Nucleic Acid Therapies for Ischemic Stroke

  • Nils HenningerEmail author
  • Yunis Mayasi


Stroke remains a leading cause of disability and death worldwide despite significant scientific and therapeutic advances. Therefore, there is a critical need to improve stroke prevention and treatment. In this review, we describe several examples that leverage nucleic acid therapeutics to improve stroke care through prevention, acute treatment, and recovery. Aptamer systems are under development to increase the safety and efficacy of antithrombotic and thrombolytic treatment, which represent the mainstay of medical stroke therapy. Antisense oligonucleotide therapy has shown some promise in treating stroke causes that are genetically determined and resistant to classic prevention approaches such as elevated lipoprotein (a) and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Targeting microRNAs may be attractive because they regulate factors involved in neuronal cell death and reperfusion-associated injury, as well as neurorestorative pathways. Lastly, microRNAs may aid reliable etiologic classification of stroke subtypes, which is important for effective secondary stroke prevention.


Stroke Neuroprotection Nucleic acid Prevention Therapy Review 


Required Author Forms

Disclosure forms provided by the authors are available with the online version of this article.

Author Contributions

Dr. Henninger and Dr. Mayasi drafted the article.


Dr. Henninger is supported by K08NS091499 from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Compliance with Ethical Standards

Competing Interests

Dr. Henninger serves on the advisory board of Omniox, Inc. and Portola Pharmaceuticals, Inc., and as a consultant for Astrocyte Pharmaceuticals, Inc. Dr. Mayasi declares no competing interests.

Supplementary material

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ESM 1 (PDF 433 kb)
13311_2019_710_MOESM2_ESM.pdf (365 kb)
ESM 2 (PDF 365 kb)


  1. 1.
    GBD 2016 DALYs and Hale Collaborators. Global, regional, and national disability-adjusted life-years (DALYs) for 333 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390:1260–1344.CrossRefGoogle Scholar
  2. 2.
    Feigin V, Krishnamurthi RV. Global Burden of Stroke. In: Grotta JC, Albers GW, Broderick JP, Kasner SE, Lo EH, Mendelow AD et al., editors. Stroke. Pathophysiology, Diagnosis, and Management. 6 ed.: Elsevier; 2016.Google Scholar
  3. 3.
    Feigin VL, Krishnamurthi RV, Parmar P et al. Update on the Global Burden of Ischemic and Hemorrhagic Stroke in 1990-2013: The GBD 2013 Study. Neuroepidemiology. 2015;45:161–176.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Benjamin EJ, Virani SS, Callaway CW et al. Heart Disease and Stroke Statistics-2018 Update: A Report From the American Heart Association. Circulation. 2018;137:e67-e492.CrossRefPubMedGoogle Scholar
  5. 5.
    Ma VY, Chan L, Carruthers KJ. Incidence, prevalence, costs, and impact on disability of common conditions requiring rehabilitation in the United States: stroke, spinal cord injury, traumatic brain injury, multiple sclerosis, osteoarthritis, rheumatoid arthritis, limb loss, and back pain. Arch Phys Med Rehabil. 2014;95:986–995.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Broderick JP, Palesch YY, Janis LS, National Institutes of Health StrokeNet I. The National Institutes of Health StrokeNet: A User's Guide. Stroke. 2016;47:301–303.CrossRefPubMedGoogle Scholar
  7. 7.
    Cramer SC, Wolf SL, Adams HP, Jr. et al. Stroke Recovery and Rehabilitation Research: Issues, Opportunities, and the National Institutes of Health StrokeNet. Stroke. 2017;48:813–819.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Adams HP, Jr., Bendixen BH, Kappelle LJ et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993;24:35–41.CrossRefPubMedGoogle Scholar
  9. 9.
    Hart RG, Diener HC, Coutts SB et al. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol. 2014;13:429–438.CrossRefPubMedGoogle Scholar
  10. 10.
    Rothwell PM, Algra A, Chen Z, Diener HC, Norrving B, Mehta Z. Effects of aspirin on risk and severity of early recurrent stroke after transient ischaemic attack and ischaemic stroke: time-course analysis of randomised trials. Lancet. 2016;388:365–375.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Bhatt DL, Fox KA, Hacke W et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006;354:1706–1717.CrossRefPubMedGoogle Scholar
  12. 12.
    Lee M, Saver JL, Hong KS, Rao NM, Wu YL, Ovbiagele B. Risk-benefit profile of long-term dual- versus single-antiplatelet therapy among patients with ischemic stroke: a systematic review and meta-analysis. Ann Intern Med. 2013;159:463–470.CrossRefPubMedGoogle Scholar
  13. 13.
    Hansen ML, Sorensen R, Clausen MT et al. Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation. Arch Intern Med. 2010;170:1433–1441.CrossRefPubMedGoogle Scholar
  14. 14.
    Kleinschnitz C, De Meyer SF, Schwarz T et al. Deficiency of von Willebrand factor protects mice from ischemic stroke. Blood. 2009;113:3600–3603.CrossRefPubMedGoogle Scholar
  15. 15.
    Denis C, Methia N, Frenette PS et al. A mouse model of severe von Willebrand disease: defects in hemostasis and thrombosis. Proc Natl Acad Sci U S A. 1998;95:9524–9529.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Kleinschnitz C, Pozgajova M, Pham M, Bendszus M, Nieswandt B, Stoll G. Targeting platelets in acute experimental stroke: impact of glycoprotein Ib, VI, and IIb/IIIa blockade on infarct size, functional outcome, and intracranial bleeding. Circulation. 2007;115:2323–2330.CrossRefPubMedGoogle Scholar
  17. 17.
    Diener JL, Daniel Lagasse HA, Duerschmied D et al. Inhibition of von Willebrand factor-mediated platelet activation and thrombosis by the anti-von Willebrand factor A1-domain aptamer ARC1779. J Thromb Haemost. 2009;7:1155–1162.CrossRefPubMedGoogle Scholar
  18. 18.
    Siedlecki CA, Lestini BJ, Kottke-Marchant KK, Eppell SJ, Wilson DL, Marchant RE. Shear-dependent changes in the three-dimensional structure of human von Willebrand factor. Blood. 1996;88:2939–2950.PubMedGoogle Scholar
  19. 19.
    Huang RH, Fremont DH, Diener JL, Schaub RG, Sadler JE. A structural explanation for the antithrombotic activity of ARC1172, a DNA aptamer that binds von Willebrand factor domain A1. Structure. 2009;17:1476–1484.CrossRefPubMedGoogle Scholar
  20. 20.
    Gilbert JC, DeFeo-Fraulini T, Hutabarat RM et al. First-in-human evaluation of anti von Willebrand factor therapeutic aptamer ARC1779 in healthy volunteers. Circulation. 2007;116:2678–2686.CrossRefPubMedGoogle Scholar
  21. 21.
    Markus HS, McCollum C, Imray C, Goulder MA, Gilbert J, King A. The von Willebrand inhibitor ARC1779 reduces cerebral embolization after carotid endarterectomy: a randomized trial. Stroke. 2011;42:2149–2153.CrossRefPubMedGoogle Scholar
  22. 22.
    Nimjee SM, Lohrmann JD, Wang H et al. Rapidly regulating platelet activity in vivo with an antidote controlled platelet inhibitor. Mol Ther. 2012;20:391–397.CrossRefPubMedGoogle Scholar
  23. 23.
    Colilla S, Crow A, Petkun W, Singer DE, Simon T, Liu X. Estimates of current and future incidence and prevalence of atrial fibrillation in the U.S. adult population. Am J Cardiol. 2013;112:1142–1147.CrossRefPubMedGoogle Scholar
  24. 24.
    Miyasaka Y, Barnes ME, Bailey KR et al. Mortality trends in patients diagnosed with first atrial fibrillation: a 21-year community-based study. J Am Coll Cardiol. 2007;49:986–992.CrossRefPubMedGoogle Scholar
  25. 25.
    Mozaffarian D, Benjamin EJ, Go AS et al. Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation. 2016;133:e38–60.PubMedGoogle Scholar
  26. 26.
    European Heart Rhythm A, European Association for Cardio-Thoracic S, Camm AJ et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J. 2010;31:2369–2429.CrossRefGoogle Scholar
  27. 27.
    Patel MR, Mahaffey KW, Garg J et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883–891.CrossRefPubMedGoogle Scholar
  28. 28.
    Connolly SJ, Ezekowitz MD, Yusuf S et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139–1151.CrossRefPubMedGoogle Scholar
  29. 29.
    Mant J, Hobbs FD, Fletcher K et al. Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet. 2007;370:493–503.CrossRefPubMedGoogle Scholar
  30. 30.
    Barnett AS, Kim S, Fonarow GC et al. Treatment of Atrial Fibrillation and Concordance With the American Heart Association/American College of Cardiology/Heart Rhythm Society Guidelines: Findings From ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation). Circ Arrhythm Electrophysiol. 2017;10.Google Scholar
  31. 31.
    Amroze A, McManus DD, Golden J et al. Supporting use of anticoagulation through provider profiling of oral anticoagulant therapy for atrial fibrillation (SUPPORT-AF). Heart Rhythm. 2018;15:S475.CrossRefGoogle Scholar
  32. 32.
    Chan PS, Maddox TM, Tang F, Spinler S, Spertus JA. Practice-level variation in warfarin use among outpatients with atrial fibrillation (from the NCDR PINNACLE program). Am J Cardiol. 2011;108:1136–1140.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Ogilvie IM, Newton N, Welner SA, Cowell W, Lip GY. Underuse of oral anticoagulants in atrial fibrillation: a systematic review. Am J Med. 2010;123:638–645 e634.CrossRefPubMedGoogle Scholar
  34. 34.
    Seaburg L, Hess EP, Coylewright M, Ting HH, McLeod CJ, Montori VM. Shared decision making in atrial fibrillation: where we are and where we should be going. Circulation. 2014;129:704–710.CrossRefPubMedGoogle Scholar
  35. 35.
    Reynolds MR, Shah J, Essebag V et al. Patterns and predictors of warfarin use in patients with new-onset atrial fibrillation from the FRACTAL Registry. Am J Cardiol. 2006;97:538–543.CrossRefPubMedGoogle Scholar
  36. 36.
    Darrat YH, Shah J, Elayi CS et al. Regional Lack of Consistency in the Management of Atrial Fibrillation (from the RECORD-AF Trial). Am J Cardiol. 2017;119:47–51.CrossRefPubMedGoogle Scholar
  37. 37.
    Man-Son-Hing M, Nichol G, Lau A, Laupacis A. Choosing antithrombotic therapy for elderly patients with atrial fibrillation who are at risk for falls. Arch Intern Med. 1999;159:677–685.CrossRefPubMedGoogle Scholar
  38. 38.
    Steinberg BA, Kim S, Thomas L et al. Lack of concordance between empirical scores and physician assessments of stroke and bleeding risk in atrial fibrillation: results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry. Circulation. 2014;129:2005–2012.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Cordonnier C. Balancing risks versus benefits of anticoagulants in stroke prevention. Lancet Neurol. 2018;17:487–488.CrossRefPubMedGoogle Scholar
  40. 40.
    Deplanque D, Leys D, Parnetti L et al. Secondary prevention of stroke in patients with atrial fibrillation: factors influencing the prescription of oral anticoagulation at discharge. Cerebrovasc Dis. 2006;21:372–379.CrossRefPubMedGoogle Scholar
  41. 41.
    Piccini JP, Hammill BG, Sinner MF et al. Clinical course of atrial fibrillation in older adults: the importance of cardiovascular events beyond stroke. Eur Heart J. 2014;35:250–256.CrossRefPubMedGoogle Scholar
  42. 42.
    Poli D, Testa S, Antonucci E, Grifoni E, Paoletti O, Lip GY. Bleeding and stroke risk in a real-world prospective primary prevention cohort of patients with atrial fibrillation. Chest. 2011;140:918–924.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Aldrugh S, Sardana M, Henninger N, Saczynski JS, McManus DD. Atrial fibrillation, cognition and dementia: A review. J Cardiovasc Electrophysiol. 2017;28:958–965.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Panza F, Lozupone M, Solfrizzi V et al. Different Cognitive Frailty Models and Health- and Cognitive-related Outcomes in Older Age: From Epidemiology to Prevention. J Alzheimers Dis. 2018;62:993–1012.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Patel A, Goddeau RP, Jr., Henninger N. Newer Oral Anticoagulants: Stroke Prevention and Pitfalls. Open Cardiovasc Med J. 2016;10:94–104.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Chan MY, Cohen MG, Dyke CK et al. Phase 1b randomized study of antidote-controlled modulation of factor IXa activity in patients with stable coronary artery disease. Circulation. 2008;117:2865–2874.CrossRefPubMedGoogle Scholar
  47. 47.
    Dyke CK, Steinhubl SR, Kleiman NS et al. First-in-human experience of an antidote-controlled anticoagulant using RNA aptamer technology: a phase 1a pharmacodynamic evaluation of a drug-antidote pair for the controlled regulation of factor IXa activity. Circulation. 2006;114:2490–2497.CrossRefPubMedGoogle Scholar
  48. 48.
    Rusconi CP, Scardino E, Layzer J et al. RNA aptamers as reversible antagonists of coagulation factor IXa. Nature. 2002;419:90–94.CrossRefPubMedGoogle Scholar
  49. 49.
    Rusconi CP, Roberts JD, Pitoc GA et al. Antidote-mediated control of an anticoagulant aptamer in vivo. Nat Biotechnol. 2004;22:1423–1428.CrossRefPubMedGoogle Scholar
  50. 50.
    Nimjee SM, Keys JR, Pitoc GA, Quick G, Rusconi CP, Sullenger BA. A novel antidote-controlled anticoagulant reduces thrombin generation and inflammation and improves cardiac function in cardiopulmonary bypass surgery. Mol Ther. 2006;14:408–415.CrossRefPubMedGoogle Scholar
  51. 51.
    Chan MY, Rusconi CP, Alexander JH, Tonkens RM, Harrington RA, Becker RC. A randomized, repeat-dose, pharmacodynamic and safety study of an antidote-controlled factor IXa inhibitor. J Thromb Haemost. 2008;6:789–796.CrossRefPubMedGoogle Scholar
  52. 52.
    Povsic TJ, Vavalle JP, Aberle LH et al. A Phase 2, randomized, partially blinded, active-controlled study assessing the efficacy and safety of variable anticoagulation reversal using the REG1 system in patients with acute coronary syndromes: results of the RADAR trial. Eur Heart J. 2013;34:2481–2489.CrossRefPubMedGoogle Scholar
  53. 53.
    Lincoff AM, Mehran R, Povsic TJ et al. Effect of the REG1 anticoagulation system versus bivalirudin on outcomes after percutaneous coronary intervention (REGULATE-PCI): a randomised clinical trial. Lancet. 2016;387:349–356.CrossRefPubMedGoogle Scholar
  54. 54.
    Ganson NJ, Povsic TJ, Sullenger BA et al. Pre-existing anti-polyethylene glycol antibody linked to first-exposure allergic reactions to pegnivacogin, a PEGylated RNA aptamer. J Allergy Clin Immunol. 2016;137:1610–1613 e1617.CrossRefPubMedGoogle Scholar
  55. 55.
    Povsic TJ, Lawrence MG, Lincoff AM et al. Pre-existing anti-PEG antibodies are associated with severe immediate allergic reactions to pegnivacogin, a PEGylated aptamer. J Allergy Clin Immunol. 2016;138:1712–1715.CrossRefPubMedGoogle Scholar
  56. 56.
    Chabata CV, Frederiksen JW, Sullenger BA, Gunaratne R. Emerging applications of aptamers for anticoagulation and hemostasis. Curr Opin Hematol. 2018;25:382–388.PubMedGoogle Scholar
  57. 57.
    Kernan WN, Ovbiagele B, Black HR et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45:2160–2236.CrossRefPubMedGoogle Scholar
  58. 58.
    Stone NJ, Robinson JG, Lichtenstein AH et al. Treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults: synopsis of the 2013 American College of Cardiology/American Heart Association cholesterol guideline. Ann Intern Med. 2014;160:339–343.CrossRefPubMedGoogle Scholar
  59. 59.
    Amarenco P, Bogousslavsky J, Callahan A, 3rd et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355:549–559.CrossRefPubMedGoogle Scholar
  60. 60.
    Cholesterol, diastolic blood pressure, and stroke: 13,000 strokes in 450,000 people in 45 prospective cohorts. Prospective studies collaboration. Lancet. 1995;346:1647–1653.Google Scholar
  61. 61.
    Pikula A, Beiser AS, Wang J et al. Lipid and lipoprotein measurements and the risk of ischemic vascular events: Framingham Study. Neurology. 2015;84:472–479.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Wilson PW, Hoeg JM, D'Agostino RB et al. Cumulative effects of high cholesterol levels, high blood pressure, and cigarette smoking on carotid stenosis. N Engl J Med. 1997;337:516–522.CrossRefPubMedGoogle Scholar
  63. 63.
    Fine-Edelstein JS, Wolf PA, O'Leary DH et al. Precursors of extracranial carotid atherosclerosis in the Framingham Study. Neurology. 1994;44:1046–1050.CrossRefPubMedGoogle Scholar
  64. 64.
    O'Leary DH, Anderson KM, Wolf PA, Evans JC, Poehlman HW. Cholesterol and carotid atherosclerosis in older persons: the Framingham Study. Ann Epidemiol. 1992;2:147–153.CrossRefPubMedGoogle Scholar
  65. 65.
    Takagi H, Umemoto T. Atorvastatin decreases lipoprotein(a): a meta-analysis of randomized trials. Int J Cardiol. 2012;154:183–186.CrossRefPubMedGoogle Scholar
  66. 66.
    Kronenberg F, Utermann G. Lipoprotein(a): resurrected by genetics. J Intern Med. 2013;273:6–30.CrossRefPubMedGoogle Scholar
  67. 67.
    Tsimikas S, Hall JL. Lipoprotein(a) as a potential causal genetic risk factor of cardiovascular disease: a rationale for increased efforts to understand its pathophysiology and develop targeted therapies. J Am Coll Cardiol. 2012;60:716–721.CrossRefPubMedGoogle Scholar
  68. 68.
    Berglund L, Ramakrishnan R. Lipoprotein(a): an elusive cardiovascular risk factor. Arterioscler Thromb Vasc Biol. 2004;24:2219–2226.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Utermann G. The mysteries of lipoprotein(a). Science. 1989;246:904–910.CrossRefPubMedGoogle Scholar
  70. 70.
    Tsimikas S, Viney NJ, Hughes SG et al. Antisense therapy targeting apolipoprotein(a): a randomised, double-blind, placebo-controlled phase 1 study. Lancet. 2015;386:1472–1483.CrossRefPubMedGoogle Scholar
  71. 71.
    Thanassoulis G, Campbell CY, Owens DS et al. Genetic associations with valvular calcification and aortic stenosis. N Engl J Med. 2013;368:503–512.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Emerging Risk Factors C, Erqou S, Kaptoge S et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA. 2009;302:412–423.CrossRefGoogle Scholar
  73. 73.
    Helgadottir A, Gretarsdottir S, Thorleifsson G et al. Apolipoprotein(a) genetic sequence variants associated with systemic atherosclerosis and coronary atherosclerotic burden but not with venous thromboembolism. J Am Coll Cardiol. 2012;60:722–729.CrossRefPubMedGoogle Scholar
  74. 74.
    Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, Nordestgaard BG. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA. 2009;301:2331–2339.CrossRefPubMedGoogle Scholar
  75. 75.
    Clarke R, Peden JF, Hopewell JC et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med. 2009;361:2518–2528.CrossRefPubMedGoogle Scholar
  76. 76.
    Nave AH, Lange KS, Leonards CO et al. Lipoprotein (a) as a risk factor for ischemic stroke: a meta-analysis. Atherosclerosis. 2015;242:496–503.CrossRefPubMedGoogle Scholar
  77. 77.
    Willeit P, Kiechl S, Kronenberg F et al. Discrimination and net reclassification of cardiovascular risk with lipoprotein(a): prospective 15-year outcomes in the Bruneck Study. J Am Coll Cardiol. 2014;64:851–860.CrossRefPubMedGoogle Scholar
  78. 78.
    Boerwinkle E, Leffert CC, Lin J, Lackner C, Chiesa G, Hobbs HH. Apolipoprotein(a) gene accounts for greater than 90% of the variation in plasma lipoprotein(a) concentrations. J Clin Invest. 1992;90:52–60.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Boffa MB. Emerging Therapeutic Options for Lowering of Lipoprotein(a): Implications for Prevention of Cardiovascular Disease. Curr Atheroscler Rep. 2016;18:69.CrossRefPubMedGoogle Scholar
  80. 80.
    Ranga GS, Kalra OP, Tandon H, Gambhir JK, Mehrotra G. Effect of aspirin on lipoprotein(a) in patients with ischemic stroke. J Stroke Cerebrovasc Dis. 2007;16:220–224.CrossRefPubMedGoogle Scholar
  81. 81.
    Leebmann J, Roeseler E, Julius U et al. Lipoprotein apheresis in patients with maximally tolerated lipid-lowering therapy, lipoprotein(a)-hyperlipoproteinemia, and progressive cardiovascular disease: prospective observational multicenter study. Circulation. 2013;128:2567–2576.CrossRefPubMedGoogle Scholar
  82. 82.
    Davis RA. Cell and molecular biology of the assembly and secretion of apolipoprotein B-containing lipoproteins by the liver. Biochim Biophys Acta. 1999;1440:1–31.CrossRefPubMedGoogle Scholar
  83. 83.
    Akdim F, Visser ME, Tribble DL et al. Effect of mipomersen, an apolipoprotein B synthesis inhibitor, on low-density lipoprotein cholesterol in patients with familial hypercholesterolemia. Am J Cardiol. 2010;105:1413–1419.CrossRefPubMedGoogle Scholar
  84. 84.
    Akdim F, Stroes ES, Sijbrands EJ et al. Efficacy and safety of mipomersen, an antisense inhibitor of apolipoprotein B, in hypercholesterolemic subjects receiving stable statin therapy. J Am Coll Cardiol. 2010;55:1611–1618.CrossRefPubMedGoogle Scholar
  85. 85.
    Stein EA, Dufour R, Gagne C et al. Apolipoprotein B synthesis inhibition with mipomersen in heterozygous familial hypercholesterolemia: results of a randomized, double-blind, placebo-controlled trial to assess efficacy and safety as add-on therapy in patients with coronary artery disease. Circulation. 2012;126:2283–2292.CrossRefPubMedGoogle Scholar
  86. 86.
    McGowan MP, Tardif JC, Ceska R et al. Randomized, placebo-controlled trial of mipomersen in patients with severe hypercholesterolemia receiving maximally tolerated lipid-lowering therapy. PLoS One. 2012;7:e49006.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Raal FJ, Santos RD, Blom DJ et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet. 2010;375:998–1006.CrossRefPubMedGoogle Scholar
  88. 88.
    Duell PB, Santos RD, Kirwan BA, Witztum JL, Tsimikas S, Kastelein JJP. Long-term mipomersen treatment is associated with a reduction in cardiovascular events in patients with familial hypercholesterolemia. J Clin Lipidol. 2016;10:1011–1021.CrossRefPubMedGoogle Scholar
  89. 89.
    Santos RD, Raal FJ, Catapano AL, Witztum JL, Steinhagen-Thiessen E, Tsimikas S. Mipomersen, an antisense oligonucleotide to apolipoprotein B-100, reduces lipoprotein(a) in various populations with hypercholesterolemia: results of 4 phase III trials. Arterioscler Thromb Vasc Biol. 2015;35:689–699.CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Marcovina SM, Albers JJ, Wijsman E, Zhang Z, Chapman NH, Kennedy H. Differences in Lp[a] concentrations and apo[a] polymorphs between black and white Americans. J Lipid Res. 1996;37:2569–2585.PubMedGoogle Scholar
  91. 91.
    Refusal of the marketing authorisation for Kynamro (mipomersen). European Medicines Agency. 2012 [online]. Available at: Accessed December 26, 2018.
  92. 92.
    Tan RY, Markus HS. Monogenic causes of stroke: now and the future. J Neurol. 2015;262:2601–2616.CrossRefPubMedGoogle Scholar
  93. 93.
    Tikka S, Ng YP, Di Maio G et al. CADASIL mutations and shRNA silencing of NOTCH3 affect actin organization in cultured vascular smooth muscle cells. J Cereb Blood Flow Metab. 2012;32:2171–2180.CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Francis J, Raghunathan S, Khanna P. The role of genetics in stroke. Postgrad Med J. 2007;83:590–595.CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Razvi SS, Davidson R, Bone I, Muir KW. The prevalence of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) in the west of Scotland. J Neurol Neurosurg Psychiatry. 2005;76:739–741.CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Chabriat H, Joutel A, Dichgans M, Tournier-Lasserve E, Bousser MG. Cadasil. Lancet Neurol. 2009;8:643–653.CrossRefPubMedGoogle Scholar
  97. 97.
    Andersson ER, Lendahl U. Therapeutic modulation of Notch signalling--are we there yet? Nat Rev Drug Discov. 2014;13:357–378.CrossRefPubMedGoogle Scholar
  98. 98.
    Bersano A, Bedini G, Oskam J et al. CADASIL: Treatment and Management Options. Curr Treat Options Neurol. 2017;19:31.CrossRefPubMedGoogle Scholar
  99. 99.
    Machuca-Parra AI, Bigger-Allen AA, Sanchez AV et al. Therapeutic antibody targeting of Notch3 signaling prevents mural cell loss in CADASIL. J Exp Med. 2017;214:2271–2282.CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Rutten JW, Dauwerse HG, Peters DJ et al. Therapeutic NOTCH3 cysteine correction in CADASIL using exon skipping: in vitro proof of concept. Brain. 2016;139:1123–1135.CrossRefPubMedGoogle Scholar
  101. 101.
    Chung JW, Park SH, Kim N et al. Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification and vascular territory of ischemic stroke lesions diagnosed by diffusion-weighted imaging. J Am Heart Assoc. 2014;3.Google Scholar
  102. 102.
    Fisher M, Henninger N. Translational research in stroke: taking advances in the pathophysiology and treatment of stroke from the experimental setting to clinical trials. Curr Neurol Neurosci Rep. 2007;7:35–41.CrossRefPubMedGoogle Scholar
  103. 103.
    Saver JL. Time is brain--quantified. Stroke. 2006;37:263–266.CrossRefPubMedGoogle Scholar
  104. 104.
    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;333:1581–1587.Google Scholar
  105. 105.
    Hacke W, Kaste M, Fieschi C et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA. 1995;274:1017–1025.CrossRefPubMedGoogle Scholar
  106. 106.
    Hacke W, Kaste M, Fieschi C et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet. 1998;352:1245–1251.CrossRefPubMedGoogle Scholar
  107. 107.
    Hacke W, Kaste M, Bluhmki E et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359:1317–1329.CrossRefPubMedGoogle Scholar
  108. 108.
    Thomalla G, Simonsen CZ, Boutitie F et al. MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset. N Engl J Med. 2018;379:611–622.CrossRefPubMedGoogle Scholar
  109. 109.
    Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. The NINDS t-PA Stroke Study Group. Stroke. 1997;28:2109–2118.Google Scholar
  110. 110.
    Yaghi S, Willey JZ, Cucchiara B et al. Treatment and Outcome of Hemorrhagic Transformation After Intravenous Alteplase in Acute Ischemic Stroke: A Scientific Statement for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2017;48:e343-e361.PubMedGoogle Scholar
  111. 111.
    Seners P, Turc G, Maier B, Mas JL, Oppenheim C, Baron JC. Incidence and Predictors of Early Recanalization After Intravenous Thrombolysis: A Systematic Review and Meta-Analysis. Stroke. 2016;47:2409–2412.CrossRefPubMedGoogle Scholar
  112. 112.
    Wang YF, Tsirka SE, Strickland S, Stieg PE, Soriano SG, Lipton SA. Tissue plasminogen activator (tPA) increases neuronal damage after focal cerebral ischemia in wild-type and tPA-deficient mice. Nat Med. 1998;4:228–231.CrossRefPubMedGoogle Scholar
  113. 113.
    Tsirka SE, Gualandris A, Amaral DG, Strickland S. Excitotoxin-induced neuronal degeneration and seizure are mediated by tissue plasminogen activator. Nature. 1995;377:340–344.CrossRefPubMedGoogle Scholar
  114. 114.
    Wang X, Lee SR, Arai K et al. Lipoprotein receptor-mediated induction of matrix metalloproteinase by tissue plasminogen activator. Nat Med. 2003;9:1313–1317.CrossRefPubMedGoogle Scholar
  115. 115.
    Bjerregaard N, Botkjaer KA, Helsen N, Andreasen PA, Dupont DM. Tissue-type plasminogen activator-binding RNA aptamers inhibiting low-density lipoprotein receptor family-mediated internalisation. Thromb Haemost. 2015;114:139–149.CrossRefPubMedGoogle Scholar
  116. 116.
    Yepes M, Sandkvist M, Moore EG, Bugge TH, Strickland DK, Lawrence DA. Tissue-type plasminogen activator induces opening of the blood-brain barrier via the LDL receptor-related protein. J Clin Invest. 2003;112:1533–1540.CrossRefPubMedPubMedCentralGoogle Scholar
  117. 117.
    Shen Q, Ren H, Cheng H, Fisher M, Duong TQ. Functional, perfusion and diffusion MRI of acute focal ischemic brain injury. J Cereb Blood Flow Metab. 2005;25:1265–1279.CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Fisher M. The ischemic penumbra: a new opportunity for neuroprotection. Cerebrovasc Dis. 2006;21 Suppl 2:64–70.CrossRefPubMedGoogle Scholar
  119. 119.
    Puyal J, Ginet V, Clarke PG. Multiple interacting cell death mechanisms in the mediation of excitotoxicity and ischemic brain damage: a challenge for neuroprotection. Prog Neurobiol. 2013;105:24–48.CrossRefPubMedGoogle Scholar
  120. 120.
    Goyal M, Hill MD, Saver JL, Fisher M. Challenges and Opportunities of Endovascular Stroke Therapy. Ann Neurol. 2016;79:11–17.CrossRefPubMedGoogle Scholar
  121. 121.
    Bracard S, Ducrocq X, Mas JL et al. Mechanical thrombectomy after intravenous alteplase versus alteplase alone after stroke (THRACE): a randomised controlled trial. Lancet Neurol. 2016;15:1138–1147.CrossRefPubMedGoogle Scholar
  122. 122.
    Jovin TG, Chamorro A, Cobo E et al. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med. 2015;372:2296–2306.CrossRefPubMedGoogle Scholar
  123. 123.
    Saver JL, Goyal M, Bonafe A et al. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. New England Journal of Medicine. 2015;372:2285–2295.CrossRefPubMedGoogle Scholar
  124. 124.
    Goyal M, Demchuk AM, Menon BK et al. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med. 2015;372:1019–1030.CrossRefPubMedGoogle Scholar
  125. 125.
    Berkhemer OA, Fransen PS, Beumer D et al. A randomized trial of intraarterial treatment for acute ischemic stroke. New England Journal of Medicine. 2015;372:11–20.CrossRefPubMedGoogle Scholar
  126. 126.
    Campbell BC, Mitchell PJ, Kleinig TJ et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med. 2015;372:1009–1018.CrossRefPubMedGoogle Scholar
  127. 127.
    Albers GW, Marks MP, Kemp S et al. Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging. N Engl J Med. 2018;378:708–718.CrossRefPubMedGoogle Scholar
  128. 128.
    Nogueira RG, Jadhav AP, Haussen DC et al. Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct. N Engl J Med. 2018;378:11–21.CrossRefPubMedGoogle Scholar
  129. 129.
    Henninger N, Kumar R, Fisher M. Acute ischemic stroke therapy. Expert Rev Cardiovasc Ther. 2010;8:1389–1398.CrossRefPubMedGoogle Scholar
  130. 130.
    O'Collins VE, Macleod MR, Donnan GA, Horky LL, van der Worp BH, Howells DW. 1,026 experimental treatments in acute stroke. Ann Neurol. 2006;59:467–477.CrossRefPubMedGoogle Scholar
  131. 131.
    Savitz SI, Fisher M. Future of neuroprotection for acute stroke: in the aftermath of the SAINT trials. Ann Neurol. 2007;61:396–402.CrossRefPubMedGoogle Scholar
  132. 132.
    Stroke Therapy Academic Industry R. Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke. 1999;30:2752–2758.CrossRefGoogle Scholar
  133. 133.
    Stroke Therapy Academic Industry R, II. Recommendations for clinical trial evaluation of acute stroke therapies. Stroke. 2001;32:1598–1606.CrossRefGoogle Scholar
  134. 134.
    Fisher M, Feuerstein G, Howells DW et al. Update of the stroke therapy academic industry roundtable preclinical recommendations. Stroke. 2009;40:2244–2250.CrossRefPubMedPubMedCentralGoogle Scholar
  135. 135.
    Saver JL, Jovin TG, Smith WS et al. Stroke treatment academic industry roundtable: research priorities in the assessment of neurothrombectomy devices. Stroke. 2013;44:3596–3601.CrossRefPubMedPubMedCentralGoogle Scholar
  136. 136.
    Sena E, van der Worp HB, Howells D, Macleod M. How can we improve the pre-clinical development of drugs for stroke? Trends Neurosci. 2007;30:433–439.CrossRefPubMedGoogle Scholar
  137. 137.
    Henninger N, Bratane BT, Bastan B, Bouley J, Fisher M. Normobaric hyperoxia and delayed tPA treatment in a rat embolic stroke model. J Cereb Blood Flow Metab. 2009;29:119–129.CrossRefPubMedGoogle Scholar
  138. 138.
    Bardutzky J, Meng X, Bouley J, Duong TQ, Ratan R, Fisher M. Effects of intravenous dimethyl sulfoxide on ischemia evolution in a rat permanent occlusion model. J Cereb Blood Flow Metab. 2005;25:968–977.CrossRefPubMedPubMedCentralGoogle Scholar
  139. 139.
    Terpolilli NA, Kim SW, Thal SC et al. Inhalation of nitric oxide prevents ischemic brain damage in experimental stroke by selective dilatation of collateral arterioles. Circ Res. 2012;110:727–738.CrossRefPubMedGoogle Scholar
  140. 140.
    Sorensen SS, Nygaard AB, Nielsen MY, Jensen K, Christensen T. miRNA expression profiles in cerebrospinal fluid and blood of patients with acute ischemic stroke. Transl Stroke Res. 2014;5:711–718.CrossRefPubMedGoogle Scholar
  141. 141.
    Di Y, Lei Y, Yu F, Changfeng F, Song W, Xuming M. MicroRNAs expression and function in cerebral ischemia reperfusion injury. J Mol Neurosci. 2014;53:242–250.CrossRefPubMedGoogle Scholar
  142. 142.
    Yuan Y, Kang R, Yu Y et al. Crosstalk between miRNAs and their regulated genes network in stroke. Sci Rep. 2016;6:20429.CrossRefPubMedPubMedCentralGoogle Scholar
  143. 143.
    Baczynska D, Michalowska D, Witkiewicz W. The role of microRNA in ischemic diseases--impact on the regulation of inflammatory apoptosis and angiogenesis processes, Przegl Lek. 2013;70:135–142.PubMedGoogle Scholar
  144. 144.
    Sun H, Zhong D, Jin J, Liu Q, Wang H, Li G. Upregulation of miR-215 exerts neuroprotection effects against ischemic injury via negative regulation of Act1/IL-17RA signaling. Neurosci Lett. 2018;662:233–241.CrossRefPubMedGoogle Scholar
  145. 145.
    Wu-Wong JR, Nakane M, Ma J. Vitamin D analogs modulate the expression of plasminogen activator inhibitor-1, thrombospondin-1 and thrombomodulin in human aortic smooth muscle cells. J Vasc Res. 2007;44:11–18.CrossRefPubMedGoogle Scholar
  146. 146.
    Hacke W, Schwab S, Horn M, Spranger M, De Georgia M, von Kummer R. 'Malignant' middle cerebral artery territory infarction: clinical course and prognostic signs. Arch Neurol. 1996;53:309–315.CrossRefPubMedGoogle Scholar
  147. 147.
    Vahedi K, Hofmeijer J, Juettler E et al. Early decompressive surgery in malignant infarction of the middle cerebral artery: a pooled analysis of three randomised controlled trials. Lancet Neurol. 2007;6:215–222.CrossRefPubMedGoogle Scholar
  148. 148.
    Xu X, Wen Z, Zhao N et al. MicroRNA-1906, a Novel Regulator of Toll-Like Receptor 4, Ameliorates Ischemic Injury after Experimental Stroke in Mice. J Neurosci. 2017;37:10498–10515.CrossRefPubMedGoogle Scholar
  149. 149.
    Ouyang YB. Inflammation and stroke. Neurosci Lett. 2013;548:1–3.CrossRefPubMedGoogle Scholar
  150. 150.
    Ouyang YB, Stary CM, Yang GY, Giffard R. microRNAs: innovative targets for cerebral ischemia and stroke. Curr Drug Targets. 2013;14:90–101.CrossRefPubMedPubMedCentralGoogle Scholar
  151. 151.
    Di G, Wang Z, Wang W, Cheng F, Liu H. AntagomiR-613 protects neuronal cells from oxygen glucose deprivation/re-oxygenation via increasing SphK2 expression. Biochem Biophys Res Commun. 2017;493:188–194.CrossRefPubMedGoogle Scholar
  152. 152.
    Yao X, Wang Y, Zhang D. microRNA-21 Confers Neuroprotection Against Cerebral Ischemia-Reperfusion Injury and Alleviates Blood-Brain Barrier Disruption in Rats via the MAPK Signaling Pathway. J Mol Neurosci. 2018;65:43–53.CrossRefPubMedGoogle Scholar
  153. 153.
    Song S, Lin F, Zhu P et al. Extract of Spatholobus suberctus Dunn ameliorates ischemia-induced injury by targeting miR-494. PLoS One. 2017;12:e0184348.CrossRefPubMedPubMedCentralGoogle Scholar
  154. 154.
    Toyama T, Wada-Takahashi S, Takamichi M et al. Reactive oxygen species scavenging activity of Jixueteng evaluated by electron spin resonance (ESR) and photon emission. Nat Prod Commun. 2014;9:1755–1759.PubMedGoogle Scholar
  155. 155.
    Bazan HA, Hatfield SA, Brug A, Brooks AJ, Lightell DJ, Jr., Woods TC. Carotid Plaque Rupture Is Accompanied by an Increase in the Ratio of Serum circR-284 to miR-221 Levels. Circ Cardiovasc Genet. 2017;10.Google Scholar
  156. 156.
    Sheth KN, Elm JJ, Molyneaux BJ et al. Safety and efficacy of intravenous glyburide on brain swelling after large hemispheric infarction (GAMES-RP): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2016;15:1160–1169.CrossRefPubMedGoogle Scholar
  157. 157.
    Zador Z, Stiver S, Wang V, Manley GT. Role of aquaporin-4 in cerebral edema and stroke. Handb Exp Pharmacol. 2009:159–170.Google Scholar
  158. 158.
    Pirici I, Balsanu TA, Bogdan C et al. Inhibition of Aquaporin-4 Improves the Outcome of Ischaemic Stroke and Modulates Brain Paravascular Drainage Pathways. Int J Mol Sci. 2017;19.Google Scholar
  159. 159.
    Nicchia GP, Frigeri A, Liuzzi GM, Svelto M. Inhibition of aquaporin-4 expression in astrocytes by RNAi determines alteration in cell morphology, growth, and water transport and induces changes in ischemia-related genes. Faseb j. 2003;17:1508–1510.CrossRefPubMedGoogle Scholar
  160. 160.
    Cramer SC. Treatments to Promote Neural Repair after Stroke. J Stroke. 2018;20:57–70.CrossRefPubMedPubMedCentralGoogle Scholar
  161. 161.
    Zhang ZG, Chopp M. Neurorestorative therapies for stroke: underlying mechanisms and translation to the clinic. Lancet Neurol. 2009;8:491–500.CrossRefPubMedPubMedCentralGoogle Scholar
  162. 162.
    Dancause N, Barbay S, Frost SB et al. Extensive cortical rewiring after brain injury. J Neurosci. 2005;25:10167–10179.CrossRefPubMedGoogle Scholar
  163. 163.
    Chopp M, Li Y, Zhang ZG. Mechanisms underlying improved recovery of neurological function after stroke in the rodent after treatment with neurorestorative cell-based therapies. Stroke. 2009;40:S143–145.CrossRefPubMedGoogle Scholar
  164. 164.
    Jones TA, Kleim JA, Greenough WT. Synaptogenesis and dendritic growth in the cortex opposite unilateral sensorimotor cortex damage in adult rats: a quantitative electron microscopic examination. Brain Res. 1996;733:142–148.CrossRefPubMedGoogle Scholar
  165. 165.
    Ding G, Jiang Q, Li L et al. Magnetic resonance imaging investigation of axonal remodeling and angiogenesis after embolic stroke in sildenafil-treated rats. J Cereb Blood Flow Metab. 2008;28:1440–1448.CrossRefPubMedPubMedCentralGoogle Scholar
  166. 166.
    Clarkson AN, Huang BS, Macisaac SE, Mody I, Carmichael ST. Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke. Nature. 2010;468:305–309.CrossRefPubMedPubMedCentralGoogle Scholar
  167. 167.
    Hermann DM, Chopp M. Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation. Lancet Neurol. 2012;11:369–380.CrossRefPubMedPubMedCentralGoogle Scholar
  168. 168.
    Chollet F, Tardy J, Albucher JF et al. Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial. Lancet Neurol. 2011;10:123–130.CrossRefPubMedGoogle Scholar
  169. 169.
    Graham C, Lewis S, Forbes J et al. The FOCUS, AFFINITY and EFFECTS trials studying the effect(s) of fluoxetine in patients with a recent stroke: statistical and health economic analysis plan for the trials and for the individual patient data meta-analysis. Trials. 2017;18:627.CrossRefPubMedPubMedCentralGoogle Scholar
  170. 170.
    Carmichael ST. Gene expression changes after focal stroke, traumatic brain and spinal cord injuries. Curr Opin Neurol. 2003;16:699–704.CrossRefPubMedGoogle Scholar
  171. 171.
    Liu XS, Zhang ZG, Zhang RL et al. Stroke induces gene profile changes associated with neurogenesis and angiogenesis in adult subventricular zone progenitor cells. J Cereb Blood Flow Metab. 2007;27:564–574.CrossRefPubMedGoogle Scholar
  172. 172.
    Costa A, Afonso J, Osorio C et al. miR-363-5p regulates endothelial cell properties and their communication with hematopoietic precursor cells. J Hematol Oncol. 2013;6:87.CrossRefPubMedPubMedCentralGoogle Scholar
  173. 173.
    Pecot CV, Rupaimoole R, Yang D et al. Tumour angiogenesis regulation by the miR-200 family. Nat Commun. 2013;4:2427.CrossRefPubMedPubMedCentralGoogle Scholar
  174. 174.
    Suarez Y, Fernandez-Hernando C, Pober JS, Sessa WC. Dicer dependent microRNAs regulate gene expression and functions in human endothelial cells. Circ Res. 2007;100:1164–1173.CrossRefPubMedGoogle Scholar
  175. 175.
    Huang X, Le QT, Giaccia AJ. MiR-210--micromanager of the hypoxia pathway. Trends Mol Med. 2010;16:230–237.CrossRefPubMedPubMedCentralGoogle Scholar
  176. 176.
    Liu DZ, Tian Y, Ander BP et al. Brain and blood microRNA expression profiling of ischemic stroke, intracerebral hemorrhage, and kainate seizures. J Cereb Blood Flow Metab. 2010;30:92–101.CrossRefPubMedGoogle Scholar
  177. 177.
    Yin KJ, Hamblin M, Chen YE. Angiogenesis-regulating microRNAs and Ischemic Stroke. Curr Vasc Pharmacol. 2015;13:352–365.CrossRefPubMedPubMedCentralGoogle Scholar
  178. 178.
    Yang X, Tang X, Sun P et al. MicroRNA-15a/16-1 Antagomir Ameliorates Ischemic Brain Injury in Experimental Stroke. Stroke. 2017;48:1941–1947.CrossRefPubMedPubMedCentralGoogle Scholar
  179. 179.
    Caballero-Garrido E, Pena-Philippides JC, Lordkipanidze T et al. In Vivo Inhibition of miR-155 Promotes Recovery after Experimental Mouse Stroke. J Neurosci. 2015;35:12446–12464.CrossRefPubMedPubMedCentralGoogle Scholar
  180. 180.
    Zhang Y, Ueno Y, Liu XS et al. The MicroRNA-17-92 cluster enhances axonal outgrowth in embryonic cortical neurons. J Neurosci. 2013;33:6885–6894.CrossRefPubMedPubMedCentralGoogle Scholar
  181. 181.
    Xin H, Katakowski M, Wang F et al. MicroRNA cluster miR-17-92 Cluster in Exosomes Enhance Neuroplasticity and Functional Recovery After Stroke in Rats. Stroke. 2017;48:747–753.CrossRefPubMedPubMedCentralGoogle Scholar
  182. 182.
    Bouley J, Fisher M, Henninger N. Comparison between coated vs. uncoated suture middle cerebral artery occlusion in the rat as assessed by perfusion/diffusion weighted imaging. Neurosci Lett. 2007;412:185–190.CrossRefPubMedGoogle Scholar
  183. 183.
    Henninger N, Sicard KM, Schmidt KF, Bardutzky J, Fisher M. Comparison of ischemic lesion evolution in embolic versus mechanical middle cerebral artery occlusion in Sprague Dawley rats using diffusion and perfusion imaging. Stroke. 2006;37:1283–1287.CrossRefPubMedGoogle Scholar
  184. 184.
    Zaidi SF, Aghaebrahim A, Urra X et al. Final infarct volume is a stronger predictor of outcome than recanalization in patients with proximal middle cerebral artery occlusion treated with endovascular therapy. Stroke. 2012;43:3238–3244.CrossRefPubMedGoogle Scholar
  185. 185.
    Yoo AJ, Chaudhry ZA, Nogueira RG et al. Infarct Volume Is a Pivotal Biomarker After Intra-Arterial Stroke Therapy. Stroke. 2012.Google Scholar
  186. 186.
    Schiemanck SK, Kwakkel G, Post MW, Prevo AJ. Predictive value of ischemic lesion volume assessed with magnetic resonance imaging for neurological deficits and functional outcome poststroke: A critical review of the literature. Neurorehabil Neural Repair. 2006;20:492–502.CrossRefPubMedGoogle Scholar
  187. 187.
    Ay H, Furie KL, Singhal A, Smith WS, Sorensen AG, Koroshetz WJ. An evidence-based causative classification system for acute ischemic stroke. Ann Neurol. 2005;58:688–697.CrossRefPubMedGoogle Scholar
  188. 188.
    Amarenco P, Bogousslavsky J, Caplan LR, Donnan GA, Hennerici MG. Classification of stroke subtypes. Cerebrovasc Dis. 2009;27:493–501.CrossRefPubMedGoogle Scholar
  189. 189.
    Liu X, Cheng Y, Yang J, Xu L, Zhang C. Cell-specific effects of miR-221/222 in vessels: molecular mechanism and therapeutic application. J Mol Cell Cardiol. 2012;52:245–255.CrossRefPubMedGoogle Scholar
  190. 190.
    Matthews H, Hanison J, Nirmalan N. “Omics”-Informed Drug and Biomarker Discovery: Opportunities, Challenges and Future Perspectives. Proteomes. 2016;4.Google Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2019

Authors and Affiliations

  1. 1.Department of NeurologyUniversity of Massachusetts Medical SchoolWorcesterUSA
  2. 2.Department of PsychiatryUniversity of Massachusetts Medical SchoolWorcesterUSA
  3. 3.Division of Neurocritical Care, Department of Anesthesiology and Critical Care MedicineJohns Hopkins UniversityBaltimoreUSA

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