Skip to main content
Top
Published in: Translational Stroke Research 4/2012

01-12-2012 | Review Article

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

Authors: Amit Ayer, Brian Y. Hwang, Geoffrey Appelboom, E. Sander Connolly Jr.

Published in: Translational Stroke Research | Issue 4/2012

Login to get access

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.
Literature
1.
2.
go back to reference 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. 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.
go back to reference 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 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
4.
go back to reference Mendelow AD, Unterberg A. Surgical treatment of intracerebral haemorrhage. Curr Opin Crit Care. 2007;13:169–74.PubMedCrossRef Mendelow AD, Unterberg A. Surgical treatment of intracerebral haemorrhage. Curr Opin Crit Care. 2007;13:169–74.PubMedCrossRef
5.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
6.
go back to reference Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) investigators. Antihypertensive treatment of acute cerebral hemorrhage. Crit Care Med. 2010;38:637–48.CrossRef Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) investigators. Antihypertensive treatment of acute cerebral hemorrhage. Crit Care Med. 2010;38:637–48.CrossRef
7.
go back to reference Qureshi AI. Antihypertensive treatment of acute cerebral hemorrhage (ATACH): rationale and design. Neurocrit Care. 2007;6:56–66.PubMedCrossRef Qureshi AI. Antihypertensive treatment of acute cerebral hemorrhage (ATACH): rationale and design. Neurocrit Care. 2007;6:56–66.PubMedCrossRef
8.
9.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
10.
go back to reference Xue M, Yong VW. Matrix metalloproteinases in intracerebral hemorrhage. Neurol Res. 2008;30:775–82.PubMedCrossRef Xue M, Yong VW. Matrix metalloproteinases in intracerebral hemorrhage. Neurol Res. 2008;30:775–82.PubMedCrossRef
11.
go back to reference Lyden P, Wahlgren NG. Mechanisms of action of neuroprotectants in stroke. J Stroke Cerebrovasc Dis. 2000;9:9–14.PubMedCrossRef Lyden P, Wahlgren NG. Mechanisms of action of neuroprotectants in stroke. J Stroke Cerebrovasc Dis. 2000;9:9–14.PubMedCrossRef
12.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
13.
go back to reference 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.CrossRef 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.CrossRef
14.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
15.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
16.
go back to reference 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.CrossRef 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.CrossRef
17.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
18.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
19.
go back to reference Clark W, Gunion-Rinker L, Lessov N, Hazel K. Citicoline treatment for experimental intracerebral hemorrhage in mice. Stroke. 1998;29:2136–40.PubMedCrossRef Clark W, Gunion-Rinker L, Lessov N, Hazel K. Citicoline treatment for experimental intracerebral hemorrhage in mice. Stroke. 1998;29:2136–40.PubMedCrossRef
20.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
21.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
22.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
23.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
24.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
25.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
26.
go back to reference Naval NS, Mirski MA, Carhuapoma JR. Impact of statins on validation of ich mortality prediction models. Neurol Res. 2009;31:425–9.PubMedCrossRef Naval NS, Mirski MA, Carhuapoma JR. Impact of statins on validation of ich mortality prediction models. Neurol Res. 2009;31:425–9.PubMedCrossRef
27.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
28.
go back to reference 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.CrossRef 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.CrossRef
29.
go back to reference 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.CrossRef 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.CrossRef
30.
go back to reference 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. 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.
31.
go back to reference 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.CrossRef 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.CrossRef
32.
go back to reference Vaughan CJ, Murphy MB, Buckley BM. Statins do more than just lower cholesterol. Lancet. 1996;348:1079–82.PubMedCrossRef Vaughan CJ, Murphy MB, Buckley BM. Statins do more than just lower cholesterol. Lancet. 1996;348:1079–82.PubMedCrossRef
33.
go back to reference Endres M, Laufs U. Effects of statins on endothelium and signaling mechanisms. Stroke. 2004;35:2708–11.PubMedCrossRef Endres M, Laufs U. Effects of statins on endothelium and signaling mechanisms. Stroke. 2004;35:2708–11.PubMedCrossRef
34.
go back to reference Wang J, Doré S. Inflammation after intracerebral hemorrhage. J Cereb Blood Flow Metab. 2007;27:894–908.PubMedCrossRef Wang J, Doré S. Inflammation after intracerebral hemorrhage. J Cereb Blood Flow Metab. 2007;27:894–908.PubMedCrossRef
35.
go back to reference Nakamura T, Keep RF, Hua Y, Hoff JT, Xi G. Oxidative DNA injury after experimental intracerebral hemorrhage. Brain Res. 2005;1039:30–6.PubMedCrossRef Nakamura T, Keep RF, Hua Y, Hoff JT, Xi G. Oxidative DNA injury after experimental intracerebral hemorrhage. Brain Res. 2005;1039:30–6.PubMedCrossRef
36.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
37.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
38.
go back to reference 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 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
39.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
40.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
41.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
42.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
43.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
44.
go back to reference Selim M. Deferoxamine mesylate: a new hope for intracerebral hemorrhage: From bench to clinical trials. Stroke. 2009;40:S90–1.PubMedCrossRef Selim M. Deferoxamine mesylate: a new hope for intracerebral hemorrhage: From bench to clinical trials. Stroke. 2009;40:S90–1.PubMedCrossRef
45.
go back to reference Hua Y, Keep R, Hoff J, Xi G. Brain injury after intracerebral hemorrhage: the role of thrombin and iron. Stroke. 2007;38:759.PubMedCrossRef Hua Y, Keep R, Hoff J, Xi G. Brain injury after intracerebral hemorrhage: the role of thrombin and iron. Stroke. 2007;38:759.PubMedCrossRef
46.
go back to reference Kase CS. Intracerebral haemorrhage. Baillieres Clin Neurol. 1995;4:247–78.PubMed Kase CS. Intracerebral haemorrhage. Baillieres Clin Neurol. 1995;4:247–78.PubMed
47.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
48.
go back to reference Xi G, Hua Y, Keep R, Younger J, Hoff J. Systemic complement depletion diminishes perihematomal brain edema in rats. Stroke. 2001;32:162.PubMedCrossRef Xi G, Hua Y, Keep R, Younger J, Hoff J. Systemic complement depletion diminishes perihematomal brain edema in rats. Stroke. 2001;32:162.PubMedCrossRef
49.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
50.
go back to reference 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 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
51.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
52.
go back to reference Regan RF, Panter SS. Hemoglobin potentiates excitotoxic injury in cortical cell culture. J Neurotrauma. 1996;13:223–31.PubMed Regan RF, Panter SS. Hemoglobin potentiates excitotoxic injury in cortical cell culture. J Neurotrauma. 1996;13:223–31.PubMed
53.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
54.
go back to reference Zhao X, Grotta J, Gonzales N, Aronowski J. Hematoma resolution as a therapeutic target: the role of microglia/macrophages. Stroke. 2009;40:S92–4.PubMedCrossRef Zhao X, Grotta J, Gonzales N, Aronowski J. Hematoma resolution as a therapeutic target: the role of microglia/macrophages. Stroke. 2009;40:S92–4.PubMedCrossRef
55.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
56.
go back to reference Xi G, Keep RF, Hoff JT. Mechanisms of brain injury after intracerebral haemorrhage. Lancet Neurol. 2006;5:53–63.PubMedCrossRef Xi G, Keep RF, Hoff JT. Mechanisms of brain injury after intracerebral haemorrhage. Lancet Neurol. 2006;5:53–63.PubMedCrossRef
57.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
58.
go back to reference 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.CrossRef 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.CrossRef
59.
go back to reference Savitz SI, Fisher M. Future of neuroprotection for acute stroke: in the aftermath of the saint trials. Ann Neurol. 2007;61:396–402.PubMedCrossRef Savitz SI, Fisher M. Future of neuroprotection for acute stroke: in the aftermath of the saint trials. Ann Neurol. 2007;61:396–402.PubMedCrossRef
60.
go back to reference 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.CrossRef 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.CrossRef
61.
go back to reference 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.CrossRef 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.CrossRef
62.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
63.
go back to reference Maletic-Savatic M, Malinow R, Svoboda K. Rapid dendritic morphogenesis in ca1 hippocampal dendrites induced by synaptic activity. Science. 1999;283:1923–7.PubMedCrossRef Maletic-Savatic M, Malinow R, Svoboda K. Rapid dendritic morphogenesis in ca1 hippocampal dendrites induced by synaptic activity. Science. 1999;283:1923–7.PubMedCrossRef
64.
go back to reference 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.CrossRef 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.CrossRef
65.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
66.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
67.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
68.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
69.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
70.
go back to reference Danton GH, Dietrich WD. The search for neuroprotective strategies in stroke. AJNR Am J Neuroradiol. 2004;25:181–94.PubMed Danton GH, Dietrich WD. The search for neuroprotective strategies in stroke. AJNR Am J Neuroradiol. 2004;25:181–94.PubMed
71.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
72.
go back to reference Gidday JM. Pharmacologic preconditioning: translating the promise. Transl Stroke Res. 2010;1:19–30.PubMedCrossRef Gidday JM. Pharmacologic preconditioning: translating the promise. Transl Stroke Res. 2010;1:19–30.PubMedCrossRef
73.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
74.
go back to reference Lipton S, Chen HS. Paradigm shift in neuroprotective drug development: clinically tolerated nmda receptor inhibition by memantine. Cell Death Differ. 2004;11:18–20.PubMedCrossRef Lipton S, Chen HS. Paradigm shift in neuroprotective drug development: clinically tolerated nmda receptor inhibition by memantine. Cell Death Differ. 2004;11:18–20.PubMedCrossRef
75.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
Metadata
Title
Clinical Trials for Neuroprotective Therapies in Intracerebral Hemorrhage: A New Roadmap from Bench to Bedside
Authors
Amit Ayer
Brian Y. Hwang
Geoffrey Appelboom
E. Sander Connolly Jr.
Publication date
01-12-2012
Publisher
Springer-Verlag
Published in
Translational Stroke Research / Issue 4/2012
Print ISSN: 1868-4483
Electronic ISSN: 1868-601X
DOI
https://doi.org/10.1007/s12975-012-0207-4

Other articles of this Issue 4/2012

Translational Stroke Research 4/2012 Go to the issue