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Clinical Trials for Neuroprotective Therapies in Intracerebral Hemorrhage: A New Roadmap from Bench to Bedside

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Abstract

The most deadly form of stroke, intracerebral hemorrhage (ICH) continues to puzzle researchers and produce substantial decrements in the quality of patients’ lives. Intensive basic research has devised many agents with putative benefit in mitigating the devastating effects of ICH, but these therapies have been largely ineffective in the transition to clinical trials. However, a steady translational pipeline continues to provide new avenues of treatment that may be effective in the management of this condition. In this review, we aim to summarize the array of neuroprotective clinical trials and techniques used in the history of ICH, and delineate the progression of relevant research to date. Furthermore, we provide insight into methods that may allow for better translation of basic science advances into productive clinical trials.

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References

  1. Qureshi AI, Mendelow AD, Hanley DF. Intracerebral haemorrhage. Lancet. 2009;373:1632–44.

    Article  PubMed  Google Scholar 

  2. Adeoye O, Ringer A, Hornung R, Khatri P, Zuccarello M, Kleindorfer D. Trends in surgical management and mortality of intracerebral hemorrhage in the united states before and after the stich trial. Neurocrit Care. 2010.

  3. Mendelow AD, Gregson BA, Fernandes HM, Murray GD, Teasdale GM, Hope DT, Karimi A, Shaw MDM, Barer DH, STICH investigators. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the international surgical trial in intracerebral haemorrhage (stich): A randomised trial. Lancet. 2005;365:387–97.

    PubMed  Google Scholar 

  4. Mendelow AD, Unterberg A. Surgical treatment of intracerebral haemorrhage. Curr Opin Crit Care. 2007;13:169–74.

    Article  PubMed  Google Scholar 

  5. Delcourt C, Huang Y, Wang J, Heeley E, Lindley R, Stapf C, Tzourio C, Arima H, Parsons M, Sun J, Neal B, Chalmers J, Anderson C, Investigators I. The second (main) phase of an open, randomised, multicentre study to investigate the effectiveness of an intensive blood pressure reduction in acute cerebral haemorrhage trial (interact2). Int J Stroke. 2010;5:110–6.

    Article  PubMed  CAS  Google Scholar 

  6. Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) investigators. Antihypertensive treatment of acute cerebral hemorrhage. Crit Care Med. 2010;38:637–48.

    Article  Google Scholar 

  7. Qureshi AI. Antihypertensive treatment of acute cerebral hemorrhage (ATACH): rationale and design. Neurocrit Care. 2007;6:56–66.

    Article  PubMed  CAS  Google Scholar 

  8. Schrot RJ, Muizelaar JP. Mannitol in acute traumatic brain injury. Lancet. 2002;359:1633–4.

    Article  PubMed  Google Scholar 

  9. Hwang BY, Appelboom G, Ayer A, Kellner CP, Kotchetkov IS, Gigante PR, Haque R, Kellner M, Connolly ES. Advances in neuroprotective strategies: potential therapies for intracerebral hemorrhage. Cerebrovasc Dis. 2011;31:211–22.

    Article  PubMed  Google Scholar 

  10. Xue M, Yong VW. Matrix metalloproteinases in intracerebral hemorrhage. Neurol Res. 2008;30:775–82.

    Article  PubMed  Google Scholar 

  11. Lyden P, Wahlgren NG. Mechanisms of action of neuroprotectants in stroke. J Stroke Cerebrovasc Dis. 2000;9:9–14.

    Article  PubMed  CAS  Google Scholar 

  12. Sacco RL, DeRosa JT, Haley EC Jr, Levin B, Ordronneau P, Phillips SJ, Rundek T, Snipes RG, Thompson JL, Glycine Antagonist in Neuroprotection (GAIN) Americas Investigators. Glycine antagonist in neuroprotection for patients with acute stroke: GAIN Americas: a randomized controlled trial. JAMA. 2001;285:1719–28.

    Article  PubMed  CAS  Google Scholar 

  13. The North American Glycine Antagonist in Neuroprotection (GAIN) Investigators. Phase II studies of the glycine antagonist gv150526 in acute stroke: the north American experience. The north American glycine antagonist in neuroprotection (gain) investigators. Stroke. 2000;31:358–65.

    Article  Google Scholar 

  14. Lees KR, Lavelle JF, Cunha L, Diener HC, Sanders EA, Tack P, Wester P, Group GPIES. Glycine antagonist (gv150526) in acute stroke: a multicentre, double-blind placebo-controlled phase II trial. Cerebrovasc Dis. 2001;11:20–9.

    Article  PubMed  CAS  Google Scholar 

  15. Yam PS, Dunn LT, Graham DI, Dewar D, McCulloch J. NMDA receptor blockade fails to alter axonal injury in focal cerebral ischemia. J Cereb Blood Flow Metab. 2000;20:772–9.

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  17. Lyden PD, Shuaib A, Lees KR, Davalos A, Davis SM, Diener H-C, Grotta JC, Ashwood TJ, Hardemark H-G, Svensson HH, Rodichok L, Wasiewski WW, Ahlberg G, Investigators CT. Safety and tolerability of nxy-059 for acute intracerebral hemorrhage: The chant trial. Stroke. 2007;38:2262–9.

    Article  PubMed  CAS  Google Scholar 

  18. Iranmanesh F, Vakilian A. Efficiency of citicoline in increasing muscular strength of patients with nontraumatic cerebral hemorrhage: a double-blind randomized clinical trial. J Stroke Cerebrovasc Dis. 2008;17:153–5.

    Article  PubMed  Google Scholar 

  19. Clark W, Gunion-Rinker L, Lessov N, Hazel K. Citicoline treatment for experimental intracerebral hemorrhage in mice. Stroke. 1998;29:2136–40.

    Article  PubMed  CAS  Google Scholar 

  20. Secades JJ, Alvarez-Sabin J, Rubio F, Lozano R, Davalos A, Castillo J. Citicoline in intracerebral haemorrhage: a double-blind, randomized, placebo-controlled, multi-centre pilot study. Cerebrovasc Dis. 2006;21:380–5.

    Article  PubMed  CAS  Google Scholar 

  21. Gomis M, Ois A, Rodríguez-Campello A, Cuadrado-Godia E, Jiménez-Conde J, Subirana I, Dávalos A, Roquer J. Outcome of intracerebral haemorrhage patients pre-treated with statins. Eur J Neurol. 2010;17:443–8.

    Article  PubMed  CAS  Google Scholar 

  22. Karki K, Knight RA, Han Y, Yang D, Zhang J, Ledbetter KA, Chopp M, Seyfried DM. Simvastatin and atorvastatin improve neurological outcome after experimental intracerebral hemorrhage. Stroke. 2009;40:3384–9.

    Article  PubMed  CAS  Google Scholar 

  23. Leker RR, Khoury ST, Rafaeli G, Shwartz R, Eichel R, Tanne D, Investigators N. Prior use of statins improves outcome in patients with intracerebral hemorrhage: prospective data from the national acute stroke israeli surveys (nasis). Stroke. 2009;40:2581–4.

    Article  PubMed  CAS  Google Scholar 

  24. Naval NS, Abdelhak TA, Urrunaga N, Zeballos P, Mirski MA, Carhuapoma JR. An association of prior statin use with decreased perihematomal edema. Neurocrit Care. 2008;8:13–8.

    Article  PubMed  Google Scholar 

  25. Naval NS, Abdelhak TA, Zeballos P, Urrunaga N, Mirski MA, Carhuapoma JR. Prior statin use reduces mortality in intracerebral hemorrhage. Neurocrit Care. 2008;8:6–12.

    Article  PubMed  Google Scholar 

  26. Naval NS, Mirski MA, Carhuapoma JR. Impact of statins on validation of ich mortality prediction models. Neurol Res. 2009;31:425–9.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  28. Tapia-Perez H, Sanchez-Aguilar M, Torres-Corzo JG, Rodriguez-Leyva I, Gonzalez-Aguirre D, Gordillo-Moscoso A, Chalita-Williams C. Use of statins for the treatment of spontaneous intracerebral hemorrhage: results of a pilot study. Cen Eur Neurosurg. 2009;70:15–20.

    Article  CAS  Google Scholar 

  29. Dowlatshahi D, Demchuk AM, Fang J, Kapral MK, Sharma M, Smith EE. Association of statins and statin discontinuation with poor outcome and survival after intracerebral hemorrhage. Stroke J Cereb Circ. 2012;43:1518–23.

    Article  CAS  Google Scholar 

  30. McKinney JS, Kostis WJ. Statin therapy and the risk of intracerebral hemorrhage: a meta-analysis of 31 randomized controlled trials. Stroke; a journal of cerebral circulation. Stroke. 2012;43(8):2149–56.

    Google Scholar 

  31. Selim M, Yeatts S, Goldstein JN, Gomes J, Greenberg S, Morgenstern LB, Schlaug G, Torbey M, Waldman B, Xi G, Palesch Y. Safety and tolerability of deferoxamine mesylate in patients with acute intracerebral hemorrhage. Stroke J Cereb Circ. 2011;42:3067–74.

    Article  CAS  Google Scholar 

  32. Vaughan CJ, Murphy MB, Buckley BM. Statins do more than just lower cholesterol. Lancet. 1996;348:1079–82.

    Article  PubMed  CAS  Google Scholar 

  33. Endres M, Laufs U. Effects of statins on endothelium and signaling mechanisms. Stroke. 2004;35:2708–11.

    Article  PubMed  CAS  Google Scholar 

  34. Wang J, Doré S. Inflammation after intracerebral hemorrhage. J Cereb Blood Flow Metab. 2007;27:894–908.

    Article  PubMed  CAS  Google Scholar 

  35. Nakamura T, Keep RF, Hua Y, Hoff JT, Xi G. Oxidative DNA injury after experimental intracerebral hemorrhage. Brain Res. 2005;1039:30–6.

    Article  PubMed  CAS  Google Scholar 

  36. Davis SM, Broderick J, Hennerici M, Brun NC, Diringer MN, Mayer SA, Begtrup K, Steiner T, Investigators RAFVIHT. Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage. Neurology. 2006;66:1175–81.

    Article  PubMed  CAS  Google Scholar 

  37. Gebel JM, Jauch EC, Brott TG, Khoury J, Sauerbeck L, Salisbury S, Spilker J, Tomsick TA, Duldner J, Broderick JP. Relative edema volume is a predictor of outcome in patients with hyperacute spontaneous intracerebral hemorrhage. Stroke. 2002;33:2636–41.

    Article  PubMed  Google Scholar 

  38. Tapia-Pérez H, González-Aguirre D, Sánchez-Aguilar M, Torres-Corzo J, Rodríguez-Leyva I, Gordillo-Moscoso A. Evaluation of changes in the treatment of spontaneous intracerebral haemorrhage in a regional hospital in mexico. Rev Neurol. 2010;50:201–6.

    PubMed  Google Scholar 

  39. Park H-K, Lee S-H, Chu K, Roh J-K. Effects of celecoxib on volumes of hematoma and edema in patients with primary intracerebral hemorrhage. J Neurol Sci. 2009;279:43–6.

    Article  PubMed  CAS  Google Scholar 

  40. Chu K, Jeong S-W, Jung K-H, Han S-Y, Lee S-T, Kim M, Roh J-K. Celecoxib induces functional recovery after intracerebral hemorrhage with reduction of brain edema and perihematomal cell death. J Cereb Blood Flow Metab. 2004;24:926–33.

    Article  PubMed  CAS  Google Scholar 

  41. Sinn D-I, Lee S-T, Chu K, Jung K-H, Song E-C, Kim J-M, Park D-K, Kim M, Roh J-K. Combined neuroprotective effects of celecoxib and memantine in experimental intracerebral hemorrhage. Neurosci Lett. 2007;411:238–42.

    Article  PubMed  CAS  Google Scholar 

  42. Nakamura T, Keep RF, Hua Y, Schallert T, Hoff JT, Xi G. Deferoxamine-induced attenuation of brain edema and neurological deficits in a rat model of intracerebral hemorrhage. Neurosurg Focus. 2003;15:ECP4.

    Article  PubMed  Google Scholar 

  43. Okauchi M, Hua Y, Keep RF, Morgenstern LB, Xi G. Effects of deferoxamine on intracerebral hemorrhage-induced brain injury in aged rats. Stroke. 2009;40:1858–63.

    Article  PubMed  CAS  Google Scholar 

  44. Selim M. Deferoxamine mesylate: a new hope for intracerebral hemorrhage: From bench to clinical trials. Stroke. 2009;40:S90–1.

    Article  PubMed  CAS  Google Scholar 

  45. Hua Y, Keep R, Hoff J, Xi G. Brain injury after intracerebral hemorrhage: the role of thrombin and iron. Stroke. 2007;38:759.

    Article  PubMed  CAS  Google Scholar 

  46. Kase CS. Intracerebral haemorrhage. Baillieres Clin Neurol. 1995;4:247–78.

    PubMed  CAS  Google Scholar 

  47. Ducruet AF, Zacharia BE, Hickman ZL, Grobelny BT, Yeh ML, Sosunov SA, Connolly Jr ES. The complement cascade as a therapeutic target in intracerebral hemorrhage. Exp Neurol. 2009;219:398–403.

    Article  PubMed  CAS  Google Scholar 

  48. Xi G, Hua Y, Keep R, Younger J, Hoff J. Systemic complement depletion diminishes perihematomal brain edema in rats. Stroke. 2001;32:162.

    Article  PubMed  CAS  Google Scholar 

  49. Qing WG, Dong YQ, Ping TQ, Lai LG, Fang LD, Min HW, Xia L, Heng PY. Brain edema after intracerebral hemorrhage in rats: the role of iron overload and aquaporin 4. J Neurosurg. 2009;110:462–8.

    Article  PubMed  Google Scholar 

  50. Zaman K, Ryu H, Hall D, O’Donovan K, Lin KI, Miller MP, Marquis JC, Baraban JM, Semenza GL, Ratan RR. Protection from oxidative stress-induced apoptosis in cortical neuronal cultures by iron chelators is associated with enhanced DNA binding of hypoxia-inducible factor-1 and atf-1/creb and increased expression of glycolytic enzymes, p21(waf1/cip1), and erythropoietin. J Neurosci. 1999;19:9821–30.

    PubMed  CAS  Google Scholar 

  51. Tanji K, Imaizumi T, Matsumiya T, Itaya H, Fujimoto K, Cui X, Toki T, Ito E, Yoshida H, Wakabayashi K, Satoh K. Desferrioxamine, an iron chelator, upregulates cyclooxygenase-2 expression and prostaglandin production in a human macrophage cell line. Biochim Biophys Acta. 2001;1530:227–35.

    Article  PubMed  CAS  Google Scholar 

  52. Regan RF, Panter SS. Hemoglobin potentiates excitotoxic injury in cortical cell culture. J Neurotrauma. 1996;13:223–31.

    PubMed  CAS  Google Scholar 

  53. Lee S-R, Kim H-Y, Hong J-S, Baek W-K, Park J-W. PPARgamma agonist pioglitazone reduces matrix metalloproteinase-9 activity and neuronal damage after focal cerebral ischemia. Biochem Biophys Res Commun. 2009;380:17–21.

    Article  PubMed  CAS  Google Scholar 

  54. Zhao X, Grotta J, Gonzales N, Aronowski J. Hematoma resolution as a therapeutic target: the role of microglia/macrophages. Stroke. 2009;40:S92–4.

    Article  PubMed  CAS  Google Scholar 

  55. Hyong A, Jadhav V, Lee S, Tong W, Rowe J, Zhang JH, Tang J. Rosiglitazone, a PPAR gamma agonist, attenuates inflammation after surgical brain injury in rodents. Brain Res. 2008;1215:218–24.

    Article  PubMed  CAS  Google Scholar 

  56. Xi G, Keep RF, Hoff JT. Mechanisms of brain injury after intracerebral haemorrhage. Lancet Neurol. 2006;5:53–63.

    Article  PubMed  Google Scholar 

  57. Rodrigues CM, Sola S, Nan Z, Castro RE, Ribeiro PS, Low WC, Steer CJ. Tauroursodeoxycholic acid reduces apoptosis and protects against neurological injury after acute hemorrhagic stroke in rats. Proc Natl Acad Sci U S A. 2003;100:6087–92.

    Article  PubMed  CAS  Google Scholar 

  58. Albers GW, Goldstein LB, Hess DC, Wechsler LR, Furie KL, Gorelick PB, Hurn P, Liebeskind DS, Nogueira RG, Saver JL. Stroke treatment academic industry roundtable (stair) recommendations for maximizing the use of intravenous thrombolytics and expanding treatment options with intra-arterial and neuroprotective therapies. Stroke J Cereb Circ. 2011;42:2645–50.

    Article  Google Scholar 

  59. Savitz SI, Fisher M. Future of neuroprotection for acute stroke: in the aftermath of the saint trials. Ann Neurol. 2007;61:396–402.

    Article  PubMed  CAS  Google Scholar 

  60. Baron JC, von Kummer R, del Zoppo GJ. Treatment of acute ischemic stroke. Challenging the concept of a rigid and universal time window. Stroke J Cereb Circ. 1995;26:2219–21.

    Article  CAS  Google Scholar 

  61. Gladstone DJ, Black SE, Hakim AM. Toward wisdom from failure: lessons from neuroprotective stroke trials and new therapeutic directions. Stroke J Cereb Circ. 2002;33:2123–36.

    Article  Google Scholar 

  62. Wasserman JK, Schlichter LC. Neuron death and inflammation in a rat model of intracerebral hemorrhage: effects of delayed minocycline treatment. Brain Res. 2007;1136:208–18.

    Article  PubMed  CAS  Google Scholar 

  63. Maletic-Savatic M, Malinow R, Svoboda K. Rapid dendritic morphogenesis in ca1 hippocampal dendrites induced by synaptic activity. Science. 1999;283:1923–7.

    Article  PubMed  CAS  Google Scholar 

  64. Lee JC, Cho GS, Choi BO, Kim HC, Kim YS, Kim WK. Intracerebral hemorrhage-induced brain injury is aggravated in senescence-accelerated prone mice. Stroke J Cereb Circ. 2006;37:216–22.

    Article  Google Scholar 

  65. Gong Y, Xi G, Wan S, Gu Y, Keep RF, Hua Y. Effects of aging on complement activation and neutrophil infiltration after intracerebral hemorrhage. Acta Neurochir Suppl. 2008;105:67–70.

    Article  PubMed  CAS  Google Scholar 

  66. Wasserman JK, Yang H, Schlichter LC. Glial responses, neuron death and lesion resolution after intracerebral hemorrhage in young vs. Aged rats. Eur J Neurosci. 2008;28:1316–28.

    Article  PubMed  Google Scholar 

  67. Thiex R, Kuker W, Muller HD, Rohde I, Schroder JM, Gilsbach JM, Rohde V. The long-term effect of recombinant tissue-plasminogen-activator (rt-pa) on edema formation in a large-animal model of intracerebral hemorrhage. Neurol Res. 2003;25:254–62.

    Article  PubMed  CAS  Google Scholar 

  68. Stys PK. Anoxic and ischemic injury of myelinated axons in cns white matter: from mechanistic concepts to therapeutics. J Cereb Blood Flow Metab. 1998;18:2–25.

    Article  PubMed  CAS  Google Scholar 

  69. Schabitz WR, Li F, Fisher M. The N-methyl-d-aspartate antagonist CNS 1102 protects cerebral gray and white matter from ischemic injury following temporary focal ischemia in rats. Stroke. 2000;31:1709–14.

    Article  PubMed  CAS  Google Scholar 

  70. Danton GH, Dietrich WD. The search for neuroprotective strategies in stroke. AJNR Am J Neuroradiol. 2004;25:181–94.

    PubMed  Google Scholar 

  71. Gigante PR, Appelboom G, Hwang BY, Haque RM, Yeh ML, Ducruet AF, Kellner CP, Gorski J, Keesecker SE, Connolly Jr ES. Isoflurane preconditioning affords functional neuroprotection in a murine model of intracerebral hemorrhage. Acta Neurochir Suppl. 2011;111:141–4.

    Article  PubMed  Google Scholar 

  72. Gidday JM. Pharmacologic preconditioning: translating the promise. Transl Stroke Res. 2010;1:19–30.

    Article  PubMed  CAS  Google Scholar 

  73. Nakamura T, Kuroda Y, Yamashita S, Zhang X, Miyamoto O, Tamiya T, Nagao S, Xi G, Keep RF, Itano T. Edaravone attenuates brain edema and neurologic deficits in a rat model of acute intracerebral hemorrhage. Stroke. 2008;39:463–9.

    Article  PubMed  CAS  Google Scholar 

  74. Lipton S, Chen HS. Paradigm shift in neuroprotective drug development: clinically tolerated nmda receptor inhibition by memantine. Cell Death Differ. 2004;11:18–20.

    Article  PubMed  CAS  Google Scholar 

  75. Barrachina M, Dominguez I, Ambrosio S, Secades J, Lozano R, Ferrer I. Neuroprotective effect of citicoline in 6-hydroxydopamine-lesioned rats and in 6-hydroxydopamine-treated sh-sy5y human neuroblastoma cells. J Neurol Sci. 2003;215:105–10.

    Article  PubMed  CAS  Google Scholar 

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Ayer, A., Hwang, B.Y., Appelboom, G. et al. Clinical Trials for Neuroprotective Therapies in Intracerebral Hemorrhage: A New Roadmap from Bench to Bedside. Transl. Stroke Res. 3, 409–417 (2012). https://doi.org/10.1007/s12975-012-0207-4

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