Emerging experimental therapies for intracerebral hemorrhage: targeting mechanisms of secondary brain injury

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Intracerebral hemorrhage (ICH) is associated with a higher degree of morbidity and mortality than other stroke subtypes. Despite this burden, currently approved treatments have demonstrated limited efficacy. To date, therapeutic strategies have principally targeted hematoma expansion and resultant mass effect. However, secondary mechanisms of brain injury are believed to be critical effectors of cell death and neurological outcome following ICH. This article reviews the pathophysiology of secondary brain injury relevant to ICH, examines pertinent experimental models, and highlights emerging therapeutic strategies. Treatment paradigms discussed include thrombin inhibitors, deferoxamine, minocycline, statins, granulocyte-colony stimulating factors, and therapeutic hypothermia. Despite promising experimental and preliminary human data, further studies are warranted prior to effective clinical translation.

Abbreviations used in this paper:BBB = blood-brain barrier; G-CSF = granulocyte colony-stimulating factor; ICH = intracerebral hemorrhage; MMP = matrix metalloproteinase; TNF = tumor necrosis factor.

Intracerebral hemorrhage (ICH) is associated with a higher degree of morbidity and mortality than other stroke subtypes. Despite this burden, currently approved treatments have demonstrated limited efficacy. To date, therapeutic strategies have principally targeted hematoma expansion and resultant mass effect. However, secondary mechanisms of brain injury are believed to be critical effectors of cell death and neurological outcome following ICH. This article reviews the pathophysiology of secondary brain injury relevant to ICH, examines pertinent experimental models, and highlights emerging therapeutic strategies. Treatment paradigms discussed include thrombin inhibitors, deferoxamine, minocycline, statins, granulocyte-colony stimulating factors, and therapeutic hypothermia. Despite promising experimental and preliminary human data, further studies are warranted prior to effective clinical translation.

Abbreviations used in this paper:BBB = blood-brain barrier; G-CSF = granulocyte colony-stimulating factor; ICH = intracerebral hemorrhage; MMP = matrix metalloproteinase; TNF = tumor necrosis factor.

Intracerebral hemorrhage accounts for 10%–15% of all strokes, but is associated with disproportionately high morbidity and mortality rates.63 Nearly 50% of patients with ICH die within 1 month of presentation, and only 20% of survivors achieve functional independence at 6 months.14 Standard management is principally supportive, including airway protection, maintenance of hemodynamic stability, and control of intracranial pressure.4

Extravasation of blood products into brain parenchyma initiates hematoma formation, edema, and cell death.34 Hematoma development and resultant mass effect account for the initial neurological deficits associated with ICH.8,37 Early administration of hemostatic agents46,47 and meticulous blood pressure control1,2,59,60 have been used to limit hematoma expansion. Large studies have examined the impact of reducing clot burden and mass effect through early surgical evacuation and catheter hematoma aspiration.24,48,79 These studies have yielded mixed results.63

Recently, in translational ICH studies the attention of investigators has shifted toward secondary mechanisms of injury following hematoma expansion. The pathophysiological basis of cerebral edema and cell death has been examined in the laboratory. Putative agents targeting mechanisms of secondary brain injury have been assessed in animal ICH models and clinical trials. Our paper reviews these treatments. We discuss the pathophysiological mechanisms underlying secondary brain injury in ICH, review the virtues and limitations of the major animal models, and survey emerging therapeutic strategies targeting secondary mechanisms of injury in the setting of ICH.

Mechanisms of Secondary Brain Injury

In the hours following ICH, mass effect generated by the hematoma mechanically deforms and disrupts neuronal and glial cell membranes, resulting in calcium influx and excitotoxic neurotransmitter release.89 This results in cell necrosis and cytotoxic edema.39 Homeostasis is altered at the cellular level and further injury occurs. Secondary brain injury following ICH involves direct cellular toxicity, BBB disruption, vasogenic edema, and upregulation of inflammatory mediators.31 These processes function in a positive feedback cycle.

Activation of the coagulation cascade results in thrombin formation.31 Thrombin initially limits hematoma expansion and at low concentrations induces neuroprotective heat shock proteins and iron scavengers. However, at the high concentrations evident in ICH, thrombin initiates multiple destructive pathways.28

Thrombin stimulates glial cells to produce inflammatory cytokines. Upregulation of TNF-α results in disruption of BBB integrity, apoptosis, and recruitment of proinflammatory mediators.5,29 Upregulation of various MMPs61 results in degradation of the extracellular matrix.18 The BBB breakdown then leads to vasogenic edema and infiltration by inflammatory cells.31

Vasogenic edema resulting from BBB permeability may contribute to functional deterioration over the course of weeks.94 The mass effect of perihematomal edema can cause regional hypoperfusion by mechanically compressing blood vessels.77 This leads to dysfunctional adenosine triphosphate generation, failure of ion and neurotransmitter regulation, and free radical generation.69 Whether this process generates true ischemia is controversial.4

Thrombin-initiated activation of the complement cascade further enhances inflammatory cell migration through anaphylatoxins and direct cellular destruction via the membrane attack complex. Lysis of endothelial cells by the membrane attack complex in turn causes additional BBB disruption.30 Iron released from red blood cell lysis and free radicals produced by inflammatory cells generate oxidative stress, leading to further cell death and BBB breakdown.4,31 It should be noted, however, that although many of these inflammatory pathways appear to be harmful in the short term, they are critical for hematoma clearance and long-term recovery.31

The mechanisms of secondary brain injury outlined above suggest potential avenues for therapeutic intervention in the setting of ICH. Treatment modalities have been tailored according to these concepts and are currently progressing toward clinical testing and application. However, translational progress remains slow. One potential reason is the inability of current animal models to provide a sufficient recapitulation of the clinical disease.40 The following sections will describe relevant animal ICH models and review the treatments (in both experimental paradigms and clinical trials) applied toward secondary brain injury following ICH.

Experimental Animal Models of ICH

There are 2 widely used experimental techniques to simulate ICH in animal models: an autologous whole-blood protocol and a collagenase protocol. In the autologous whole-blood model, blood is harvested from a superficial vessel and stereotactically injected into the striatum.40 This method was originally hindered by backflow along the needle tract, resulting in undesired intraventricular and subarachnoid hemorrhaging.91 Thus, it was modified into a double injection. Initially, a small volume of blood is slowly infused into the striatum to allow clotting along the needle tract. The remaining blood is then injected to generate the hematoma. Double injection allows for reproducible hematoma volumes with substantially lower incidences of ventricular and subarachnoid infiltration.13 However, because the hematoma arises from a single bolus injection of blood, it fails to reproduce the temporal expansion evident in clinical ICH. Furthermore, this model does not achieve the rebleeding phenomenon that is typical of clinical ICH.43 Finally, injection of whole blood produces a less severe neurological deficit than seen in the clinical setting45 and can even allow for spontaneous recovery.21,33,70

In the collagenase model, bacterial collagenase is injected into the caudate nucleus to erode the basal lamina of blood vessels and induce in situ hemorrhage. Bleeding is typically seen 10 minutes after injection, but hematoma expansion continues up to 24 hours. This more accurately simulates clinically relevant ICH hematoma expansion.62 Furthermore, because of the diffuse activity of collagenase, rebleeding is often achieved.81 Neurological deficits seen in this model are typically more severe than in whole-blood injection,45 and animals do not frequently exhibit spontaneous recovery.6,42,80 The major drawback of the collagenase model is that levels of inflammation and cellular toxicity tend to be significantly higher than those evident in spontaneous human ICH.45

Both ICH models are performed in rodents, which are relatively inexpensive to house, genetically modifiable, and have well-established parameters for functional assessment.40 However, mice and rats are disadvantaged by a relative lack of white matter when compared with humans.17 The techniques have also been adapted in pigs, dogs, and rabbits. Species-specific differences in brain matter composition and structure are less extensive in these animals than in mice and rats, but criteria for neurobehavioral testing are not as well defined. The inability of any one model truly to simulate human ICH renders assessment in multiple paradigms useful prior to clinical testing.40 Furthermore, translation is impacted by experimental parameters. Age is an important predictor of functional outcome in clinical ICH.12 Also, ICH is most prevalent in older patients with substantial medical comorbidities.78 Evidence suggests that aged rats demonstrate more profound inflammation and neurological deficits than their younger counterparts.19 However, the majority of ICH experiments are performed in young, healthy animals.40 These disparities have tempered the process of translating positive preclinical results to the clinical arena.40

Therapies Under Investigation

Literature Review

Table 1 lists published reports for each kind of therapy discussed.

TABLE 1:

Literature review of studies on experimental ICH treatment modalities

Therapy; Authors & YearICH Study TypeResults
thrombin inhibitors
 Kitaoka et al., 2002rat autologous whole-blood & collagenase modelsdecreased edema, no potentiation of rebleeding in collagenase model
 Nagatsuna et al., 2005rat collagenase modeldecreased edema & inflammatory cell migration, no potentiation of re-bleeding
 Nakamura et al., 2010rat autologous whole-blood & collagenase modelsdecreased edema & oxidative DNA damage, no potentiation of rebleeding in collagenase model
 Sun et al., 2009rat autologous whole-blood modeldecreased edema, possibly through downregulation of aquaporin-4 & aquaporin-9
deferoxamine
 Gu et al., 2009piglet autologous whole-blood modelmitigated cell death/tissue loss
 Gu et al., 2011piglet autologous whole-blood modeldecreased oxidative DNA damage
 Hatakeyama et al., 2011aged rat autologous whole-blood modelmitigated cell death/tissue loss, attenuated neurological deficits/improved functional outcome
 Nakamura et al., 2004rat autologous whole-blood modeldecreased edema & oxidative DNA damage, mitigated cell death/tissue loss, attenuated neurological deficits/improved functional outcome
 Okauchi et al., 2009 & 2010aged rat autologous whole-blood modeldecreased edema, mitigated cell death/tissue loss, attenuated neurological deficits/improved functional outcome
 Qing et al., 2009rat autologous whole-blood modeldecreased edema & oxidative DNA damage, mitigated cell death/tissue loss, attenuated neurological deficits/improved functional outcome
 Selim et al., 2011clinical trialPhase I: infusions found to be tolerable up to 62 mg/kg/day; Phase II: in development
 Song et al., 2007rat hippocampal hemoglobin injection modeldecreased oxidative DNA damage, mitigated cell death/tissue loss
 Wu et al., 2011mouse collagenase modeldecreased edema & oxidative DNA damage, mitigated cell death/tissue loss, attenuated neurological deficits/improved functional outcome
minocycline
 Shi et al., 2011rat collagenase modelpreserved BBB integrity, decreased edema & inflammatory cell migration
 Wasserman & Schlichter, 2007rat collagenase modelpreserved BBB integrity, decreased edema & inflammatory cell migration
 Wasserman et al., 2007rat collagenase modeldecreased expression of TNF-α & MMP-12
 Wu et al., 2009rat autologous whole-blood modelmitigated cell death/tissue loss, attenuated neurological deficits/improved functional outcome
 Wu et al., 2011rat autologous whole-blood modelmitigated cell death/tissue loss, attenuated neurological deficits/improved functional outcome
 Zhao et al., 2011rat autologous whole-blood modelmitigated cell death/tissue loss, attenuated neurological deficits/improved functional outcome
statins
 Cui et al., 2012rat collagenase modeldownregulation of MMP-9, decreased edema, mitigated cell death/tissue loss
 Jung et al., 2004rat collagenase modelmitigated cell death/tissue loss, attenuated neurological deficits/improved functional outcome
 Karki et al., 2009rat autologous whole-blood modelmitigated cell death/tissue loss, attenuated neurological deficits/improved functional outcome
 Naval et al., 200852retrospective clinical study on statin use prior to ICHdecreased perihematomal edema
 Naval et al., 200853retrospective clinical study on statin use prior to ICHdecreased mortality rate, w/ a 12-fold increase in survival (p = 0.05)
 Seyfried et al., 2004rat autologous whole-blood modelmitigated cell death/tissue loss, attenuated neurological deficits/improved functional outcome
 Tapia-Perez et al., 2009prospective clinical cohort studydecreased mortality rate (5.6%) compared to historical controls (15.8%)
 Yang et al., 2011rat autologous whole-blood modelpreserved BBB integrity, decreased edema, promoted synaptogenesis
G-CSF
 Park et al., 2005rat collagenase modeldecreased edema & inflammatory cell migration, mitigated cell death/tissue loss, attenuated neurological deficits/improved functional outcome
 Sobrino et al., 2009prospective clinical cohort studyimproved 3-mo clinical outcome
therapeutic hypothermia
 Fingas et al., 2007rat autologous whole-blood modeldecreased edema
 Fingas et al., 2009rat autologous whole-blood modelattenuated neurological deficits/improved functional outcome
 Kawai et al., 2001rat basal ganglia thrombin injection modelpreserved BBB integrity, decreased edema
 Kawanishi et al., 2008rat autologous whole-blood modeldecreased oxidative DNA damage, mitigated cell death/tissue loss, attenuated neurological deficits/improved functional outcome
 MacLellan et al., 2004rat collagenase modelmitigated cell death/tissue loss, attenuated neurological deficits/improved functional outcome
 Rincon, 2013*clinical trialPhase I: in progress
 Staykov et al., 2013prospective clinical cohort studydecreased perihematomal edema, decreased mortality rate (8.3% at 3 mos & 28% at 1 yr) vs historical controls (16.7% at 3 mos & 44% at 1 yr); major adverse effect: pneumonia (adequately managed by antibiotics)

Thrombin Inhibitors

Despite concerns regarding hemorrhage exacerbation and facilitation of hematoma expansion, thrombin inhibition has been investigated in animal models of ICH. In the autologous whole-blood rat model, Sun et al.74 demonstrated that hirudin, a direct thrombin inhibitor, was found to decrease perihematomal edema significantly through presumed downregulation of aquaporin-4 and aquaporin-9. In the rat collagenase model, Nagatsuna et al.49 found that systemic administration of argatroban, an inhibitor of free and clot-bound thrombin, reduced edema and neutrophil/monocyte infiltration. Delayed argatroban administration also reduced edema. Kitaoka et al.41 demonstrated improvements with argatroban delivery 3 hours (intracerebral) or 6 hours (systemically) after whole-blood or collagenase injections. No beneficial effect was seen when treatment was delayed by 24 hours. Finally, nafamostat mesilate, a serine protease inhibitor, attenuated both edema and DNA oxidation when delivered systemically to rats 6 hours after whole-blood or collagenase injections.51 Importantly, rebleeding in collagenase models was not potentiated by any of the thrombin inhibitors, because treatment and control groups had similar hematoma volumes.41,49,51 The success of delayed administration suggests a therapeutic window.51 Although these results are promising, they are not correlated with functional outcome. However, low concentrations of thrombin are believed to be neuroprotective in the acute phase and to be involved in neuronal plasticity after brain injury.27,92 Therefore, excessive thrombin inhibition could exacerbate injury and inhibit long-term recovery.4

Deferoxamine

The iron chelator deferoxamine has been extensively tested in animal models of ICH and has progressed further in clinical assessment than other ICH treatment modalities.63 Deferoxamine rapidly crosses the BBB38 and mitigates iron accumulation and oxidative stress secondary to red blood cell hemolysis.31 Song et al.72 demonstrated that deferoxamine reduces DNA damage, neuron loss, and brain atrophy caused by hippocampal hemoglobin injection in rats. In rodent whole-blood and collagenase ICH models, deferoxamine has been shown to decrease edema and oxidative DNA damage, while preventing brain atrophy and improving neurological function.50,58,88 Furthermore, these results have been corroborated in aged rats and piglets.22,23,26,54,55 It should be noted, however, that 2 studies of deferoxamine in rat collagenase models found no improvement in neurobehavioral function.3,82 The multicenter Phase I study, Dose Finding and Safety Study of Deferoxamine in Patients with Brain Hemorrhage (DFO in ICH), found daily infusions of deferoxamine to be tolerable up to 62 mg/kg/day (maximum 6000 mg/day), with no serious adverse effects or deaths. High-Dose Deferoxamine in Intracerebral Hemorrhage (HI-DEF) is a Phase II trial currently in development that will evaluate the efficacy of deferoxamine in the setting of ICH.66

Minocycline

Minocycline is a tetracycline-class antibiotic with documented neuroprotective effects in multiple models of CNS trauma and neurodegeneration.57 Minocycline therapy has generated significant interest in the context of ICH, due to its ability to cross the BBB.83 Multiple potential mechanisms of benefit have been proposed. Minocycline suppresses inflammation by inhibiting cyclooxygenase-2 and mitigates oxidative stress by direct scavenging of oxygen free radicals. Furthermore, it inhibits apoptosis by upregulating bcl-2 and limiting calcium influx across mitochondrial membranes.57 Finally, minocycline blocks the activity of MMP-9 and MMP-12.31,34 Wasserman and colleagues83,85 used a rat ICH model to demonstrate that daily systemic administration of minocycline, starting 6 hours after collagenase injection, reduced TNF-α and MMP-12 expression. Minocycline also preserved BBB integrity, attenuated edema formation, and limited neutrophil infiltration.68,83 Other groups showed that repeated minocycline administration over several days decreased neuronal cell death, brain atrophy, and neurological deficits. However, these studies administered a first dose of minocycline within 2 hours of whole-blood injection.87,88,96 When a first dose was given at 3 or 6 hours after collagenase injection, no decrease in neuronal loss or improvement in functional outcome was noted.75,84 Szymanska et al.75 propose that minocycline modulates critical inflammatory events that occur within the first 3 hours after hemorrhage, which would, ultimately, undermine its practicality in clinical use.

Statins

Statins impede cholesterol synthesis by inhibiting the hydroxymethylglutaryl–coenzyme A reductase enzyme. Statins also exhibit antiinflammatory effects and have shown neuroprotective promise in ischemic stroke.90 These properties have prompted investigations into their utility as a treatment for ICH. Daily oral simvastatin or atorvastatin started at 24 hours after whole-blood injection and continued for 7 days reduced edema, preserved BBB integrity, and promoted synaptogenesis in rats. This enhanced neuronal plasticity could benefit long-term recovery.90 Atorvastatin and simvastatin also inhibited neuron apoptosis and improved functional outcome in whole-blood and collagenase ICH models.32,33,67 Other groups suggested potential mechanisms of action through N-methyl-d-aspartate receptor–mediated excitotoxicity blockade93 and MMP-9 downregulation.11

Retrospective clinical studies suggest that statin use prior to ICH is associated with decreased perihematomal edema52 and a lower mortality rate. A greater than 12-fold odds of survival (p = 0.05) was calculated for the statin group.53 Furthermore, a prospective cohort of 18 patients with ICH treated with rosuvastatin demonstrated a 5.6% mortality rate, compared with a 15.8% rate in 57 historical controls.76 The Simvastatin for Intracerebral Hemorrhage Study, a Phase II clinical trial scheduled to begin in 2008, was terminated due to poor recruitment (http://clinicaltrials.gov/ct2/show/NCT00718328?term=NCT0071832). Despite this setback, statin therapy appears poised for clinical investigation.

Granulocyte Colony-Stimulating Factor

This factor has a well-known role in stimulating neutrophil differentiation and proliferation. In rat models of focal ischemia, G-CSF has also been found to reduce infarct volume64 and decrease mortality rates through inhibition of neuronal programmed cell death.65 Studies with collagenase-induced rat ICH models have shown that G-CSF also confers neuroprotection by facilitating hemopoietic stem cell and neural stem cell migration into the perivascular hemorrhagic region.95 Additionally, G-CSF has demonstrated antiinflammatory effects through downregulation of TNF-α and interferon-γ.20,25 Using the collagenase-induced rat ICH model, recombinant human G-CSF administration resulted in less vasogenic edema and less inflammatory response as measured by fewer neutrophils and microglia. This also translated into significantly better clinical outcomes and hemispheric/cortical atrophy at 6 weeks.56

Granulocyte colony-stimulating factor appears to be a promising therapy; studies have already shown higher levels correlating with better clinical outcome in humans with ICH. Sobrino et al.71 showed that despite confounders such as discrepancy in baseline ICH volume and clinical state, higher G-CSF serum levels were still independently associated with a better 3-month clinical outcome.

Therapeutic Hypothermia

Hypothermia is an established neuroprotectant, which has demonstrated the capacity to prevent neuronal loss and improve functional outcome in rodent models of cerebral ischemia.9,10 It also has been clinically shown to reduce the mortality rate and augment neurological recovery in patients with cardiac arrest.7 Results have been mixed in the setting of ICH. Most studies achieve brain temperatures of 30°–35°C. Following thrombin injection into the basal ganglia, rats housed for 24 hours in a 5°C room demonstrated less edema and BBB permeability than those housed in a 25°C room.35 In a rat whole-blood model, selective brain hypothermia was induced by implanting a cooling coil beneath the temporalis muscle. Hypothermia achieved at 1 hour after injection and continued for 3 days led to decreased edema. However, no improvement in tissue loss or functional outcome was evident. Delayed initiation of hypothermia (12 hours after injection) was not associated with histopathological or functional benefit.15 When treatment duration was extended to 6 days, an improvement was seen in a single test of neurological function.16

Conflicting results have been generated in the collagenase ICH model. MacLellan et al.44 demonstrated that tissue loss was mitigated and functional outcome improved following delayed hypothermia (12 hours). One explanation is that collagenase models offer more potential for therapeutic benefit than whole-blood models, due to more severe neurological deficits and lack of spontaneous recovery in untreated animals. The authors noted no decrease in tissue loss when hypothermia was initiated less than 12 hours after collagenase injection. They postulated that early hypothermia can exacerbate hematoma expansion by causing coagulopathy and hypertension. Another group demonstrated that systemic hypothermia, initiated at 6 hours after whole-blood injection and continued for 2 days, reduced neutrophil infiltration, oxidative DNA damage, and neurological deficits. However, the long-term functional outcome was not assessed.36

The most promising results, thus far, derive from clinical cohort studies. The data suggest that mild hypothermia, administered for 8–10 days, decreases perihematomal edema and mortality. Staykov et al.73 induced hypothermia via endovascular catheterization in a cohort of 25 patients with ICH. The study demonstrated a mortality rate of 8.3% at 3 months, compared with 16.7% in 25 historical controls. At 1 year, the mortality rate in the treatment cohort was 28% (versus 44% in the controls). Pneumonia was the major adverse side effect, noted in 96% of treated patients versus 78% of controls. It was sufficiently managed with intravenous antibiotics. The Safety and Feasibility Study of Targeted Temperature Management After ICH (TTM-ICH) is a Phase I clinical trial in which the aim is to assess the tolerability of therapeutic hypothermia in patients with ICH. It is currently in progress (see Rincon; http://clinicaltrials.gov/ct2/show/NCT01607151).

Conclusions

To date, ICH treatments targeting direct mass effect and clot expansion have provided limited impact on functional neurological outcome. Recent investigative efforts have focused on secondary mechanisms of brain injury. These processes are complicated and multifactorial. Nonetheless, we have begun to understand the underlying pathophysiological mechanisms and have identified potential treatment strategies. Various putative therapeutic agents have demonstrated efficacy in animal models. However, the current experimental systems do not ideally simulate spontaneous human ICH. Thus, generation of positive data may warrant corroboration in multiple models prior to clinical translation. Therapies targeting secondary brain injury may ultimately function in synergy with strategies designed to limit early, direct mass effect and clot expansion in the setting of ICH.

Disclosure

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author contributions to the study and manuscript preparation include the following. Conception and design: all authors. Drafting the article: Belur. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors.

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    Knight RAHan YNagaraja TNWhitton PDing JChopp M: Temporal MRI assessment of intracerebral hemorrhage in rats. Stroke 39:259626022008

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    Leonardo CCRobbins SDoré S: Translating basic science research to clinical application: models and strategies for intracerebral hemorrhage. Front Neurol 3:852012

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    MacLellan CLGirgis JColbourne F: Delayed onset of prolonged hypothermia improves outcome after intracerebral hemorrhage in rats. J Cereb Blood Flow Metab 24:4324402004

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    Manaenko AChen HZhang JHTang J: Comparison of different preclinical models of intracerebral hemorrhage. Acta Neurochir Suppl 111:9142011

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    • Export Citation
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    Mayer SABrun NCBegtrup KBroderick JDavis SDiringer MN: Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 358:212721372008

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    Mayer SABrun NCBegtrup KBroderick JDavis SDiringer MN: Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 352:7777852005

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    Mendelow ADGregson BAFernandes HMMurray GDTeasdale GMHope DT: 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 365:3873972005

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    Okauchi MHua YKeep RFMorgenstern LBSchallert TXi G: Deferoxamine treatment for intracerebral hemorrhage in aged rats: therapeutic time window and optimal duration. Stroke 41:3753822010

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    Park HKChu KLee STJung KHKim EHLee KB: Granulocyte colony-stimulating factor induces sensorimotor recovery in intracerebral hemorrhage. Brain Res 1041:1251312005

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    Qureshi AI: Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH): rationale and design. Neurocrit Care 6:56662007

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    Qureshi AIPalesch YY: Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) II: design, methods, and rationale. Neurocrit Care 15:5595762011

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    Rosenberg GA: Matrix metalloproteinases in neuroinflammation. Glia 39:2792912002

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    Rosenberg GAMun-Bryce SWesley MKornfeld M: Collagenase-induced intracerebral hemorrhage in rats. Stroke 21:8018071990

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Article Information

Contributor Notes

Address correspondence to: William J. Mack, M.D., 1200 North State Street, Suite 3300, Los Angeles, California 90033. email: wjmack@gmail.com.Please include this information when citing this paper: DOI: 10.31712013.2.FOCUS1317.
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    Mayer SABrun NCBegtrup KBroderick JDavis SDiringer MN: Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 358:212721372008

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    Mayer SABrun NCBegtrup KBroderick JDavis SDiringer MN: Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 352:7777852005

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    Mendelow ADGregson BAFernandes HMMurray GDTeasdale GMHope DT: 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 365:3873972005

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    Nakamura TKeep RFHua YSchallert THoff JTXi G: Deferoxamine-induced attenuation of brain edema and neurological deficits in a rat model of intracerebral hemorrhage. J Neurosurg 100:6726782004

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    Nakamura TKuroda YHosomi NOkabe NKawai NTamiya T: Serine protease inhibitor attenuates intracerebral hemorrhage-induced brain injury and edema formation in rat. Acta Neurochir Suppl 106:3073102010

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    Naval NSAbdelhak TAZeballos PUrrunaga NMirski MACarhuapoma JR: Prior statin use reduces mortality in intracerebral hemorrhage. Neurocrit Care 8:6122008

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    Okauchi MHua YKeep RFMorgenstern LBSchallert TXi G: Deferoxamine treatment for intracerebral hemorrhage in aged rats: therapeutic time window and optimal duration. Stroke 41:3753822010

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    • Export Citation
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    Okauchi MHua YKeep RFMorgenstern LBXi G: Effects of deferoxamine on intracerebral hemorrhage-induced brain injury in aged rats. Stroke 40:185818632009

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    • Export Citation
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    Park HKChu KLee STJung KHKim EHLee KB: Granulocyte colony-stimulating factor induces sensorimotor recovery in intracerebral hemorrhage. Brain Res 1041:1251312005

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    • Export Citation
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    Plane JMShen YPleasure DEDeng W: Prospects for minocycline neuroprotection. Arch Neurol 67:144214482010

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    Qing WGDong YQPing TQLai LGFang LDMin HW: Brain edema after intracerebral hemorrhage in rats: the role of iron overload and aquaporin 4. Laboratory investigation. J Neurosurg 110:4624682009

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    • Export Citation
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    Qureshi AI: Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH): rationale and design. Neurocrit Care 6:56662007

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    Qureshi AIPalesch YY: Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) II: design, methods, and rationale. Neurocrit Care 15:5595762011

    • Search Google Scholar
    • Export Citation
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    Rosenberg GA: Matrix metalloproteinases in neuroinflammation. Glia 39:2792912002

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    Rosenberg GAMun-Bryce SWesley MKornfeld M: Collagenase-induced intracerebral hemorrhage in rats. Stroke 21:8018071990

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    Sangha NGonzales NR: Treatment targets in intracerebral hemorrhage. Neurotherapeutics 8:3743872011

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    Schäbitz WRKollmar RSchwaninger MJuettler EBardutzky JSchölzke MN: Neuroprotective effect of granulocyte colony-stimulating factor after focal cerebral ischemia. Stroke 34:7457512003

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    • Export Citation
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    Schneider AKrüger CSteigleder TWeber DPitzer CLaage R: The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis. J Clin Invest 115:208320982005

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    • Export Citation
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    Selim MYeatts SGoldstein JNGomes JGreenberg SMorgenstern LB: Safety and tolerability of deferoxamine mesylate in patients with acute intracerebral hemorrhage. Stroke 42:306730742011

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    • Export Citation
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