–93.

    CAS  PubMed  Google Scholar 

  16. Benes V, Zabranski JM, Boston M, et al. Effect of intraarterial antifibrinolytic agents on autologous arterial emboli in the cerebral circulation of rabbits. Stroke. 1990;21:1594–9.

    CAS  PubMed  Google Scholar 

  17. Phillips DA, Fisher M, Smith TW, et al. The safety and angiographic efficacy of tissue plasminogen activator in a cerebral embolization model. Ann Neurol. 1988;23:391–4.

    CAS  PubMed  Google Scholar 

  18. Phillips DA, Davis MA, Fisher M. Selective embolization and clot dissolution with tPA in the internal carotid artery circulation of the rabbit. Am J Neuradiol. 1988;9:899–902.

    CAS  Google Scholar 

  19. Kissel P, Chchrazi B, Seibert JA, et al. Digital angiographic quantification of blood flow dynamics in embolic stroke treated with tissue-type plasminogen activator. J Neurosurg. 1987;67:399–405.

    CAS  PubMed  Google Scholar 

  20. Papadopulous SM, Chandler WF, Salamat MS, et al. Recombinant human tissue-type plasminogen activator therapy in acute thromboembolic stroke. J Neurosurg. 1987;67:394–8.

    Google Scholar 

  21. Chehrazi BB, Seibert JA, Hein L, Brock J, Kissel P. Differential effect of recombinant tissue plasminogen activator-induced thrombolysis in the central nervous system and systemic arteries. Neurosurgery. 1991;28(3):364–9.

    CAS  PubMed  Google Scholar 

  22. Wardlaw JM, Koumellis P, Liu M. Thrombolysis (different doses, routes of administration and agents) for acute ischaemic stroke. Cochrane Database Syst Rev. 2013;5, CD000514.

    PubMed  Google Scholar 

  23. Fears R. Biochemical pharmacology and therapeutic aspects of thrombolytic agents. Pharmacol Rev. 1990;42:202–22.

    Google Scholar 

  24. Phillips DA, Fisher M, Smith TW, et al. The effects of a new tissue plasminogen activator analogue Fb-Fb-CF, on cerebral reperfusion in a rabbit embolic stroke model. Ann Neurol. 1989;25:281–5.

    CAS  PubMed  Google Scholar 

  25. Phillips DA, Fisher M, Davis MA, et al. Delayed treatment with a tPA analogue and streptokinase in a rabbit embolic stroke model. Stroke. 1990;21:602–5.

    CAS  PubMed  Google Scholar 

  26. Fisher M, Phillips DA, Smith TW, et al. Early and delayed thrombolytic therapy in rabbit cerebral embolization model using a tPA analogue. In: Ginsberg MD, Dietrich WD, editors. Cerebrovascular disease. New York, NY: Raven; 1989. p. 29–32.

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  29. Haley Jr EC, Thompson JL, Grotta JC, Lyden PD, Hemmen TG, Brown DL, Fanale C, Libman R, Kwiatkowski TG, Llinas RH, Levine SR, Johnston KC, Buchsbaum R, Levy G, Levin B, Tenecteplase in Stroke Investigators. Phase IIB/III trial of tenecteplase in acute ischemic stroke: results of a prematurely terminated randomized clinical trial. Stroke. 2010;41:707–11.

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Binbrek A, Rao N, Absher PM, Vande Werf F, Sobel B. The relative rapidity of recanalization induced by recombinant tissue-type plasminogen activator (r-tPA) and TNK-tPA, assessed with enzymatic methods. Coron Artery Dis. 2000;11:429–35.

    CAS  PubMed  Google Scholar 

  31. 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;185:154–9.

    CAS  PubMed  Google Scholar 

  32. Zhang RL, Zhang L, Jiang A, Zhang ZG, Goussev A, Chopp M. Postischemic intracarotid treatment with TNK-tPA reduces infarct volume and improves neurological deficits in embolic stroke in the unanesthetized rat. Brain Res. 2000;878:64–71.

    CAS  PubMed  Google Scholar 

  33. Verstraete M, Lijnen H, Collen D. Thrombolytic agents in development. Drugs. 1995;50:29–39.

    CAS  PubMed  Google Scholar 

  34. Bringmann P, Gruber D, Liese A, Toschi L, Krätzschmar J, Schleuning W-D, Donner P. Structural features mediating fibrin selectivity of vampire bat plasminogen activators. J Biol Chem. 1995;270:25596–603.

    CAS  PubMed  Google Scholar 

  35. Toschi L, Bringmann P, Petri T, Donner P, Schleuning W-D. Fibrin selectivity of the isolated protease domains of tissue-type and vampire bat salivary gland plasminogen activators. Eur J Biochem. 1998;252(1):108–12.

    CAS  PubMed  Google Scholar 

  36. Liberatore GT, Samson A, Bladin C, Schleuning W-D, Medcalf R. Vampire bat salivary plasminogen activator (Desmoteplase): a unique fibrinolytic enzyme that does not promote neurodegeneration. Stroke. 2003;34:537–43.

    CAS  PubMed  Google Scholar 

  37. Mellott MJ, Ramjit DR, Stabilito II, Hare TR, Senderak ET, Lynch JJ, Gardell SJ. Vampire bat salivary plasminogen activator evokes minimal bleeding relative to tissue-type plasminogen activator as assessed by a rabbit cuticle bleeding time model. Thromb Haemost. 1994;73:478483.

    Google Scholar 

  38. Witt W, Mass B, Baldas B, Hildebrand M, Donner P, Schleuning W-D. Coronary thrombolysis with Desmodus salivary plasminogen activator in dogs. Circulation. 1995;9:91–6.

    Google Scholar 

  39. Alexander LF, Yamamoto Y, Ayoubi S, et al. Efficacy of tissue plasminogen activator in the lysis of thrombosis of the cerebral venous sinus. Neurosurgery. 1990;26:559–64.

    CAS  PubMed  Google Scholar 

  40. García-Yébenes I, Sobrado M, Zarruk JG, Castellanos M, Pérez de la Ossa N, Dávalos A, Serena J, Lizasoain I, Moro MA. A mouse model of hemorrhagic transformation by delayed tissue plasminogen activator administration after in situ thromboembolic stroke. Stroke. 2011;42(1):196–203.

    PubMed  Google Scholar 

  41. Orset C, Macrez R, Young AR, Panthou D, Angles-Cano E, Maubert E, Agin V, Vivien D. Mouse model of in situ thromboembolic stroke and reperfusion. Stroke. 2007;38(10):2771–8.

    PubMed  Google Scholar 

  42. Yepes M, Roussel BD, Ali C, Vivien D. Tissue-type plasminogen activator in the ischemic brain: more than a thrombolytic. Trends Neurosci. 2009;32(1):48–55.

    CAS  PubMed  Google Scholar 

  43. Zhao BQ, Ikeda Y, Ihara H, Urano T, Fan W, Mikawa S, Suzuki Y, Kondo K, Sato K, Nagai N, Umemura K. Essential role of endogenous tissue plasminogen activator through matrix metalloproteinase 9 induction and expression on heparin-produced cerebral hemorrhage after cerebral ischemia in mice. Blood. 2004;103(7):2610–6.

    CAS  PubMed  Google Scholar 

  44. Barone FC, Feuerstein GZ. Inflammatory mediators and stroke: new opportunities for novel therapeutics. J Cereb Blood Flow Metab. 1999;19(8):819–34.

    CAS  PubMed  Google Scholar 

  45. Lambertsen KL, Biber K, Finsen B. Inflammatory cytokines in experimental and human stroke. J Cereb Blood Flow Metab. 2012;32(9):1677–98.

    CAS  PubMed Central  PubMed  Google Scholar 

  46. Romanic AM, White RF, Arleth AJ, Ohlstein EH, Barone FC. Matrix metalloproteinase expression increases after cerebral focal ischemia in rats: inhibition of matrix metalloproteinase-9 reduces infarct size. Stroke. 1998;29(5):1020–30.

    CAS  PubMed  Google Scholar 

  47. Sumii T, Lo EH. Involvement of matrix metalloproteinase in thrombolysis-associated hemorrhagic transformation after embolic focal ischemia in rats. Stroke. 2002;33(3):831–6.

    CAS  PubMed  Google Scholar 

  48. Tsuji K, Aoki T, Tejima E, Arai K, Lee SR, Atochin DN, Huang PL, Wang X, Montaner J, Lo EH. Tissue plasminogen activator promotes matrix metalloproteinase-9 upregulation after focal cerebral ischemia. Stroke. 2005;36(9):1954–9.

    CAS  PubMed  Google Scholar 

  49. Adibhatla RM, Hatcher JF. Tissue plasminogen activator (tPA) and matrix metalloproteinases in the pathogenesis of stroke: therapeutic strategies. CNS Neurol Disord Drug Targets. 2008;7(3):243–53.

    CAS  PubMed Central  PubMed  Google Scholar 

  50. Cojocarui IM, Cojocaru M, Sapira V, Socoliuc G, Hertea C, Paveliu S. Changes in plasma matrix metalloproteinase-9 levels in patients with acute ischemic stroke. Rom J Intern Med. 2012;50(2):155–8.

    PubMed  Google Scholar 

  51. Tejima E, Katayama Y, Suzuki Y, Kano T, Lo EH. Hemorrhagic transformation after fibrinolysis with tissue plasminogen activator: evaluation of role of hypertension with rat thromboembolic stroke model. Stroke. 2001;32(6):1336–40.

    CAS  PubMed  Google Scholar 

  52. Ning R, Chopp M, Yan T, Zacharek A, Zhang C, Roberts C, Cui X, Lu M, Chen J. Tissue plasminogen activator treatment of stroke in type-1 diabetes rats. Neuroscience. 2012;222:326–32.

    CAS  PubMed Central  PubMed  Google Scholar 

  53. Fan X, Ning M, Lo EH, Wang X. Early insulin glycemic control combined with tPA thrombolysis reduces acute brain tissue damages in a focal embolic stroke model of diabetic rats. Stroke. 2013;44(1):255–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  54. Fan X, Lo EH, Wang X. Effects of minocycline plus tissue plasminogen activator combination therapy after focal embolic stroke in type 1 diabetic rats. Stroke. 2013;44(3):745–52.

    CAS  PubMed Central  PubMed  Google Scholar 

  55. Morimoto N, Hashimoto H, Kosaka F. Effect of heparin-urokinase on brain damage induced by cerebral ischemia in dogs. Stroke. 1989;20:154 (abstr).

    Google Scholar 

  56. Matsuo T, Koide M, Kario K. Development of argatroban, a direct thrombin inhibitor, and its clinical application. Semin Thromb Hemost. 1997;23(6):517–22.

    CAS  PubMed  Google Scholar 

  57. Chen B, Friedman B, Whitney MA, Winkle JA, Lei IF, Olson ES, Cheng Q, Pereira B, Zhao L, Tsien RY, Lyden PD. Thrombin activity associated with neuronal damage during acute focal ischemia. J Neurosci. 2012;32(22):7622–31.

    CAS  PubMed Central  PubMed  Google Scholar 

  58. Chen B, Cheng Q, Yang K, Lyden PD. Thrombin mediates severe neurovascular injury during ischemia. Stroke. 2010;41(10):2348–52.

    CAS  PubMed  Google Scholar 

  59. Ohyama H, Hosomi N, Takahashi T, Mizushige K, Kohno M. Thrombin inhibition attenuates neurodegeneration and cerebral edema formation following transient forebrain ischemia. Brain Res. 2001;902(2):264–71.

    CAS  PubMed  Google Scholar 

  60. Hosomi N, Naya T, Kohno M, Kobayashi S, Koziol JA, Japan Standard Stroke Registry Study Group. Efficacy of anti-coagulant treatment with argatroban on cardioembolic stroke. J Neurol. 2007;254(5):605–12.

    CAS  PubMed  Google Scholar 

  61. Barreto AD, Alexandrov AV, Lyden P, Lee J, Martin-Schild S, Shen L, Wu TC, Sisson A, Pandurengan R, Chen Z, Rahbar MH, Balucani C, Barlinn K, Sugg RM, Garami Z, Tsivgoulis G, Gonzales NR, Savitz SI, Mikulik R, Demchuk AM, Grotta JC. The argatroban and tissue-type plasminogen activator stroke study: final results of a pilot safety study. Stroke. 2012;43(3):770–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  62. Sugg RM, Pary JK, Uchino K, Baraniuk S, Shaltoni HM, Gonzales NR, Mikulik R, Garami Z, Shaw SG, Matherne DE, Moyé LA, Alexandrov AV, Grotta JC. Argatroban tPA stroke study: study design and results in the first treated cohort. Arch Neurol. 2006;63(8):1057–62.

    PubMed  Google Scholar 

  63. Morris DC, Zhang L, Zhang ZG, Lu M, Berens KL, Brown PM, Chopp M. Extension of the therapeutic window for recombinant tissue plasminogen activator with argatroban in a rat model of embolic stroke. Stroke. 2001;32(11):2635–40.

    CAS  PubMed  Google Scholar 

  64. Fagan SC, Bowes MP, Berri SA, Zivin JA. Combination treatment for acute ischemic stroke: A ray of Hope? J Stroke Cerebrovasc Dis. 1999;8(6):359–67.

    CAS  PubMed  Google Scholar 

  65. Lapchak PA, Araujo DM. Reducing bleeding complications after thrombolytic therapy for stroke: clinical potential of metalloproteinase inhibitors and spin trap agents. CNS Drugs. 2001;15(11):819–29.

    CAS  PubMed  Google Scholar 

  66. Saver JL. Improving reperfusion therapy for acute ischaemic stroke. J Thromb Haemost. 2011;9 Suppl 1:333–43.

    PubMed  Google Scholar 

  67. Amaro S, Chamorro Á. Translational stroke research of the combination of thrombolysis and antioxidant therapy. Stroke. 2011;42(5):1495–9.

    CAS  PubMed  Google Scholar 

  68. Pancioli AM, Adeoye O, Schmit P, Khoury J, Levine SR, Tomsick T, Sucharew H, Brooks C, Crocco T, Guttmann L, Hemmen T, Kasner SE, Kleindorfer D, Knight WA, Martini S, McKinney J, Meurer W, Meyer BC, Schneider A, Scott PA, Starkman S, Warach S, Broderick JP, for The CLEAR-ER Investigators. The combined approach to lysis utilizing eptifibatide and rt-PA in acute ischemic stroke - Enhanced regimen (CLEAR-ER) stroke trial. Stroke. 2013;44:2381–7.

    PubMed Central  PubMed  Google Scholar 

  69. 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;215:95–100.

    CAS  PubMed  Google Scholar 

  70. Jia L, Chopp M, Zhang L, Lu M, Zhang Z. Erythropoietin in combination of tissue plasminogen activator exacerbates brain hemorrhage when treatment is initiated 6 hours after stroke. Stroke. 2010;41(9):2071–6.

    CAS  PubMed Central  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  72. Asadi B, Askari GR, Khorvash F, Bagherpur A, Mehrabi F, Karimi M, Ghasemi M, Najjaran A. Neuroprotective effects of erythropoietin in acute ischemic stroke. Int J Prev Med. 2013;4 Suppl 2:S306–12.

    PubMed Central  PubMed  Google Scholar 

  73. Barsan WG, Brott TG, Olinger CP, et al. Identification and entry of the patient with acute cerebral infarction. Ann Emerg Med. 1988;17:1192–5.

    CAS  PubMed  Google Scholar 

  74. Gaberel T, Magheru C, Emery E. Management of non-traumatic intraventricular hemorrhage. Neurosurg Rev. 2012;35(4):485–94.

    PubMed  Google Scholar 

  75. Weinstein PR, Anderson GG, Telles DA. Neurological deficit and cerebral infarction after temporary middle cerebral artery occlusion in unanesthesized cats. Stroke. 1986;17:318–24.

    CAS  PubMed  Google Scholar 

  76. Boisvert DP, Gelb AW, Tang C, et al. Brain tolerance to middle cerebral artery occlusion during hypotension in primates. Surg Neurol. 1989;31:6–13.

    CAS  PubMed  Google Scholar 

  77. Crowell RM, Olsson Y, Klatzo I, et al. Temporary occlusion of the middle cerebral artery in the monkey: clinical and pathological observations. Stroke. 1970;1:439–48.

    CAS  PubMed  Google Scholar 

  78. Whisnant JP, Millikan CH, Seikert RG. Cerebral infarction and fibrinolytic agents. In: Roberts HR, Gevatz JD, editors. Proceedings of the Conference on Thrombolytic Agents, Chicago; 1970. p. 235–45.

    Google Scholar 

  79. Centeno RS, Hackney PB, Jr R. Streptokinase clot lysis in acute occlusions of the cranial circulation: study in rabbits. Am J Neuroradiol. 1985;6:589–94.

    CAS  PubMed  Google Scholar 

  80. Hirschberg M, Hofferberth B. Rapid fibrinolysis at different time intervals in a canine model of acute stroke. Stroke. 1987;18:292 (abstr).

    Google Scholar 

  81. Hirschberg M, Korves M, Koc I, et al. Thrombolysis of cerebral thromboembolism by urokinase in an animal model. Schweiz Med Wochenschr. 1987;117:1811–3.

    CAS  PubMed  Google Scholar 

  82. DeLey G, Weyne J, Demeester G, et al. Experimental thromboembolic stroke by positron emission tomography: immediate versus delayed reperfusion by fibrinolysis. J Cereb Blood Flow Metab. 1988;8:539–45.

    CAS  Google Scholar 

  83. Penar PL, Greer CA. The effect of intravenous tissue-type plasminogen activator in a rat model of embolic cerebral ischemia. Yale J Biol Med. 1987;60:233–43.

    CAS  PubMed Central  PubMed  Google Scholar 

  84. Watson BD, Prado R, Dietrich W, et al. Mitigation of evolving cortical infarction in rats by recombinant tissue plasminogen activator following photochemically induced thrombosis. In: Raichle ME, Powers WJ, editors. Cerebrovascular diseases. New York, NY: Raven; 1987. p. 317–30.

    Google Scholar 

  85. Chechraza BB, Seibert JA, Kissel P. Evaluation of recombinant tissue plasminogen activator in embolic stroke. Neurosurgery. 1989;24:355–60.

    Google Scholar 

  86. Bednar MM, McAuliffe M, Raymond S, et al. Tissue plasminogen activator reduces brain injury in a rabbit model of thromboembolic stroke. Stroke. 1990;21:1705–9.

    CAS  PubMed  Google Scholar 

  87. Quartermain D, Li YS, Jonas S. The low molecular weight heparin enoxaparin reduces infarct size in a rat model of temporary focal ischemia. Cerebrovasc Dis. 2003;16(4):346–55.

    CAS  PubMed  Google Scholar 

  88. Yang Y, Li Q, Nakada MT, Yang T, Shuaib A. Angiographic evaluation of middle cerebral artery reperfusion caused by platelet glycoprotein IIb/IIIa receptor complex antagonist murine 7E3 F(ab′)2 in a model of focal cerebral ischemia in rats. J Neurosurg. 2001;94:582–8.

    CAS  PubMed  Google Scholar 

  89. Zhang L, Zhang ZG, Zhang R, Morris D, Lu M, Coller BS, Chopp M. Adjuvant treatment with a glycoprotein IIb/IIIa receptor inhibitor increases the therapeutic window for low-dose tissue plasminogen activator administration in a rat model of embolic stroke. Circulation. 2003;107(22):2837–43.

    CAS  PubMed  Google Scholar 

  90. Ding G, Jiang Q, Zhang L, Zhang ZG, Li L, et al. Analysis of combined treatment of embolic stroke in rat with r-tPA and a GPIIb/IIIa inhibitor. J Cereb Blood Flow Metab. 2005;25(1):87–97.

    CAS  PubMed  Google Scholar 

  91. Gahn G, Barlinn K, Dzialowski I, Puetz V, Kunz A, et al. Combined thrombolysis with abciximab and rt-PA in patients with middle cerebral artery occlusion. Acta Neurol Scand. 2010;121(1):63–6.

    CAS  PubMed  Google Scholar 

  92. Deshmukh VR, Fiorella DJ, Albuquerque FC, Frey J, Flaster M, et al. Intra-arterial thrombolysis for acute ischemic stroke: preliminary experience with platelet glycoprotein IIb/IIIa inhibitors as adjunctive therapy. Neurosurgery. 2005;56(1):46–54.

    PubMed  Google Scholar 

  93. Adams Jr HP, Effron MB, Torner J, Davalos A, Frayne J, Teal P, et al. Emergency administration of abciximab for treatment of patients with acute ischemic stroke: Results of an international phase III trial: Abciximab in emergency treatment of stroke trial (ABESTT-II). Stroke. 2008;39:87–99.

    CAS  PubMed  Google Scholar 

  94. Qureshi AI, Harris-Lane P, Kirmani JF, Janjua N, Divani AA, Mohammad YM, Suarez JI, Montgomery MO. Intra-arterial reteplase and intravenous abciximab in patients with acute ischemic stroke: an open-label, dose-ranging, phase I study. Neurosurgery. 2006;59(4):789–96.

    PubMed  Google Scholar 

  95. Pancioli AM, Brott TG. Therapeutic potential of platelet glycoprotein IIb/IIIa receptor antagonists in acute ischaemic stroke: scientific rationale and available evidence. CNS Drugs. 2004;18(14):981–8.

    CAS  PubMed  Google Scholar 

  96. Seitz RJ, Siebler M. Platelet GPIIb/IIIa receptor antagonists in human ischemic brain disease. Curr Vasc Pharmacol. 2008;6(1):29–36.

    CAS  PubMed  Google Scholar 

  97. Meunier JM, Holland CK, Pancioli AM, Lindsell CJ, Shaw GJ. Effect of low frequency ultrasound on combined rt-PA and eptifibatide thrombolysis in human clots. Thromb Res. 2009;123(3):528–36.

    CAS  PubMed Central  PubMed  Google Scholar 

  98. Shaw GJ, Meunier JM, Lindsell CJ, Pancioli AM, Holland CK. Making the right choice: optimizing rt-PA and eptifibatide lysis, an in vitro study. Thromb Res. 2010;126(4):e305–11.

    CAS  PubMed Central  PubMed  Google Scholar 

  99. Pancioli AM, Adeoye O, Schmit PA, Khoury J, Levine SR, et al. Combined Approach to Lysis Utilizing Eptifibatide and Recombinant Tissue Plasminogen Activator in Acute Ischemic Stroke-Enhanced Regimen Stroke Trial. Stroke. 2013;44(9):2381–7.

    PubMed Central  PubMed  Google Scholar 

  100. Mary V, Wahl F, Uzan A, Stutzmann JM. Enoxaparin in experimental stroke: neuroprotection and therapeutic window of opportunity. Stroke. 2001;32(4):993–9.

    CAS  PubMed  Google Scholar 

  101. Li PA, He QP, Siddiqui MM, Shuaib A. Posttreatment with low molecular weight heparin reduces brain edema and infarct volume in rats subjected to thrombotic middle cerebral artery occlusion. Brain Res. 1998;801(1–2):220–3.

    CAS  PubMed  Google Scholar 

  102. Jonas S, Quartermain D. Low molecular weight heparin and the treatment of ischemic stroke. Animal results, the reasons for failure in human stroke trials, mechanisms of action, and the possibilities for future use in stroke. Ann N Y Acad Sci. 2001;939:268–70.

    CAS  PubMed  Google Scholar 

  103. The Publications Committee for the Trial of ORG 10172 in Acute Stroke Trial Investigators. Low molecular weight heparinoid, ORG 10172 (Danaparoid), and outcome after acute ischemic stroke: a randomized controlled trial. JAMA. 1998;279:1265–72.

    Google Scholar 

  104. Mikulík R, Dufek M, Goldemund D, Reif M. A pilot study on systemic thrombolysis followed by low molecular weight heparin in ischemic stroke. Eur J Neurol. 2006;13(10):1106–11.

    PubMed  Google Scholar 

  105. Bednar MM, Quilley J, Russell SR, Fuller SP, Booth C, et al. The effect of oral antiplatelet agents on tissue plasminogen activator-mediated thrombolysis in a rabbit model of thromboembolic stroke. Neurosurgery. 1996;39(2):352–9.

    CAS  PubMed  Google Scholar 

  106. Thomas GR, Thibodeaux H, Errett CJ, Bednar MM, Gross CE, et al. Intravenous aspirin causes a paradoxical attenuation of cerebrovascular thrombolysis. Stroke. 1995;26(6):1039–46.

    CAS  PubMed  Google Scholar 

  107. Zinkstok SM, Roos YB, ARTIS investigators. Early administration of aspirin in patients treated with alteplase for acute ischaemic stroke: a randomised controlled trial. Lancet. 2012;380(9843):731–7.

    CAS  PubMed  Google Scholar 

  108. Asahi M, Huang Z, Thomas S, Yoshimura S, Sumii T, Mori T, Qiu J, Amin-Hanjani S, Huang PL, Liao JK, Lo EH, Moskowitz MA. Protective effects of statins involving both eNOS and tPA in focal cerebral ischemia. J Cereb Blood Flow Metab. 2005;25(6):722–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  109. Amin-Hanjani S, Stagliano NE, Yamada M, Huang PL, Liao JK, Moskowitz MA. Mevastatin, an HMG-CoA reductase inhibitor, reduces stroke damage and upregulates endothelial nitric oxide synthase in mice. Stroke. 2001;32(4):980–6.

    CAS  PubMed  Google Scholar 

  110. Nagotani S, Hayashi T, Sato K, Zhang W, Deguchi K, Nagano I, Shoji M, Abe K. Reduction of cerebral infarction in stroke-prone spontaneously hypertensive rats by statins associated with amelioration of oxidative stress. Stroke. 2005;36(3):670–2.

    CAS  PubMed  Google Scholar 

  111. Lapchak PA, Han MK. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor simvastatin reduces thrombolytic-induced intracerebral hemorrhage in embolized rabbits. Brain Res. 2009;1303:144–50.

    CAS  PubMed  Google Scholar 

  112. Quizzato A, Romualdi E, Dentali F, Ageno W. Statins for acute ischemic stroke. Cochrane Database Syst Rev. 2011;8, CD007551.

    Google Scholar 

  113. Ní Chróinín D, Asplund K, Åsberg S, Callaly E, Cuadrado-Godia E, Díez-Tejedor E, Di Napoli M, Engelter ST, Furie KL, Giannopoulos S, Gotto Jr AM, Hannon N, Jonsson F, Kapral MK, Martí-Fàbregas J, Martínez-Sánchez P, Milionis HJ, Montaner J, Muscari A, Pikija S, Probstfield J, Rost NS, Thrift AG, Vemmos K, Kelly PJ. Statin therapy and outcome after ischemic stroke: systematic review and meta-analysis of observational studies and randomized trials. Stroke. 2013;44(2):448–56.

    PubMed  Google Scholar 

  114. Winkler J, Shoup JP, Czap A, Staff I, Fortunato G, McCullough LD, Sansing LH. Long-term improvement in outcome after intracerebral hemorrhage in patients treated with statins. J Stroke Cerebrovasc Dis. 2013;22(8):e541–5. doi:10.1016/j.jstrokecerebrovasdis.2013.06.015.

    PubMed  Google Scholar 

  115. Bustamante A, Giralt D, Garcia-Bonilla L, Campos M, Rosell A, Montaner J. Citicoline in pre-clinical animal models of stroke: a meta-analysis shows the optimal neuroprotective profile and the missing steps for jumping into a stroke clinical trial. J Neurochem. 2012;123(2):217–25.

    CAS  PubMed  Google Scholar 

  116. Clark WM. Efficacy of citicoline as an acute stroke treatment. Expert Opin Pharmacother. 2009;10(5):839–46.

    CAS  PubMed  Google Scholar 

  117. Clark WM, Clark TD. Stroke: treatment for acute stroke—the end of the citicoline saga. Nat Rev Neurol. 2012;8:484–5. doi:10.1038/nrneurol.2012.166.

    CAS  PubMed  Google Scholar 

  118. Alonso de Leciñana M, Gutiérrez M, Roda JM, Carceller F, Díez-Tejedor E. Effect of combined therapy with thrombolysis and citicoline in a rat model of embolic stroke. J Neurol Sci. 2006;247(2):121–9.

    PubMed  Google Scholar 

  119. Andersen M, Overgaard K, Meden P, Boysen G, Choi SC. Effects of citicoline combined with thrombolytic therapy in a rat embolic stroke model. Stroke. 1999;30(7):1464–71.

    CAS  PubMed  Google Scholar 

  120. Cho HJ, Kim YJ. Efficacy and safety of oral citicoline in acute ischemic stroke: drug surveillance study in 4,191 cases. Methods Find Exp Clin Pharmacol. 2009;31(3):171–6. doi:10.1358/mf.2009.31.3.1364241.

    CAS  PubMed  Google Scholar 

  121. Clark WM, Williams BJ, Selzer KA, Zweifler RM, Sabounjian LA, Gammans RE. A randomized efficacy trial of citicoline in patients with acute ischemic stroke. Stroke. 1999;30(12):2592–7.

    CAS  PubMed  Google Scholar 

  122. Mitta M, Goel D, Bansal KK, Puri P. Edaravone—citicoline comparative study in acute ischemic stroke (ECCS-AIS). J Assoc Physicians India. 2012;60:36–8.

    PubMed  Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  124. Westermaier T, Stetter C, Kunze E, Willner N, Raslan F, et al. Magnesium treatment for neuroprotection in ischemic diseases of the brain. Exp Transl Stroke Med. 2013;5(1):6.

    CAS  PubMed Central  PubMed  Google Scholar 

  125. Zhu HD, Martin R, Meloni B, Oltvolgyi C, Moore S, et al. Magnesium sulfate fails to reduce infarct volume following transient focal cerebral ischemia in rats. Neurosci Res. 2004;49(3):347–53.

    CAS  PubMed  Google Scholar 

  126. Stewart D, Marder VJ, Starkman S, Saver JL. Magnesium sulfate neither potentiates nor inhibits tissue plasminogen activator-induced thrombolysis. J Thromb Haemost. 2006;4(7):1575–9.

    CAS  PubMed  Google Scholar 

  127. Muir KW, Lees KR, Ford I, Davis S. Magnesium for acute stroke (Intravenous Magnesium Efficacy in Stroke trial): randomised controlled trial. Lancet. 2004;5(9407):439–45.

    Google Scholar 

  128. Sutherland BA, Minnerup J, Balami JS, Arba F, Buchan AM, et al. Neuroprotection for ischaemic stroke: translation from the bench to the bedside. Int J Stroke. 2012;7(5):407–18.

    PubMed  Google Scholar 

  129. Belayev L, Liu Y, Zhao W, Busto R, Ginsberg MD. Human albumin therapy of acute ischemic stroke: marked neuroprotective efficacy at moderate doses and with a broad therapeutic window. Stroke. 2001;32:553–60.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  131. Tang J, Li YJ, Mu J, Li Q, Yang DY, Xie P. Albumin ameliorates tissue plasminogen activator-mediated blood–brain barrier permeability and ischemic brain injury in rats. Neurol Res. 2009;31(2):189–94.

    CAS  PubMed  Google Scholar 

  132. Ginsberg MD, Hill MD, Palesch YY, Ryckborst KJ, Tamariz D. The ALIAS Pilot Trial: a dose-escalation and safety study of albumin therapy for acute ischemic stroke – I: Physiological responses and safety results. Stroke. 2006;37:2100–6.

    PubMed  Google Scholar 

  133. Palesch YY, Hill MD, Ryckborst KJ, Tamariz D, Ginsberg MD. The ALIAS Pilot Trial: a dose-escalation and safety study of albumin therapy for acute ischemic stroke—II: neurologic outcome and efficacy analysis. Stroke. 2006;37:2107–14.

    CAS  PubMed  Google Scholar 

  134. Ginsberg MD, Palesch YY, Hill MD. The ALIAS (ALbumin In Acute Stroke) Phase III randomized multicentre clinical trial: design and progress report. Biochem Soc Trans. 2006;34(Pt 6):1323–6.

    CAS  PubMed  Google Scholar 

  135. Tang XN, Liu L, Yenari MA. Combination therapy with hypothermia for treatment of cerebral ischemia. J Neurotrauma. 2009;26:325–31. doi:10.1089/neu.2008.0594.

    PubMed Central  PubMed  Google Scholar 

  136. Wang GJ, Deng HY, Maier CM, Sun GH, Yenari MA. Mild hypothermia reduces ICAM-1 expression, neutrophil infiltration and microglia/monocyte accumulation following experimental stroke. Neuroscience. 2002;114(4):1081–90.

    CAS  PubMed  Google Scholar 

  137. Kallmünzer B, Schwab S, Kollmar R. Mild hypothermia of 34 °C reduces side effects of rt-PA treatment after thromboembolic stroke in rats. Exp Transl Stroke Med. 2012;4(1):3. doi:10.1186/2040-7378-4-3.

    PubMed Central  PubMed  Google Scholar 

  138. Tang XN, Liu L, Koike MA, Yenari MA. Mild hypothermia reduces tissue plasminogen activator-related hemorrhage and blood brain barrier disruption after experimental stroke. Ther Hypothermia Temp Manag. 2013;3(2):74–83.

    PubMed Central  PubMed  Google Scholar 

  139. Kollmar R, Schwab S. Hypothermia and ischemic stroke. Curr Treat Options Neurol. 2012;14:188–96.

    Google Scholar 

  140. Zhang C, Chopp M, Cui Y, Wang L, Zhang R, et al. Cerebrolysin enhances neurogenesis in the ischemic brain and improves functional outcome after stroke. J Neurosci Res. 2010;88(15):3275–81.

    CAS  PubMed Central  PubMed  Google Scholar 

  141. Zhang L, Chopp M, Meier DH, Winter S, Wang L, et al. Sonic hedgehog signaling pathway mediates cerebrolysin-improved neurological function after stroke. Stroke. 2013;44(7):1965–72.

    CAS  PubMed  Google Scholar 

  142. Heiss WD, Brainin M, Bornstein NM, Tuomilehto J, Hong Z, Cerebrolysin Acute Stroke Treatment in Asia (CASTA) Investigators. Cerebrolysin in patients with acute ischemic stroke in Asia: results of a double-blind, placebo-controlled randomized trial. Stroke. 2012;43(3):630–6.

    CAS  PubMed  Google Scholar 

  143. Lang W, Stadler CH, Poljakovic Z, Fleet D, Lyse Study Group. A prospective, randomized, placebo-controlled, double-blind trial about safety and efficacy of combined treatment with alteplase (rt-PA) and Cerebrolysin in acute ischaemic hemispheric stroke. Int J Stroke. 2013;8(2):95–104.

    PubMed  Google Scholar 

  144. 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.

    CAS  PubMed  Google Scholar 

  145. Stieg PE, Sathi S, Warach S, Le DA, Lipton SA. Neuroprotection by the NMDA receptor-associated open-channel blocker memantine in a photothrombotic model of cerebral focal ischemia in neonatal rat. Eur J Pharmacol. 1999;375(1–3):115–20.

    CAS  PubMed  Google Scholar 

  146. Montagne A, Hébert M, Jullienne A, Lesept F, Le Béhot A, et al. Memantine improves safety of thrombolysis for stroke. Stroke. 2012;43(10):2774–81.

    CAS  PubMed  Google Scholar 

  147. Back T, Otto D, Kittner D, Schüler OG, Hennerici MG, et al. Failure to improve the effect of thrombolysis by memantine in a rat embolic stroke model. Neurol Res. 2007;29(3):264–9.

    CAS  PubMed  Google Scholar 

  148. Williams HE, Claybourn M, Green AR. Investigating the free radical trapping ability of NXY-059. S-PBN and PBN Free Radic Res. 2007;41(9):1047–52.

    CAS  Google Scholar 

  149. Yoshimoto T, Kanakaraj P, Ying Ma J, Cheng M, Kerr I, et al. NXY-059 maintains Akt activation and inhibits release of cytochrome C after focal cerebral ischemia. Brain Res. 2002;947(2):191–8.

    CAS  PubMed  Google Scholar 

  150. Marshall JW, Duffin KJ, Green AR, Ridley RM. NXY-059, a free radical—trapping agent, substantially lessens the functional disability resulting from cerebral ischemia in a primate species. Stroke. 2001;32(1):190–8.

    CAS  PubMed  Google Scholar 

  151. 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.

    CAS  PubMed  Google Scholar 

  152. Diener HC, Lees KR, Lyden P, Grotta J, Davalos A, et al. NXY-059 for the treatment of acute stroke: pooled analysis of the SAINT I and II trials. Stroke. 2008;39(6):1751–8.

    CAS  PubMed  Google Scholar 

  153. Amaro S, Planas AM, Chamorro A. Uric acid administration in patients with acute stroke: a novel approach to neuroprotection. Expert Rev Neurother. 2008;8:259–70.

    CAS  PubMed  Google Scholar 

  154. Yu ZF, Bruce-Keller AJ, Goodman Y, Mattson MP. Uric acid protects neurons against excitotoxic and metabolic insults in cell culture, and against focal ischemic brain injury in vivo. J Neurosci Res. 1998;53:613–25.

    CAS  PubMed  Google Scholar 

  155. Romanos E, Planas AM, Amaro S, Chamorro A. Uric acid reduces brain damage and improves the benefits of rt-PA in a rat model of thromboembolic stroke. J Cereb Blood Flow Metab. 2007;27:14–20.

    CAS  PubMed  Google Scholar 

  156. Hong JM, Bang OY, Chung CS, Joo IS, Gwag BJ, Ovbiagele B. Influence of recanalization on uric acid patterns in acute ischemic stroke. Cerebrovasc Dis. 2010;29:431–9.

    CAS  PubMed  Google Scholar 

  157. Amaro S, Soy D, Obach V, Cervera A, Planas AM, Chamorro A. A pilot study of dual treatment with recombinant tissue plasminogen activator and uric acid in acute ischemic stroke. Stroke. 2007;38:2173–5.

    CAS  PubMed  Google Scholar 

  158. Chamorro A, Obach V, Cervera A, Revilla M, Deulofeu R, Aponte JH. Prognostic significance of uric acid serum concentration in patients with acute ischemic stroke. Stroke. 2002;33:1048–452.

    CAS  PubMed  Google Scholar 

  159. Amaro S, Urra X, Go´mez-Choco M, Obach V, Cervera A, Vargas M, et al. Uric acid levels are relevant in patients with stroke treated with thrombolysis. Stroke. 2011;42 suppl 1:S28–32.

    CAS  PubMed  Google Scholar 

  160. Amaro S, Ca´novas D, Castellanos M, Ga´llego J, Martí-Fa`bregas J, Segura T, et al. The URICO-ICTUS study, a phase 3 study of combined treatment with uric acid and rt-PA administered intravenously in acute ischemic stroke patients within the first 4.5 h of onset of symptoms. Int J Stroke. 2010;5:325–8.

    PubMed  Google Scholar 

  161. Balami JS, Chen R, Sutherland BA, Buchan AM. Thrombolytic agents for acute ischaemic stroke treatment: the past, present and future. CNS Neurol Disord Drug Targets. 2013;12(2):145–54.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  163. Kikuchi K, Tancharoen S, Matsuda F, Biswas KK, Ito T, Morimoto Y, Oyama Y, Takenouchi K, Miura N, Arimura N, Nawa Y, Meng X, Shrestha B, Arimura S, Iwata M, Mera K, Sameshima H, Ohno Y, Maenosono R, Tajima Y, Uchikado H, Kuramoto T, Nakayama K, Shigemori M, Yoshida Y, Hashiguchi T, Maruyama I, Kawahara K. Edaravone attenuates cerebral ischemic injury by suppressing aquaporin-4. Biochem Biophys Res Commun. 2009;390(4):1121–5.

    CAS  PubMed  Google Scholar 

  164. Deguchi K, Miyazaki K, Tian F, Liu N, Liu W, Kawai H, Omote Y, Kono S, Yunoki T, Deguchi S, Abe K. Modifying neurorepair and neuroregenerative factors with tPA and edaravone after transient middle cerebral artery occlusion in rat brain. Brain Res. 2012;1436:168–77.

    CAS  PubMed  Google Scholar 

  165. Yagi K, Kitazato KT, Uno M, Tada Y, Kinouchi T, Shimada K, Nagahiro S. Edaravone, a free radical scavenger, inhibits MMP-9-related brain hemorrhage in rats treated with tissue plasminogen activator. Stroke. 2009;40(2):626–31.

    CAS  PubMed  Google Scholar 

  166. Isahaya K, Yamada K, Yamatoku M, Sakurai K, Takaishi S, Kato B, Hirayama T, Hasegawa Y. Effects of edaravone, a free radical scavenger, on serum levels of inflammatory biomarkers in acute brain infarction. J Stroke Cerebrovasc Dis. 2012;21(2):102–7.

    PubMed  Google Scholar 

  167. Unno Y, Katayama M, Shimizu H. Does functional outcome in acute ischaemic stroke patients correlate with the amount of free-radical scavenger treatment? A retrospective study of edaravone therapy. Clin Drug Investig. 2010;30(3):143–55.

    CAS  PubMed  Google Scholar 

  168. Yoshifumi T. Benefits of pre-treatment with edaravone in tPA intravenous therapy for acute cerebral infarction. XXIII International Symposium on Cerebral Blood Flow. J Cereb Blood Flow Metab. 2007;Suppl 1:BP34-06 M.

    Google Scholar 

  169. Fischer BR, Palkovic S, Holling M, Wölfer J, Wassmann H. Rationale of hyperbaric oxygenation in cerebral vascular insult. Curr Vasc Pharmacol. 2010;8(1):35–43.

    CAS  PubMed  Google Scholar 

  170. Yang ZJ, Xie Y, Bosco GM, Chen C, Camporesi EM. Hyperbaric oxygenation alleviates MCAO-induced brain injury and reduces hydroxyl radical formation and glutamate release. Eur J Appl Physiol. 2010;108(3):513–22.

    CAS  PubMed  Google Scholar 

  171. Sun L, Strelow H, Mies G, Veltkamp R. Oxygen therapy improves energy metabolism in focal cerebral ischemia. Brain Res. 2011;1415:103–8.

    CAS  PubMed  Google Scholar 

  172. Sun L, Zhou W, Mueller C, Sommer C, Heiland S, Bauer AT, Marti HH, Veltkamp R. Oxygen therapy reduces secondary hemorrhage after thrombolysis in thromboembolic cerebral ischemia. J Cereb Blood Flow Metab. 2010;30(9):1651–60.

    CAS  PubMed Central  PubMed  Google Scholar 

  173. Michalski D, Heindl M, Kacza J, Laignel F, Küppers-Tiedt L, Schneider D, Grosche J, Boltze J, Löhr M, Hobohm C, Härtig W. Spatio-temporal course of macrophage-like cell accumulation after experimental embolic stroke depending on treatment with tissue plasminogen activator and its combination with hyperbaric oxygenation. Eur J Histochem. 2012;56(2):e14.

    CAS  PubMed Central  PubMed  Google Scholar 

  174. Michalski D, Pelz J, Weise C, Kacza J, Boltze J, Grosche J, Kamprad M, Schneider D, Hobohm C, Härtig W. Early outcome and blood–brain barrier integrity after co-administered thrombolysis and hyperbaric oxygenation in experimental stroke. Exp Transl Stroke Med. 2011;3(1):5.

    PubMed Central  PubMed  Google Scholar 

  175. Küppers-Tiedt L, Manaenko A, Michalski D, Guenther A, Hobohm C, Wagner A, Zhang JH, Schneider D. Combined systemic thrombolysis with alteplase and early hyperbaric oxygen therapy in experimental embolic stroke in rats: relationship to functional outcome and reduction of structural damage. Acta Neurochir Suppl. 2011;111:167–72.

    PubMed  Google Scholar 

  176. Kumar S, Rajshekher G, Prabhakar S. Platelet glycoprotein IIb/IIIa inhibitors in acute ischemic stroke. Neurol India. 2008;56(4):399–404.

    PubMed  Google Scholar 

  177. Kumaria A, Tolias CM. Normobaric hyperoxia therapy for traumatic brain injury and stroke: a review. Br J Neurosurg. 2009;23(6):576–84.

    PubMed  Google Scholar 

  178. Nagaoka T, Fagan KA, Gebb SA, et al. Inhaled Rho kinase inhibitors are potent and selective vasodilators in rat pulmonary hypertension. Am J Respir Crit Care Med. 2005;171:494–9.

    PubMed  Google Scholar 

  179. Shi J, Wei L. Rho kinases in cardiovascular physiology and pathophysiology: the effect of fasudil. J Cardiovasc Pharmacol. 2013;62(4):341–54.

    CAS  PubMed  Google Scholar 

  180. Li Q, Huang XJ, He W, Ding J, Jia JT, Fu G, Wang HX, Guo LJ. Neuroprotective potential of fasudil mesylate in brain ischemia-reperfusion injury of rats. Cell Mol Neurobiol. 2009;29(2):169–80.

    CAS  PubMed  Google Scholar 

  181. Satoh S, Toshima Y, Hitomi A, Ikegaki I, Seto M, Asano T. Wide therapeutic time window for Rho-kinase inhibition therapy in ischemic brain damage in a rat cerebral thrombosis model. Brain Res. 2008;1193:102–8.

    CAS  PubMed  Google Scholar 

  182. Yagita Y, Kitagawa K, Sasaki T, Terasaki Y, Todo K, Omura-Matsuoka E, Kaibuchi K, Hori M. Rho-kinase activation in endothelial cells contributes to expansion of infarction after focal cerebral ischemia. J Neurosci Res. 2007;85(11):2460–9.

    CAS  PubMed  Google Scholar 

  183. Liu K, Li Z, Wu T, Ding S. Role of rho kinase in microvascular damage following cerebral ischemia reperfusion in rats. Int J Mol Sci. 2011;12(2):1222–31.

    CAS  PubMed Central  PubMed  Google Scholar 

  184. Rikitake Y, Kim HH, Huang Z, Seto M, Yano K, Asano T, Moskowitz MA, Liao JK. Inhibition of Rho kinase (ROCK) leads to increased cerebral blood flow and stroke protection. Stroke. 2005;36(10):2251–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  185. Satoh S, Hitomi A, Ikegaki I, Kawasaki K, Nakazono O, Iwasaki M, Mohri M, Asano T. Amelioration of endothelial damage/dysfunction is a possible mechanism for the neuroprotective effects of Rho-kinase inhibitors against ischemic brain damage. Brain Res Bull. 2010;81(1):191–5.

    CAS  PubMed  Google Scholar 

  186. Zemke D, Majid A. The potential of minocycline for neuroprotection in human neurologic disease. Clin Neuropharmacol. 2004;27(6):293–8.

    CAS  PubMed  Google Scholar 

  187. Giuliani F, Hader W, Yong VW. Minocycline attenuates T cell and microglia activity to impair cytokine production in T cell-microglia interaction. J Leukoc Biol. 2005;78(1):135–43.

    CAS  PubMed  Google Scholar 

  188. Yong VW, Wells J, Giuliani F, Casha S, Power C, Metz LM. The promise of minocycline in neurology. Lancet Neurol. 2004;3(12):744–51.

    PubMed  Google Scholar 

  189. Nagel S, Su Y, Horstmann S, Heiland S, Gardner H, Koziol J, Martinez-Torres FJ, Wagner S. Minocycline and hypothermia for reperfusion injury after focal cerebral ischemia in the rat: effects on BBB breakdown and MMP expression in the acute and subacute phase. Brain Res. 2008;1188:198–206.

    CAS  PubMed  Google Scholar 

  190. Machado LS, Kozak A, Ergul A, Hess DC, Borlongan CV, Fagan SC. Delayed minocycline inhibits ischemia-activated matrix metalloproteinases 2 and 9 after experimental stroke. BMC Neurosci. 2006;7:56.

    PubMed Central  PubMed  Google Scholar 

  191. Morimoto N, Shimazawa M, Yamashima T, Nagai H, Hara H. Minocycline inhibits oxidative stress and decreases in vitro and in vivo ischemic neuronal damage. Brain Res. 2005;1044(1):8–15.

    CAS  PubMed  Google Scholar 

  192. Yrjänheikki J, Tikka T, Keinänen R, Goldsteins G, Chan PH, Koistinaho J. A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci U S A. 1999;96(23):13496–500.

    PubMed Central  PubMed  Google Scholar 

  193. Hoda MN, Li W, Ahmad A, Ogbi S, Zemskova MA, Johnson MH, Ergul A, Hill WD, Hess DC, Sazonova IY. Sex-independent neuroprotection with minocycline after experimental thromboembolic stroke. Exp Transl Stroke Med. 2011;3(1):16. doi:10.1186/2040-7378-3-16.

    CAS  PubMed Central  PubMed  Google Scholar 

  194. Guan W, Kozak A, Fagan SC. Drug repurposing for vascular protection after acute ischemic stroke. Acta Neurochir Suppl. 2011;111:295–8.

    PubMed Central  PubMed  Google Scholar 

  195. Koistinaho M, Malm TM, Kettunen MI, Goldsteins G, Starckx S, Kauppinen RA, Opdenakker G, Koistinaho J. Minocycline protects against permanent cerebral ischemia in wild type but not in matrix metalloprotease-9-deficient mice. J Cereb Blood Flow Metab. 2005;25(4):460–7.

    CAS  PubMed  Google Scholar 

  196. Tang XN, Wang Q, Koike MA, Cheng D, Goris ML, Blankenberg FG, Yenari MA. Monitoring the protective effects of minocycline treatment with radiolabeled annexin V in an experimental model of focal cerebral ischemia. J Nucl Med. 2007;48(11):1822–8.

    CAS  PubMed  Google Scholar 

  197. Hayakawa K, Mishima K, Nozako M, Hazekawa M, Mishima S, Fujioka M, Orito K, Egashira N, Iwasaki K, Fujiwara M. Delayed treatment with minocycline ameliorates neurologic impairment through activated microglia expressing a high-mobility group box1-inhibiting mechanism. Stroke. 2008;39(3):951–8.

    CAS  PubMed  Google Scholar 

  198. Chu LS, Fang SH, Zhou Y, Yu GL, Wang ML, Zhang WP, Wei EQ. Minocycline inhibits 5-lipoxygenase activation and brain inflammation after focal cerebral ischemia in rats. Acta Pharmacol Sin. 2007;28(6):763–72.

    CAS  PubMed  Google Scholar 

  199. Li J, McCullough LD. Sex differences in minocycline-induced neuroprotection after experimental stroke. J Cereb Blood Flow Metab. 2009;29(4):670–4.

    CAS  PubMed Central  PubMed  Google Scholar 

  200. Murata Y, Rosell A, Scannevin RH, Rhodes KJ, Wang X, Lo EH. Extension of the thrombolytic time window with minocycline in experimental stroke. Stroke. 2008;39(12):3372–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  201. Machado LS, Sazonova IY, Kozak A, Wiley DC, El-Remessy AB, Ergul A, Hess DC, Waller JL, Fagan SC. Minocycline and tissue-type plasminogen activator for stroke: assessment of interaction potential. Stroke. 2009;40(9):3028–33.

    CAS  PubMed Central  PubMed  Google Scholar 

  202. Kelly-Cobbs AI, Prakash R, Li W, Pillai B, Hafez S, Coucha M, Johnson MH, Ogbi SN, Fagan SC, Ergul A. Targets of vascular protection in acute ischemic stroke differ in type 2 diabetes. Am J Physiol Heart Circ Physiol. 2013;304(6):H806–15.

    CAS  PubMed Central  PubMed  Google Scholar 

  203. Padma Srivastava MV, Bhasin A, Bhatia R, Garg A, Gaikwad S, Prasad K, Singh MB, Tripathi M. Efficacy of minocycline in acute ischemic stroke: a single-blinded, placebo-controlled trial. Neurol India. 2012;60(1):23–8.

    CAS  PubMed  Google Scholar 

  204. Switzer JA, Hess DC, Ergul A, Waller JL, Machado LS, Portik-Dobos V, Pettigrew LC, Clark WM, Fagan SC. Matrix metalloproteinase-9 in an exploratory trial of intravenous minocycline for acute ischemic stroke. Stroke. 2011;42(9):2633–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  205. Tran-Dinh A, Diallo D, Delbosc S, Varela-Perez LM, Dang QB, Lapergue B, Burillo E, Michel JB, Levoye A, Martin-Ventura JL, Meilhac O. HDL and endothelial protection. Br J Pharmacol. 2013;169(3):493–511.

    CAS  PubMed Central  PubMed  Google Scholar 

  206. Lapergue B, Dang BQ, Desilles JP, Ortiz-Munoz G, Delbosc S, Loyau S, Louedec L, Couraud PO, Mazighi M, Michel JB, Meilhac O, Amarenco P. High-density lipoprotein-based therapy reduces the hemorrhagic complications associated with tissue plasminogen activator treatment in experimental stroke. Stroke. 2013;44(3):699–707.

    CAS  PubMed  Google Scholar 

  207. Sacco RL, Benson RT, Kargman DE, Boden-Albala B, Tuck C, Lin IF, Cheng JF, Paik MC, Shea S, Berglund L. High-density lipoprotein cholesterol and ischemic stroke in the elderly: the Northern Manhattan Stroke Study. JAMA. 2001;285(21):2729–35.

    CAS  PubMed  Google Scholar 

  208. Demarin V, Lisak M, Morović S, Cengić T. Low high-density lipoprotein cholesterol as the possible risk factor for stroke. Acta Clin Croat. 2010;49(4):429–39.

    PubMed  Google Scholar 

  209. Cohen JA, Chun J. Mechanisms of fingolimod’s efficacy and adverse effects in multiple sclerosis. Ann Neurol. 2011;69:759–77.

    CAS  PubMed  Google Scholar 

  210. Soliven B, Miron V, Chun J. The neurobiology of sphingosine 1-phosphate signaling and sphingosine 1-phosphate receptor modulators. Neurology. 2011;76(8 Suppl 3):S9–14.

    CAS  PubMed  Google Scholar 

  211. Campos F, Qin T, Castillo J, Seo JH, Arai K, Lo EH, Waeber C. Fingolimod reduces hemorrhagic transformation associated with delayed tissue plasminogen activator treatment in a mouse thromboembolic model. Stroke. 2013;44(2):505–11.

    CAS  PubMed Central  PubMed  Google Scholar 

  212. Wei Y, Yemisci M, Kim HH, Yung LM, Shin HK, Hwang SK, Guo S, Qin T, Alsharif N, Brinkmann V, Liao JK, Lo EH, Waeber C. Fingolimod provides long-term protection in rodent models of cerebral ischemia. Ann Neurol. 2011;69(1):119–29.

    CAS  PubMed Central  PubMed  Google Scholar 

  213. Hasegawa Y, Suzuki H, Sozen T, Rolland W, Zhang JH. Activation of sphingosine 1-phosphate receptor-1 by FTY720 is neuroprotective after ischemic stroke in rats. Stroke. 2010;41(2):368–74.

    CAS  PubMed Central  PubMed  Google Scholar 

  214. Czech B, Pfeilschifter W, Mazaheri-Omrani N, Strobel MA, Kahles T, Neumann-Haefelin T, Rami A, Huwiler A, Pfeilschifter J. The immunomodulatory sphingosine 1-phosphate analog FTY720 reduces lesion size and improves neurological outcome in a mouse model of cerebral ischemia. Biochem Biophys Res Commun. 2009;389(2):251–6.

    CAS  PubMed  Google Scholar 

  215. Liu J, Zhang C, Tao W, Liu M. Systematic review and meta-analysis of the efficacy of sphingosine-1-phosphate (S1P) receptor agonist FTY720 (fingolimod) in animal models of stroke. Int J Neurosci. 2013;123(3):163–9. doi:10.3109/00207454.2012.749255. Epub 2012 Dec 21.

    CAS  PubMed  Google Scholar 

  216. Campos F, Qin T, Castillo J, Seo JH, Arai K, Lo EH, Waeber C. Fingolimod reduces hemorrhagic transformation associated with delayed tissue plasminogen activator treatment in a mouse thromboembolic model. Stroke. 2013;44(2):505–11. doi:10.1161/STROKEAHA.112.679043. Epub 2013 Jan 3.

    CAS  PubMed Central  PubMed  Google Scholar 

  217. Rolland WB, Lekic T, Krafft PR, Hasegawa Y, Altay O, Hartman R, Ostrowski R, Manaenko A, Tang J, Zhang JH. Fingolimod reduces cerebral lymphocyte infiltration in experimental models of rodent intracerebral hemorrhage. Exp Neurol. 2013;241:45–55. doi:doi: 10.1016/j.expneurol.2012.12.009. Epub 2012.

    CAS  PubMed Central  PubMed  Google Scholar 

  218. Willis MA, Cohen JA. Fingolimod therapy for multiple sclerosis. Semin Neurol. 2013;33(1):37–44.

    PubMed  Google Scholar 

  219. Reitmeir R, Kilic E, Kilic U, Bacigaluppi M, ElAli A, et al. Post-acute delivery of erythropoietin induces stroke recovery by promoting perilesional tissue remodelling and contralesional pyramidal tract plasticity. Brain. 2011;134(1):84–99.

    PubMed  Google Scholar 

  220. van der Kooij MA, Groenendaal F, Kavelaars A, Heijnen CJ, van Bel F. Neuroprotective properties and mechanisms of erythropoietin in in vitro and in vivo experimental models for hypoxia/ischemia. Brain Res Rev. 2008;59(1):22–33.

    PubMed  Google Scholar 

  221. Ehrenreich H, Hasselblatt M, Dembowski C, et al. Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med. 2002;8:495–505.

    CAS  PubMed Central  PubMed  Google Scholar 

  222. Brott T. Thrombolytic therapy for stroke. Cerebrovascular Brain Metab Rev. 1991;3:91–113.

    CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Neurology, SUNY Downstate Medical Center & Stroke Center, 450 Clarkson Avenue, MSC 1213, Brooklyn, NY, 11203-2012, USA

    Steven R. Levine M.D.

  2. Department of Physiology & Pharmacology, School of Graduate Studies, SUNY Downstate Medical Center, Brooklyn, NY, USA

    Syed Faraz Kazim M.D.

  3. Department of Neurology, SUNY Downstate Medical Center, Brooklyn, NY, USA

    Pirouz Piran M.D.

  4. Cerebrovascular Division, Department of Neurology, SUNY Downstate Medical Center, Brooklyn, NY, USA

    Frank C. Barone Ph.D.

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  1. Steven R. Levine M.D.
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  2. Syed Faraz Kazim M.D.
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  3. Pirouz Piran M.D.
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  4. Frank C. Barone Ph.D.
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Correspondence to Steven R. Levine M.D. .

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

    Patrick D Lyden

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Levine, S.R., Kazim, S.F., Piran, P., Barone, F.C. (2015). The March of Thrombolytic Therapy for Acute Ischemic Stroke to Clinical Trials: Pre-clinical Thrombolysis and Adjuncts to Thrombolysis Research. In: Lyden, P. (eds) Thrombolytic Therapy for Acute Stroke. Springer, Cham. https://doi.org/10.1007/978-3-319-07575-4_2

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