Thrombin and hemin as central factors in the mechanisms of intracerebral hemorrhage–induced secondary brain injury and as potential targets for intervention

Full access

Intracerebral hemorrhage (ICH) is a subtype of stoke that may cause significant morbidity and mortality. Brain injury due to ICH initially occurs within the first few hours as a result of mass effect due to hematoma formation. However, there is increasing interest in the mechanisms of secondary brain injury as many patients continue to deteriorate clinically despite no signs of rehemorrhage or hematoma expansion. This continued insult after primary hemorrhage is believed to be mediated by the cytotoxic, excitotoxic, oxidative, and inflammatory effects of intraparenchymal blood. The main factors responsible for this injury are thrombin and erythrocyte contents such as hemoglobin. Therapies including thrombin inhibitors, N-methyl-D-aspartate antagonists, chelators to bind free iron, and antiinflammatory drugs are currently under investigation for reducing this secondary brain injury. This review will discuss the molecular mechanisms of brain injury as a result of intraparenchymal blood, potential targets for therapeutic intervention, and treatment strategies currently in development.

Abbreviations used in this paper:ATP = adenosine triphosphate; BBB = blood-brain barrier; ICH = intracerebral hemorrhage; IL = interleukin; MMP = matrix metalloproteinase; NF = nuclear factor; NMDA = N-methyl-D-aspartate; PAR = protease-activated receptor; RBC = red blood cell; rCBF = regional cerebral blood flow; SAH = subarachnoid hemorrhage; TNF = tumor necrosis factor.

Intracerebral hemorrhage (ICH) is a subtype of stoke that may cause significant morbidity and mortality. Brain injury due to ICH initially occurs within the first few hours as a result of mass effect due to hematoma formation. However, there is increasing interest in the mechanisms of secondary brain injury as many patients continue to deteriorate clinically despite no signs of rehemorrhage or hematoma expansion. This continued insult after primary hemorrhage is believed to be mediated by the cytotoxic, excitotoxic, oxidative, and inflammatory effects of intraparenchymal blood. The main factors responsible for this injury are thrombin and erythrocyte contents such as hemoglobin. Therapies including thrombin inhibitors, N-methyl-D-aspartate antagonists, chelators to bind free iron, and antiinflammatory drugs are currently under investigation for reducing this secondary brain injury. This review will discuss the molecular mechanisms of brain injury as a result of intraparenchymal blood, potential targets for therapeutic intervention, and treatment strategies currently in development.

Stroke affects 15 million people worldwide and accounts for approximately 10% of all deaths.40 Strokes are classified as either ischemic or hemorrhagic, and occur due to blood vessel occlusion or blood vessel rupture, respectively. Approximately 13% of strokes are of the hemorrhagic subtype and include ICH and SAH.107 Intracerebral hemorrhage is the most common cause of hemorrhagic stroke and causes extravasation of blood into the parenchyma and subsequent hematoma formation, resulting in brain damage.40 Intracerebral hemorrhage frequently causes significant morbidity and death, with as many as 50% of patients dying within 1 month of presentation, and only 20% of survivors able to function independently at 6 months.33 Also, with a worldwide incidence of 10–20 cases per 100,000 people, ICH is a global public health problem.99,118

Spontaneous ICH is mainly caused by hypertension, which causes microaneurysms at the bifurcation of intracerebral arterioles that can immediately rupture.29,123 These microaneurysms may be different from the berry aneurysms at the Circle of Willis branch points that cause SAHs. Intracerebral hemorrhage may also be due to cerebral amyloid angiopathy, anticoagulant use, hematological disorders, arteriovenous malformations, arteriovenous fistulas, cavernous angiomas, and brain tumors. Intracerebral hemorrhage can be further distinguished from SAH as it is more commonly found near gray-white junctions in cerebral lobes, subcortical structures such as the basal ganglia, the brainstem, and deep cerebellar nuclei.99,101 Current management for ICH immediately after onset involves airway management, monitoring of hemodynamic parameters, control of intracranial pressure, and hematoma evacuation.

Brain injury from ICH can be described by primary and secondary mechanisms (Fig. 1). The majority of the brain injury due to ICH typically occurs within the first few hours as a result of mass effect due to hematoma formation.98 This primary injury results in increased pressure and disruption of the surrounding neural structures, resulting in early neurological deterioration. Although randomized trials have not consistently shown a clear benefit of surgical management compared with medical therapy, there may be a role for ICH evacuation in an attempt to reduce intracranial pressure and reduce mass effect to try and improve outcomes in select cases. Lack of Class I data supporting evacuation may be due to the added morbidity of the surgical procedure in eloquent areas (such as the basal ganglia), inappropriate timing of clot evacuation, variability of ICH and techniques used, and insufficient sample sizes in clinical trials.

Fig. 1.
Fig. 1.

Mechanisms and potential treatments for primary and secondary brain injury following ICH.

Because the optimal therapy for treating the primary injury associated with ICH has not yet been identified, prevention and treatment of secondary injury is imperative. As many patients continue to deteriorate clinically despite no signs of rehemorrhage or hematoma expansion, there is increasing interest in the mechanisms of secondary brain injury following ICH.30 Vasogenic and cytotoxic edema due to the breakdown of the BBB and cellular injury have been implicated in this process.146 Additional mechanisms for this secondary injury are believed to be due to the intraparenchymal accumulation of various blood components following ICH, activating cytotoxic, excitotoxic, oxidative, and inflammatory pathways.61 As a result of increased awareness of this secondary injury, specific therapeutic targets have been identified in hopes of preventing further brain damage following ICH. In this review, we will discuss the various molecular mechanisms of secondary brain injury as a result of intraparenchymal blood, potential therapeutic targets, and the various treatment strategies currently under investigation.

Mechanisms of Secondary Brain Injury

Thrombin-Induced Injury

Thrombin, a serine protease found in the brain after ICH, has been shown to induce brain injury (Fig. 2). This enzyme is produced on the plasma membranes of platelets, neutrophils, monocytes, and lymphocytes as a result of cleavage of prothrombin following activation of the intrinsic and/or extrinsic coagulation cascades.137,148 Entry of blood into the brain parenchyma activates this process, releasing large amounts of thrombin that is known to cause perihematomal edema formation after ICH due to endothelial cell damage.75,146,148 Studies have also shown continuous release of thrombin from intracerebral hematomas for 2 weeks after clot formation due to fibrinolysis.121

Fig. 2.
Fig. 2.

Once released after ICH, thrombin is able to activate the complement pathway and PARs. This leads to a variety of cytotoxic, excitotoxic, and inflammatory effects that all lead to secondary brain injury. MAPKs = mitogen-activated protein kinases.

Thrombin-induced injury may be a central mechanism for secondary injury in ICH, as many pathways are implicated. Secondary injury due to thrombin primarily occurs through PARs, a family of G protein–coupled proteins found on the surface of various cells including platelets, neurons, and endothelial cells.24 Of these receptors, PAR-1, PAR-3, and PAR-4 have been shown to be activated by thrombin.24–26 This activation occurs by cleavage of the exodomains of PARs, forming a new amino terminus that acts as a tethered ligand for receptor activation, resulting in the activation of various signaling pathways.49,78,132 Protease-activated receptor-1 has been shown to be upregulated in ischemia models and is implicated in potentiation of NMDA receptors, neurite retraction, and cell death.37,119,128,129 It has been shown that mice lacking PAR-1 have a reduction in infarct volume following focal ischemia, indicating its importance in brain injury.64,149 Additionally, studies have shown continued PAR-1 activation following ICH, with PAR-1 levels peaking at 3 days after onset.162 This effect may last for up to 14 days, implicating this process in cerebral edema initiation as it often peaks approximately 3 days after ICH.162 Protease-activated receptors also activate various intracellular enzymes such as mitogen-activated protein kinases, which play a role in the recruitment of microglia and neuronal injury.91

Red Blood Cell Lysis

The presence of extravasated RBCs in the brain following ICH also stimulates a variety of cytotoxic, oxidative, and inflammatory processes (Fig. 3). Red blood cell lysis begins to occur approximately 24 hours following ICH and occurs for several days after onset.87,133,139 This primarily occurs due to intracellular energy depletion, loss of structural integrity, and the formation of the membrane attack complex due to activation of the complement system.55 The release of the intracellular contents of these cells induces brain edema, as studies have shown increases in edema volume following reductions in hematoma size due to clot lysis.138 Studies in animals have shown delayed brain injury with intracerebral infusion of packed RBCs and dramatic edema formation within 24 hours following infusion of lysed RBCs.53,133,140,145 Infusion of lysed RBCs also causes disruption of the BBB, DNA injury, and expression of heat shock proteins, indicating cell stress.80,140,143,145 Once released from RBCs, hemoglobin is degraded into heme and iron, causing injury to surrounding cells.95,133,139,157

Fig. 3.
Fig. 3.

Hemolysis leads to the release of hemin into the extracellular space. Hemin may then intercalate into cell membranes or enter cells via the heme carrier protein 1 (HCP1). Intracellularly hemin may activate cytotoxic and inflammatory pathways. It is then degraded by heme oxygenases, producing prooxidative iron, carbon monoxide (CO), and bilirubin. Thus far, the role of CO and bilirubin in ICH-mediated injury is unclear. Hb = hemoglobin; HO-1 = heme oxygenase-1; ROS = reactive oxygen species.

Cytotoxicity

Thrombin has been shown to induce various components of the complement system, an enzymatic cascade of blood and cell surface proteins. Thrombin primarily activates complement C3d and C9.38,50,55 The presence of C3d following ICH indicates activation of the complement cascade, while deposition of C9 on the neuronal cell membranes indicates membrane attack complex formation.13,55 This activity leads to the formation of a transmembrane pore and subsequent cell lysis, which may be one of the mechanisms of neuronal death and disruption of the BBB as a result of endothelial cell damage following ICH.55 Additionally, lysis of erythrocytes may result in further damage through hemoglobin-mediated edema formation.145

Thrombin is also able to induce apoptosis in neurons and astrocytes by activation of various intracellular pathways.27,90 This occurs via RhoA, a small guanosine triphosphate-binding protein part of the Ras superfamily.27 RhoA inhibitors have been noted to attenuate thrombin-mediated cell death, implicating this mechanism as a major cause of neuronal loss following ICH. However, the exact mechanism by which RhoA induces apoptosis is currently unknown. This process may involve caspase activation, as inhibitors to these enzymes have been shown to prevent thrombin-induced cell death.128

Excitotoxicity

Potentiation of NMDA receptors by PAR-1 may cause neuronal death following ICH due to glutamate-induced excitotoxicity.37,43 This notion is supported by studies showing that PAR-1 knockout mice had reduced thrombin-mediated NMDA receptor potentiation.37,43 Also, removal of PAR-1 and the addition of NMDA receptor antagonists reduce neuronal injury associated with the addition of NMDA and transient middle cerebral artery occlusion.43 The potentiation of NMDA by PAR-1 occurs through the activation of Src, a proto-oncogene tyrosine-kinase, which is known to augment NMDA activity by phosphorylation of these receptors.113 This activity is confirmed by increased expression of Src kinases following ICH.113

Levels of extracellular amino acids such as glutamate have been shown to increase following ICH, resulting in glutamate-mediated excitotoxicity.97 This increase in levels of extracellular amino acids may be due to the release of these molecules as a result of active ischemia, as in vivo models have shown 80-fold increases in glutamate levels after middle cerebral artery occlusion.47 Because neurons have high intracellular concentrations of glutamate, ICH-induced cell death may result in the release of these stores into the extracellular space.97 Additionally, injury of astrocytes may impair glutamate removal, resulting in extracellular accumulation.

Oxidative Injury

Hemin, the oxidative form of heme, is a potent oxidant that injures cells and is well known to cause brain injury.103 Its mechanism of action occurs through oxidative stress and the activation of caspases, resulting in the injury of astrocytes, neurons, and microglia.102,135 However, microglia that clear hemin have protective mechanisms that prevent cell death.17 Following ICH, hematogenous phagocytes, microglia, and surrounding astrocytes and neurons attempt to sequester hemin.103,156 This primarily occurs via the heme carrier protein 1.103 Once within the cell, hemin is degraded by heme oxygenases, producing biliverdin, carbon monoxide, and iron.70,103 Iron released due to hemin degradation can reach high levels within the brain following ICH, resulting in the formation of hydroxyl radicals and subsequent cellular stress and DNA damage via interaction with hydrogen peroxide.3,86,133,139 Iron levels after ICH may increase up to 3-fold and remain elevated for 1 month, causing continued brain injury following the initial insult.139 However, hemin itself can also participate in redox reactions, producing free radicals that can damage intracellular structures and cause oxidative stress.57 Additionally, because hemin is lipophilic, it may intercalate into lipid membranes, altering function and fluidity.4 The roles of biliverdin, which is converted to bilirubin by biliverdin reductase, and carbon monoxide are unclear.70 Small concentrations of bilirubin have been demonstrated to inhibit glutamate uptake and induce inflammation, oxidative stress, and apoptosis.16,34,115 However, bilirubin and carbon monoxide have also been shown to have antioxidant and antiinflammatory effects.103 Also unclear is the amount of bilirubin accumulation due to hemin degradation following ICH.

Inflammation

Thrombin has also been observed to increase proinflammatory cytokines such as TNF-α and IL-1β.54,142 This increase may occur through the activation of microglia via PARs, resulting in recruitment and proliferation of these cells at the site of injury.108,120 Tumor necrosis factor-α has been shown to increase in ICH models and is implicated in edema formation because TNF-α knockout mice have less brain edema and neurological deficits compared with wild-type mice.54 Plasma TNF-α has been shown to correlate with the amount of brain edema in patients.19 Other studies have also raised other mechanisms of TNF-α mediated injury such as enhancement of leukocyte infiltration, resulting in BBB disruption and cellular apoptosis.6 Thrombin also stimulates microglia to secrete IL-1β, resulting in similar damaging effects as TNF-α, such as neurotoxicity, opening of the BBB, and induction of apoptosis.142 The role of this mechanism in ICH-mediated injury is supported by studies showing attenuation of brain edema by the overexpression of IL-1β receptor antagonists.142

Matrix metalloproteinases are zinc-containing proteases that are involved in extracellular matrix remodeling, chemotaxis, and proteolytic cleavage of various molecules.35 These proteins are produced by microglia, pericytes, and astrocytes, and when found in high levels in the brain, result in extracellular matrix degradation, BBB disruption, and neuronal death.149 The mechanism for MMP-mediated brain injury is due to activation of microglia and subsequent release of inflammatory cytokines, release of neutrophil-derived toxins from infiltrated leukocytes, and generation of toxic molecules from interaction with nitric oxide. Several MMPs including MMP-2, -3, -9, and -12 have been observed to increase following ICH and can affect clinical outcome.2,96 Additionally, studies have shown that MMP-3, -9, and -12 null mice have less brain injury as a result of ICH.136,149,150 As thrombin is able to increase expression of various MMPs, the effects of thrombin on microglial activation and neuronal apoptosis may be due to these mediators.67,150

Nuclear factor-κB, a transcription factor involved in inflammatory processes, also contributes to brain injury following ICH.5 In response to various cytokines and free radicals, NF-κB translocates to the nucleus, inducing the transcription of inflammatory enzymes, chemokines, and cytokines. Activation of NF-κB occurs within minutes of ICH and can remain active for 7 days following onset.161 This activity results in DNA fragmentation, causing cell death.46 Elucidation of the mechanisms of DNA fragmentation following NF-κB may allow for the development of therapeutic interventions to inhibit this process.

Nonhematogenous Perihematomal Mechanisms of Secondary Injury

Ischemia has been believed to play a role in secondary brain injury following ICH. Several animal studies have shown reductions in rCBF and the presence of tissue ischemia around hematomas, even though blood flow is reestablished quickly.81,88,89,100,106,151 This return to normal perfusion is observed as early as 10 minutes following hemorrhage but is likely variable, depending on factors such as size of the hematoma and the presence of increased intracranial pressure. Although there may be quick recovery, ischemic damage to the cortex overlying the hematoma has been noted, consistent with histological findings of ischemia following 5 minutes of CBF cessation.89,122 In ICH, ischemia of the surrounding tissue may be due to mechanical compression of the surrounding microvasculature by the hematoma, resulting in a hypoxic environment.82,89 Hypoxia causes brain injury by a multitude of mechanisms. The inability to synthesize ATP results in Na+/K+ ATPase dysfunction, leading to neuronal membrane depolarization and ionic imbalance.28 This may impair the function of many enzymes such as sodium-dependent glutamate transporters, resulting in increased extracellular glutamate levels and excitotoxicity.28 Low concentrations of ATP also prevent the maintenance of low calcium concentrations within cells by disrupting the Ca2+ ATPase, leading to high intracellular calcium levels that activate many DNAses and calcium-dependent proteases.28 Additionally, energy depletion results in the production of reactive oxygen species and the release of cytochrome c from the outer mitochondrial membrane, both of which result in apoptosis and further brain injury.28,126 Many of these mechanisms of injury overlap with the excitotoxic and oxidative pathways induced by thrombin and hemin, demonstrating the complexity of these damaging pathways and challenge of designing drugs to prevent this injury.

However, some animal and human studies have shown evidence against a significant ischemic penumbra following ICH.18,32,36,44,45,48,100,109,134,153 These studies did not show any ischemic tissue surrounding the clot, although there was evidence of hypoperfusion. Positron emission tomography has shown reductions in the oxygen extraction fraction in tissue surrounding hematomas, contrasting with what occurs during acute ischemia.153 Magnetic resonance imaging in patients has not shown significant changes in the apparent diffusion coefficient or mean transit time, both of which are markers of irreversible ischemia and hypoperfusion.109 The lack of prolonged reductions in rCBF after ICH may be due to incomplete vascular compression by the hematoma.100 This idea is supported by studies demonstrating rCBF within hematomas in regions of intact neural tissue.100 Complete compression of intracerebral vessels by the expanding hematoma may result in the disruption of the pia-microvasculature interface, potentially causing alterations in BBB integrity.100 Because this has not been noted to occur immediately following ICH, complete vessel compression is unlikely. In addition, white matter fibers are dense structures that provide mechanical resistance against the expanding hematoma.84 Finally, robust collateral circulation from penetrating cortical arterioles and pial vessels from other cerebral arteries may prevent significant changes in rCBF and tissue ischemia.84,100 However, due to the relatively small sample sizes in many studies, larger human studies are needed to provide more conclusive data.

Therefore, it is unclear whether perihematomal ischemia is a significant factor in secondary brain injury following ICH. Recently there has been a paradigm shift in thinking toward a metabolic instead of an ischemic penumbra. Increases in perihematomal glucose uptake and use (hyperglycolysis) have been observed in patients following ICH, consistent with what is noted following traumatic brain injury.14,154 The mechanism of focally increased glucose uptake may be due to nonconvulsive seizure activity, which is found in many patients with acute ICH.131 These repetitive depolarizations may lead to secondary injury by increasing extracellular glutamate, resulting in intracellular calcium accumulation and excitotoxicity.130 The role of seizures as a cause of increased glucose utilization is supported by the suppression of hyperglycolysis by anticonvulsant glutamate receptor antagonists.20 Further studies are needed to elucidate additional metabolic changes in this perihematomal tissue and investigate potential interventions to this ongoing injury.

Potential Therapeutic Targets and Current Treatments Under Investigation

Understanding the mechanisms of secondary injury following ICH has allowed for the development of treatments aimed at preventing this damage. Some agents have been validated in in vivo studies but have not yet been evaluated in clinical trials. However, several clinical trials have already been conducted to evaluate various neuroprotective drugs for the treatment of secondary injury from ICH.

Prevention of Cytotoxicity

One promising therapy for the prevention of secondary brain injury following ICH is the use of direct thrombin inhibitors. As thrombin plays a major role in cellular injury via a variety of pathways, inhibiting its activity would be beneficial. Inhibitors such as hirudin (a thrombin inhibitor found in leeches) and argatroban (a synthetic, direct thrombin inhibitor) have been shown to reduce brain edema following ICH in in vivo models, possibly by inhibiting PAR-1 expression.68,69,74,163 Although there is concern of prolonged bleeding with the use of these anticoagulants, the use of direct thrombin inhibitors has been shown to not cause enlargement of hematoma volume, unlike with other anticoagulants such as warfarin.72 Clinical trials are needed to evaluate the efficacy of these drugs for the prevention of brain injury following ICH.

However, complete inhibition of thrombin may actually be deleterious as low concentrations have been shown to be neuroprotective.148 This protective effect has been observed in neurons and astrocytes in in vitro models. Pretreatment with thrombin has been shown to prevent brain edema and damage induced by large doses of thrombin, ICH, and cerebral ischemia,79,144,147 but these protective effects are eliminated by thrombin inhibitors.147 Although the exact mechanism by which thrombin exerts its neuroprotective effects is unknown, it is believed to be due to the activation of PARs, production of heat shock proteins, and upregulation of endogenous thrombin inhibitors.56,62,144,147 Additionally, thrombin preconditioning has been shown to increase levels of hypoxia inducible factor-1α, transferrin, and transferrin receptor, increasing brain tolerance to erythrocyte- and iron-mediated injury.52 Further research elucidating the mechanisms of this protective effect are needed for the development of therapeutic strategies aimed to enhance this effect. The doses of thrombin inhibitors that simply reduce thrombin concentration without complete inhibition need to be clarified to augment neuroprotection. Alternatively, specific thrombin inhibitors that do not affect neuroprotective pathways should be investigated.

Due to the activation of numerous apoptotic pathways following ICH, molecules that inhibit this process have been investigated for use in ICH. One such drug is tauroursodeoxycholic acid, the taurine conjugate of the endogenous bile acid ursodeoxycholic acid.105 Tauroursodeoxycholic acid is able to inhibit production of reactive oxygen species, stabilize the mitochondrial membrane, activate antiapoptotic proteins such as Bcl-2, and inhibit the activity of proapoptotic proteins such as Bad.104,105 A Phase I trial investigating the safety of this drug has been designed.

Albumin has also been investigated as a neuroprotective agent. Studies have demonstrated numerous mechanisms of this neuroprotection including reduction of brain edema, inhibition of oxidative damage, and maintenance of normal endothelial and astrocytic function.7,8,10,12 In vivo studies have demonstrated improved functional outcome and BBB integrity following administration of albumin after ICH.9,11 The Albumin for Intracerebral Hemorrhage Intervention (ACHIEVE) trial is currently evaluating the effects of albumin in 40 patients with ICH.

Inhibition of Excitotoxicity

Gavestinel, a drug that functions as an antagonist by binding to the glycine site on the NMDA receptor, has been investigated in the Glycine Antagonist in Neuroprotection (GAIN) International and Americas trials.83 In these trials, patients were randomized to receive the drug or placebo within 6 hours of symptom onset. This time point is considered to be crucial as the majority of hematoma enlargement occurs within this period due to continuous bleeding or rebleeding.65 Outcomes of the trial were death or functional ability as determined by the Barthel Index.42 Of the 3450 patients randomized in these trials, 571 had ICH. Analysis of these patients revealed no significant differences in mortality rates between the 2 groups (p = 0.38). There was also no difference in the distribution of Barthel Index scores at 3 months between the 2 groups, although there was a trend favoring gavestinel (p = 0.091). It may be beneficial to test this agent later during the peak of secondary brain injury from ICH.

As glutamate levels have been shown to increase following ischemic injury and ICH, glutamate scavenging may provide neuroprotection. Oxaloacetate has been shown to be neuroprotective in traumatic brain injury models by reducing glutamate levels.164 The mechanism for this effect is due to the transformation of glutamate to 2-ketoglutarate by glutamate-oxaloacetate transaminase, an enzyme found in the blood.39 Human studies are needed to evaluate the efficacy of this mechanism in ICH.

Protection From Oxidative Injury

Three clinical trials have been conducted to evaluate citicoline (cytidine-5-diphosphocholine), an intermediate in the phospholipid synthetic pathway.1 Studies have shown its neuroprotective effects occur by maintaining the integrity of various cellular membranes, attenuating lipid peroxidation, restoring Na+/K+-ATPase activity, and enhancing the glutathione system.1 Additionally, citicoline may decrease glutamate release from neurons and improve astrocyte uptake, decreasing extracellular glutamate levels.58 In a randomized study of 32 patients, those receiving citicoline experienced improved muscle strength following ICH.60 Another study involving treatment of 19 patients with citicoline found that treated patients were 5-fold more likely to be functionally independent following ICH compared with those who received a placebo.110 Finally, a trial of 182 patients revealed that treatment with citicoline resulted in improvement in the Barthel Index, although no effect on the modified Rankin Scale or NIH Stroke Scale was noted.66

Due to the neurotoxic effects of iron, there is interest in the use of iron chelators for prevention of this iron-mediated injury. In vivo studies have demonstrated that deferoxamine rapidly accumulates within brain parenchyma and reduces iron concentration, brain edema, neuronal death, and neurological deficits following ICH.41,51 A multicenter Phase I trial showed that infusions of deferoxamine are tolerable and safe up to a daily dose of 6000 mg.112 Preliminary data in 4 patients with hemorrhagic stroke and 3 with ischemic stroke showed decreases in serum markers of oxidative stress.111 Currently, a Phase II trial is underway to evaluate the efficacy of deferoxamine in ICH.

Peroxisome proliferator-activated receptor γ is a transcription factor that plays a role in cellular defense mechanisms and hematoma clearance.159 This activity occurs through the upregulation of CD36, the phagocytosis-facilitating gene, resulting in faster hematoma clearance.159 In addition, it enhances expression of antioxidant molecules such as catalase and superoxide dismutase, preventing the oxidative damage of neurons and microglia.114,160 In vivo studies have demonstrated improvements in hematoma resolution and functional outcome following treatment with peroxisome proliferator-activated receptor γ agonists in ICH models.159 Currently the Safety of Pioglitazone for Hematoma Resolution in Intracerebral Hemorrhage (SHRINC) trial is evaluating the use of such agonists in 80 patients with ICH.

Haptoglobin is a protein found in blood plasma that has the ability to bind hemoglobin. It functions to bind extracellular hemoglobin, preventing hemoglobin-mediated oxidative damage.157 In the brain, haptoglobin is synthesized by oligodendrocytes, thereby protecting against extravascular hemoglobin toxicity. Animal models of ICH have demonstrated increased haptoglobin production following injury. Animals that are hypohaptoglobinemic are more susceptible to injury and have more brain damage following ICH, whereas those that overexpress haptoglobin are more protected. Haptoglobin is therefore a potential therapeutic target for the prevention of brain injury following ICH. Thus far, sulforaphane, a NF-E2–related factor–2 activator, has been shown to increase haptoglobin in the brain and reduce injury following ICH.158 Additional in vivo and human studies are needed to identify other agents that increase haptoglobin levels and establish their efficacy in preventing ICH-induced brain injury.

Another agent known to bind heme is hemopexin, a glycoprotein found in plasma.125 However, hemopexin is also expressed by neurons and is present throughout the brain.76 Mice that do not express hemopexin have greater infarct volumes and neurological deficits following middle cerebral artery occlusion.76 Hemopexin knockout mice also had increased protein oxidation and tissue heme, and decreased cell viability and locomotor activity.22 This protein may also be another modifiable target to decrease brain injury following ICH.

Reduction of Inflammation

Rosuvastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, has been investigated for its neuroprotective effects. Statins may exhibit their neuroprotective effects via a variety of mechanisms such as reduction of inflammation through inhibition of NF-κB, TNF-α, and chemokine expression,63,92 upregulation of nitric oxide synthase,31,63,73 and protection from glutamate-induced excitotoxicity.15 A prospective/retrospective nonrandomized study treated 18 patients with rosuvastatin and found improved outcomes compared with control subjects (mortality rate 5.6% vs 15.8%, respectively; NIH Stroke Scale score ≥ 15, OR 0.04).124 Larger studies are needed to provide more conclusive evidence on the efficacy of statins for the prevention of secondary brain injury following ICH. Due to the neuroprotective effects of statins, there has also been considerable interest in using these drugs following aneurysmal SAH. A meta-analysis of double-blind randomized controlled trials showed significant reductions in delayed ischemic deficits (OR 0.41, 95% CI 0.20–0.82; p < 0.001) and mortality (OR 0.29, 95% CI 0.09–0.93; p = 0.04) following statin therapy for SAH.127

Celecoxib is a nonsteroidal antiinflammatory drug that has been shown to reduce perihematomal inflammation and cell death in ICH.23,116 Because celecoxib selectively inhibits cyclooxygenase-2, it is a potential treatment for ICH because cyclooxygenase-2 is activated in ICH models, resulting in increased levels of prostaglandin E2.23 As prostaglandin E2 can induce free radical formation and glutamate-mediated excitotoxicity due to glutamate release from astrocytes, the neuroprotective effects of celecoxib are believed to occur through the reduction of prostaglandin E2 synthesis via cyclooxygenase-2 inhibition.23,59 One retrospective study analyzed the volumes of hematoma and edema in 17 patients treated with celecoxib.93 Treatment significantly reduced the volume of brain edema and the ratio of initial hematoma and edema volumes to follow-up volumes compared with the control group. The results of a Phase II trial investigating the efficacy of celecoxib are currently pending. Although trials have shown increased risk of serious cardiovascular events with use of celecoxib, short-term use in ICH may not increase these risks significantly.117

Minocycline, a broad-spectrum tetracycline antibiotic, has also been investigated as a neuroprotective agent due to its antiinflammatory properties. In vivo studies have shown reduced perihematomal brain edema, neuronal loss, BBB disruption, and improved functional outcome following ICH with minocycline treatment.141,155 Minocycline also reduces brain iron accumulation and resulting toxicity by chelating iron.21 In an open-label, blinded study, 74 patients were treated with minocycline 6–24 hours after acute ischemic stroke.71 Those treated had significantly lower NIH Stroke Scale and modified Rankin Scale scores, with higher Barthel Index scores, indicating significantly better outcome. Currently, 3 trials are in progress for evaluation of the neuroprotective effects of minocycline in stroke.

Other Investigated Agents

Other studies have evaluated the use of mannitol, glycerol, and NXY-059 (disufenton sodium) for neuroprotection in patients with ICH but did not observe any improvement in mortality or functional outcome.77,83,152 Mannitol exerts its neuroprotective effects by functioning as an osmotic diuretic, thus reducing brain edema.85 It also functions as an antioxidant, protecting against free radical–mediated damage. Neuroprotection due to glycerol occurs by hemodilution, which results in increased cerebral perfusion and reduction of cerebral edema, thereby reducing intracranial pressure.152 The free radical trapping agent NXY-059 prevents brain injury by quenching free radicals formed by hemoglobin degradation and ischemic tissue.94

Conclusions

The mechanisms of secondary brain injury following intracerebral hemorrhage are numerous and involve the initiation of cytotoxic, excitotoxic, oxidative, and inflammatory pathways. Optimal management of patients with ICH remains undefined. Surgical therapies have shown disappointing results in primary brain injury treatment. Medical therapies aimed at prevention of continued insult may improve mortality rates and functional outcomes. Although there is not yet an effective medical treatment, advances have been made in elucidating the mechanisms of brain injury following ICH. These advances have led to the development of neuroprotective therapies, many of which show promise in early clinical testing. However, further research is required to illuminate and better define the multitude of mechanisms involved in ICH pathogenesis in the hope of revealing targets for novel therapeutics. Additionally, large randomized trials are needed to establish the efficacy and safety of currently identified neuroprotective agents. Nonetheless, our focus must also be on finding efficient interventions to prevent ICH, decreasing the severe morbidity and mortality associated with this disease.

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: Adamson, Babu. Acquisition of data: Babu, Bagley, Di. Analysis and interpretation of data: Adamson, Babu. Drafting the article: Babu. Critically revising the article: Adamson, Friedman.

References

  • 1

    Adibhatla RMHatcher JFDempsey RJ: Citicoline: neuroprotective mechanisms in cerebral ischemia. J Neurochem 80:12232002

  • 2

    Alvarez-Sabín JDelgado PAbilleira SMolina CAArenillas JRibó M: Temporal profile of matrix metalloproteinases and their inhibitors after spontaneous intracerebral hemorrhage: relationship to clinical and radiological outcome. Stroke 35:131613222004

    • Search Google Scholar
    • Export Citation
  • 3

    Aronowski JZhao X: Molecular pathophysiology of cerebral hemorrhage: secondary brain injury. Stroke 42:178117862011

  • 4

    Balla GJacob HSEaton JWBelcher JDVercellotti GM: Hemin: a possible physiological mediator of low density lipoprotein oxidation and endothelial injury. Arterioscler Thromb 11:170017111991

    • Search Google Scholar
    • Export Citation
  • 5

    Barnes PJKarin M: Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 336:106610711997

    • Search Google Scholar
    • Export Citation
  • 6

    Barone FCFeuerstein GZ: Inflammatory mediators and stroke: new opportunities for novel therapeutics. J Cereb Blood Flow Metab 19:8198341999

    • Search Google Scholar
    • Export Citation
  • 7

    Belayev LBusto RZhao WClemens JAGinsberg MD: Effect of delayed albumin hemodilution on infarction volume and brain edema after transient middle cerebral artery occlusion in rats. J Neurosurg 87:5956011997

    • Search Google Scholar
    • Export Citation
  • 8

    Belayev LLiu YZhao WBusto RGinsberg MD: Human albumin therapy of acute ischemic stroke: marked neuroprotective efficacy at moderate doses and with a broad therapeutic window. Stroke 32:5535602001

    • Search Google Scholar
    • Export Citation
  • 9

    Belayev LObenaus AZhao WSaul IBusto RWu C: Experimental intracerebral hematoma in the rat: characterization by sequential magnetic resonance imaging, behavior, and histopathology. Effect of albumin therapy. Brain Res 1157:1461552007

    • Search Google Scholar
    • Export Citation
  • 10

    Belayev LPinard ENallet HSeylaz JLiu YRiyamongkol P: Albumin therapy of transient focal cerebral ischemia: in vivo analysis of dynamic microvascular responses. Stroke 33:107710842002

    • Search Google Scholar
    • Export Citation
  • 11

    Belayev LSaul IBusto RDanielyan KVigdorchik AKhoutorova L: Albumin treatment reduces neurological deficit and protects blood-brain barrier integrity after acute intracortical hematoma in the rat. Stroke 36:3263312005

    • Search Google Scholar
    • Export Citation
  • 12

    Belayev LZhao WPattany PMWeaver RGHuh PWLin B: Diffusion-weighted magnetic resonance imaging confirms marked neuroprotective efficacy of albumin therapy in focal cerebral ischemia. Stroke 29:258725991998

    • Search Google Scholar
    • Export Citation
  • 13

    Bellander BMvon Holst HFredman PSvensson M: Activation of the complement cascade and increase of clusterin in the brain following a cortical contusion in the adult rat. J Neurosurg 85:4684751996

    • Search Google Scholar
    • Export Citation
  • 14

    Bergsneider MHovda DAShalmon EKelly DFVespa PMMartin NA: Cerebral hyperglycolysis following severe traumatic brain injury in humans: a positron emission tomography study. J Neurosurg 86:2412511997

    • Search Google Scholar
    • Export Citation
  • 15

    Bösel JGandor FHarms CSynowitz MHarms UDjoufack PC: Neuroprotective effects of atorvastatin against glutamate-induced excitotoxicity in primary cortical neurones. J Neurochem 92:138613982005

    • Search Google Scholar
    • Export Citation
  • 16

    Brito MARosa AIFalcão ASFernandes ASilva RFButterfield DA: Unconjugated bilirubin differentially affects the redox status of neuronal and astroglial cells. Neurobiol Dis 29:30402008

    • Search Google Scholar
    • Export Citation
  • 17

    Cai YCho GSJu CWang SLRyu JHShin CY: Activated microglia are less vulnerable to hemin toxicity due to nitric oxide-dependent inhibition of JNK and p38 MAPK activation. J Immunol 187:131413212011

    • Search Google Scholar
    • Export Citation
  • 18

    Carhuapoma JRWang PYBeauchamp NJKeyl PMHanley DFBarker PB: Diffusion-weighted MRI and proton MR spectroscopic imaging in the study of secondary neuronal injury after intracerebral hemorrhage. Stroke 31:7267322000

    • Search Google Scholar
    • Export Citation
  • 19

    Castillo JDávalos AAlvarez-Sabín JPumar JMLeira RSilva Y: Molecular signatures of brain injury after intracerebral hemorrhage. Neurology 58:6246292002

    • Search Google Scholar
    • Export Citation
  • 20

    Chapman AG: Glutamate receptors in epilepsy. Prog Brain Res 116:3713831998

  • 21

    Chen LZhang XChen-Roetling JRegan RF: Increased striatal injury and behavioral deficits after intracerebral hemorrhage in hemopexin knockout mice. Laboratory investigation. J Neurosurg 114:115911672011

    • Search Google Scholar
    • Export Citation
  • 22

    Chen-Roetling JChen LRegan RF: Minocycline attenuates iron neurotoxicity in cortical cell cultures. Biochem Biophys Res Commun 386:3223262009

    • Search Google Scholar
    • Export Citation
  • 23

    Chu KJeong SWJung KHHan SYLee STKim M: Celecoxib induces functional recovery after intracerebral hemorrhage with reduction of brain edema and perihematomal cell death. J Cereb Blood Flow Metab 24:9269332004

    • Search Google Scholar
    • Export Citation
  • 24

    Coughlin SR: How the protease thrombin talks to cells. Proc Natl Acad Sci U S A 96:11023110271999

  • 25

    Coughlin SR: Thrombin signalling and protease-activated receptors. Nature 407:2582642000

  • 26

    Déry OCorvera CUSteinhoff MBunnett NW: Proteinase-activated receptors: novel mechanisms of signaling by serine proteases. Am J Physiol 274:C1429C14521998

    • Search Google Scholar
    • Export Citation
  • 27

    Donovan FMPike CJCotman CWCunningham DD: Thrombin induces apoptosis in cultured neurons and astrocytes via a pathway requiring tyrosine kinase and RhoA activities. J Neurosci 17:531653261997

    • Search Google Scholar
    • Export Citation
  • 28

    Doyle KPSimon RPStenzel-Poore MP: Mechanisms of ischemic brain damage. Neuropharmacology 55:3103182008

  • 29

    Eastern Stroke and Coronary Heart Disease Collaborative Research Group: Blood pressure, cholesterol, and stroke in eastern Asia. Lancet 352:180118071998

    • Search Google Scholar
    • Export Citation
  • 30

    Elijovich LPatel PVHemphill JC III: Intracerebral hemorrhage. Semin Neurol 28:6576672008

  • 31

    Endres MLaufs UHuang ZNakamura THuang PMoskowitz MA: Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc Natl Acad Sci U S A 95:888088851998

    • Search Google Scholar
    • Export Citation
  • 32

    Fainardi EBorrelli MSaletti ASchivalocchi RAzzini CCavallo M: CT perfusion mapping of hemodynamic disturbances associated to acute spontaneous intracerebral hemorrhage. Neuroradiology 50:7297402008

    • Search Google Scholar
    • Export Citation
  • 33

    Fayad PBAwad IA: Surgery for intracerebral hemorrhage. Neurology 51:3 Suppl 3S69S731998

  • 34

    Fernandes AFalcão ASSilva RFBrito MABrites D: MAPKs are key players in mediating cytokine release and cell death induced by unconjugated bilirubin in cultured rat cortical astrocytes. Eur J Neurosci 25:105810682007

    • Search Google Scholar
    • Export Citation
  • 35

    Galis ZSKhatri JJ: Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ Res 90:2512622002

    • Search Google Scholar
    • Export Citation
  • 36

    Gass A: Is there a penumbra surrounding intracerebral hemorrhage?. Cerebrovasc Dis 23:452007

  • 37

    Gingrich MBJunge CELyuboslavsky PTraynelis SF: Potentiation of NMDA receptor function by the serine protease thrombin. J Neurosci 20:458245952000

    • Search Google Scholar
    • Export Citation
  • 38

    Gong YXi GHKeep RFHoff JTHua Y: Complement inhibition attenuates brain edema and neurological deficits induced by thrombin. Acta Neurochir Suppl 95:3893922005

    • Search Google Scholar
    • Export Citation
  • 39

    Gottlieb MWang YTeichberg VI: Blood-mediated scavenging of cerebrospinal fluid glutamate. J Neurochem 87:1191262003

  • 40

    Grysiewicz RAThomas KPandey DK: Epidemiology of ischemic and hemorrhagic stroke: incidence, prevalence, mortality, and risk factors. Neurol Clin 26:871895vii2008

    • Search Google Scholar
    • Export Citation
  • 41

    Gu YHua YKeep RFMorgenstern LBXi G: Deferoxamine reduces intracerebral hematoma-induced iron accumulation and neuronal death in piglets. Stroke 40:224122432009

    • Search Google Scholar
    • Export Citation
  • 42

    Haley EC JrThompson JLLevin BDavis SLees KRPittman JG: Gavestinel does not improve outcome after acute intracerebral hemorrhage: an analysis from the GAIN International and GAIN Americas studies. Stroke 36:100610102005

    • Search Google Scholar
    • Export Citation
  • 43

    Hamill CEMannaioni GLyuboslavsky PSastre AATraynelis SF: Protease-activated receptor 1-dependent neuronal damage involves NMDA receptor function. Exp Neurol 217:1361462009

    • Search Google Scholar
    • Export Citation
  • 44

    Herweh CJüttler ESchellinger PDKlotz EJenetzky EOrakcioglu B: Evidence against a perihemorrhagic penumbra provided by perfusion computed tomography. Stroke 38:294129472007

    • Search Google Scholar
    • Export Citation
  • 45

    Herweh CJüttler ESchellinger PDKlotz ESchramm P: Perfusion CT in hyperacute cerebral hemorrhage within 3 hours after symptom onset: is there an early perihemorrhagic penumbra?. J Neuroimaging 20:3503532010

    • Search Google Scholar
    • Export Citation
  • 46

    Hickenbottom SLGrotta JCStrong RDenner LAAronowski J: Nuclear factor-kappaB and cell death after experimental intracerebral hemorrhage in rats. Stroke 30:247224781999

    • Search Google Scholar
    • Export Citation
  • 47

    Hillered LHallström ASegersvärd SPersson LUngerstedt U: Dynamics of extracellular metabolites in the striatum after middle cerebral artery occlusion in the rat monitored by intracerebral microdialysis. J Cereb Blood Flow Metab 9:6076161989

    • Search Google Scholar
    • Export Citation
  • 48

    Hirano TRead SJAbbott DFSachinidis JITochon-Danguy HJEgan GF: No evidence of hypoxic tissue on 18F-fluoromisonidazole PET after intracerebral hemorrhage. Neurology 53:217921821999

    • Search Google Scholar
    • Export Citation
  • 49

    Hollenberg MDCompton SJ: International Union of Pharmacology. XXVIII. Proteinase-activated receptors. Pharmacol Rev 54:2032172002

    • Search Google Scholar
    • Export Citation
  • 50

    Hua YKeep RFHoff JTXi G: Brain injury after intracerebral hemorrhage: the role of thrombin and iron. Stroke 38:2 Suppl7597622007

    • Search Google Scholar
    • Export Citation
  • 51

    Hua YKeep RFHoff JTXi G: Deferoxamine therapy for intracerebral hemorrhage. Acta Neurochir Suppl 105:362008

  • 52

    Hua YKeep RFHoff JTXi G: Thrombin preconditioning attenuates brain edema induced by erythrocytes and iron. J Cereb Blood Flow Metab 23:144814542003

    • Search Google Scholar
    • Export Citation
  • 53

    Hua YSchallert TKeep RFWu JHoff JTXi G: Behavioral tests after intracerebral hemorrhage in the rat. Stroke 33:247824842002

    • Search Google Scholar
    • Export Citation
  • 54

    Hua YWu JKeep RFNakamura THoff JTXi G: Tumor necrosis factor-alpha increases in the brain after intracerebral hemorrhage and thrombin stimulation. Neurosurgery 58:5425502006

    • Search Google Scholar
    • Export Citation
  • 55

    Hua YXi GKeep RFHoff JT: Complement activation in the brain after experimental intracerebral hemorrhage. J Neurosurg 92:101610222000

    • Search Google Scholar
    • Export Citation
  • 56

    Hua YXi GKeep RFWu JJiang YHoff JT: Plasminogen activator inhibitor-1 induction after experimental intracerebral hemorrhage. J Cereb Blood Flow Metab 22:55612002

    • Search Google Scholar
    • Export Citation
  • 57

    Huffman LJMiles PRShi XBowman L: Hemoglobin potentiates the production of reactive oxygen species by alveolar macrophages. Exp Lung Res 26:2032172000

    • Search Google Scholar
    • Export Citation
  • 58

    Hurtado OMoro MACárdenas ASánchez VFernández-Tomé PLeza JC: Neuroprotection afforded by prior citicoline administration in experimental brain ischemia: effects on glutamate transport. Neurobiol Dis 18:3363452005

    • Search Google Scholar
    • Export Citation
  • 59

    Iłzecka J: Prostaglandin E2 is increased in amyotrophic lateral sclerosis patients. Acta Neurol Scand 108:1251292003

  • 60

    Iranmanesh FVakilian A: Efficiency of citicoline in increasing muscular strength of patients with nontraumatic cerebral hemorrhage: a double-blind randomized clinical trial. J Stroke Cerebrovasc Dis 17:1531552008

    • Search Google Scholar
    • Export Citation
  • 61

    James MLWarner DSLaskowitz DT: Preclinical models of intracerebral hemorrhage: a translational perspective. Neurocrit Care 9:1391522008

    • Search Google Scholar
    • Export Citation
  • 62

    Jiang YWu JHua YKeep RFXiang JHoff JT: Thrombin-receptor activation and thrombin-induced brain tolerance. J Cereb Blood Flow Metab 22:4044102002

    • Search Google Scholar
    • Export Citation
  • 63

    Jung KHChu KJeong SWHan SYLee STKim JY: HMG-CoA reductase inhibitor, atorvastatin, promotes sensorimotor recovery, suppressing acute inflammatory reaction after experimental intracerebral hemorrhage. Stroke 35:174417492004

    • Search Google Scholar
    • Export Citation
  • 64

    Junge CESugawara TMannaioni GAlagarsamy SConn PJBrat DJ: The contribution of protease-activated receptor 1 to neuronal damage caused by transient focal cerebral ischemia. Proc Natl Acad Sci U S A 100:13019130242003

    • Search Google Scholar
    • Export Citation
  • 65

    Kazui SNaritomi HYamamoto HSawada TYamaguchi T: Enlargement of spontaneous intracerebral hemorrhage. Incidence and time course. Stroke 27:178317871996

    • Search Google Scholar
    • Export Citation
  • 66

    Kellner CPConnolly ES Jr: Neuroprotective strategies for intracerebral hemorrhage: trials and translation. Stroke 41:10 SupplS99S1022010

    • Search Google Scholar
    • Export Citation
  • 67

    Kim YSKim SSCho JJChoi DHHwang OShin DH: Matrix metalloproteinase-3: a novel signaling proteinase from apoptotic neuronal cells that activates microglia. J Neurosci 25:370137112005

    • Search Google Scholar
    • Export Citation
  • 68

    Kitaoka THua YXi GHoff JTKeep RF: Delayed argatroban treatment reduces edema in a rat model of intracerebral hemorrhage. Stroke 33:301230182002

    • Search Google Scholar
    • Export Citation
  • 69

    Kitaoka THua YXi GNagao SHoff JTKeep RF: Effect of delayed argatroban treatment on intracerebral hemorrhage-induced edema in the rat. Acta Neurochir Suppl 86:4574612003

    • Search Google Scholar
    • Export Citation
  • 70

    Kutty RKMaines MD: Purification and characterization of biliverdin reductase from rat liver. J Biol Chem 256:395639621981

  • 71

    Lampl YBoaz MGilad RLorberboym MDabby RRapoport A: Minocycline treatment in acute stroke: an open-label, evaluator-blinded study. Neurology 69:140414102007

    • Search Google Scholar
    • Export Citation
  • 72

    Lauer ACianchetti FAVan Cott EMSchlunk FSchulz EPfeilschifter W: Anticoagulation with the oral direct thrombin inhibitor dabigatran does not enlarge hematoma volume in experimental intracerebral hemorrhage. Circulation 124:165416622011

    • Search Google Scholar
    • Export Citation
  • 73

    Laufs UGertz KHuang PNickenig GBöhm MDirnagl U: Atorvastatin upregulates type III nitric oxide synthase in thrombocytes, decreases platelet activation, and protects from cerebral ischemia in normocholesterolemic mice. Stroke 31:244224492000

    • Search Google Scholar
    • Export Citation
  • 74

    Lee KRColon GPBetz ALKeep RFKim SHoff JT: Edema from intracerebral hemorrhage: the role of thrombin. J Neurosurg 84:91961996

    • Search Google Scholar
    • Export Citation
  • 75

    Lee KRKawai NKim SSagher OHoff JT: Mechanisms of edema formation after intracerebral hemorrhage: effects of thrombin on cerebral blood flow, blood-brain barrier permeability, and cell survival in a rat model. J Neurosurg 86:2722781997

    • Search Google Scholar
    • Export Citation
  • 76

    Li RCSaleem SZhen GCao WZhuang HLee J: Hemehemopexin complex attenuates neuronal cell death and stroke damage. J Cereb Blood Flow Metab 29:9539642009

    • Search Google Scholar
    • Export Citation
  • 77

    Lyden PDShuaib ALees KRDavalos ADavis SMDiener HC: Safety and tolerability of NXY-059 for acute intracerebral hemorrhage: the CHANT Trial. Stroke 38:226222692007

    • Search Google Scholar
    • Export Citation
  • 78

    Macfarlane SRSeatter MJKanke THunter GDPlevin R: Proteinase-activated receptors. Pharmacol Rev 53:2452822001

  • 79

    Masada TXi GHua YKeep RF: The effects of thrombin preconditioning on focal cerebral ischemia in rats. Brain Res 867:1731792000

    • Search Google Scholar
    • Export Citation
  • 80

    Matz PGWeinstein PRSharp FR: Heme oxygenase-1 and heat shock protein 70 induction in glia and neurons throughout rat brain after experimental intracerebral hemorrhage. Neurosurgery 40:1521621997

    • Search Google Scholar
    • Export Citation
  • 81

    Mendelow AD: Mechanisms of ischemic brain damage with intracerebral hemorrhage. Stroke 24:12 SupplI115I1191993

  • 82

    Mendelow ADBullock RTeasdale GMGraham DIMcCulloch J: Intracranial haemorrhage induced at arterial pressure in the rat. Part 2: Short term changes in local cerebral blood flow measured by autoradiography. Neurol Res 6:1891931984

    • Search Google Scholar
    • Export Citation
  • 83

    Misra UKKalita JRanjan PMandal SK: Mannitol in intracerebral hemorrhage: a randomized controlled study. J Neurol Sci 234:41452005

    • Search Google Scholar
    • Export Citation
  • 84

    Mutlu NBerry RGAlpers BJ: Massive cerebral hemorrhage. Clinical and pathological correlations. Arch Neurol 8:6446611963

  • 85

    Nakajima RNakamura TMiyakawa HKudo Y: Effects of mannitol on ischemia-induced degeneration in rat hippocampus. J Pharmacol Sci 95:3413482004

    • Search Google Scholar
    • Export Citation
  • 86

    Nakamura TKeep RFHua YHoff JTXi G: Oxidative DNA injury after experimental intracerebral hemorrhage. Brain Res 1039:30362005

    • Search Google Scholar
    • Export Citation
  • 87

    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

    • Search Google Scholar
    • Export Citation
  • 88

    Nath FPJenkins AMendelow ADGraham DITeasdale GM: Early hemodynamic changes in experimental intracerebral hemorrhage. J Neurosurg 65:6977031986

    • Search Google Scholar
    • Export Citation
  • 89

    Nath FPKelly PTJenkins AMendelow ADGraham DITeasdale GM: Effects of experimental intracerebral hemorrhage on blood flow, capillary permeability, and histochemistry. J Neurosurg 66:5555621987

    • Search Google Scholar
    • Export Citation
  • 90

    Noorbakhsh FVergnolle NHollenberg MDPower C: Proteinase-activated receptors in the nervous system. Nat Rev Neurosci 4:9819902003

    • Search Google Scholar
    • Export Citation
  • 91

    Ohnishi MKatsuki HFujimoto STakagi MKume TAkaike A: Involvement of thrombin and mitogen-activated protein kinase pathways in hemorrhagic brain injury. Exp Neurol 206:43522007

    • Search Google Scholar
    • Export Citation
  • 92

    Ortego MBustos CHernández-Presa MATunón JDíaz CHernández G: Atorvastatin reduces NF-kappaB activation and chemokine expression in vascular smooth muscle cells and mononuclear cells. Atherosclerosis 147:2532611999

    • Search Google Scholar
    • Export Citation
  • 93

    Park HKLee SHChu KRoh JK: Effects of celecoxib on volumes of hematoma and edema in patients with primary intracerebral hemorrhage. J Neurol Sci 279:43462009

    • Search Google Scholar
    • Export Citation
  • 94

    Peeling JDel Bigio MRCorbett DGreen ARJackson DM: Efficacy of disodium 4-[(tert-butylimino)methyl]benzene-1,3-disulfonate N-oxide (NXY-059), a free radical trapping agent, in a rat model of hemorrhagic stroke. Neuropharmacology 40:4334392001

    • Search Google Scholar
    • Export Citation
  • 95

    Peeling JYan HJChen SGCampbell MDel Bigio MR: Protective effects of free radical inhibitors in intracerebral hemorrhage in rat. Brain Res 795:63701998

    • Search Google Scholar
    • Export Citation
  • 96

    Power CHenry SDel Bigio MRLarsen PHCorbett DImai Y: Intracerebral hemorrhage induces macrophage activation and matrix metalloproteinases. Ann Neurol 53:7317422003

    • Search Google Scholar
    • Export Citation
  • 97

    Qureshi AIAli ZSuri MFShuaib ABaker GTodd K: Extracellular glutamate and other amino acids in experimental intracerebral hemorrhage: an in vivo microdialysis study. Crit Care Med 31:148214892003

    • Search Google Scholar
    • Export Citation
  • 98

    Qureshi AIMendelow ADHanley DF: Intracerebral haemorrhage. Lancet 373:163216442009

  • 99

    Qureshi AITuhrim SBroderick JPBatjer HHHondo HHanley DF: Spontaneous intracerebral hemorrhage. N Engl J Med 344:145014602001

    • Search Google Scholar
    • Export Citation
  • 100

    Qureshi AIWilson DAHanley DFTraystman RJ: No evidence for an ischemic penumbra in massive experimental intracerebral hemorrhage. Neurology 52:2662721999

    • Search Google Scholar
    • Export Citation
  • 101

    Rasool AHRahman ARChoudhury SRSingh RB: Blood pressure in acute intracerebral haemorrhage. J Hum Hypertens 18:1871922004

  • 102

    Regan RFWang YMa XChong AGuo Y: Activation of extracellular signal-regulated kinases potentiates hemin toxicity in astrocyte cultures. J Neurochem 79:5455552001

    • Search Google Scholar
    • Export Citation
  • 103

    Robinson SRDang TNDringen RBishop GM: Hemin toxicity: a preventable source of brain damage following hemorrhagic stroke. Redox Rep 14:2282352009

    • Search Google Scholar
    • Export Citation
  • 104

    Rodrigues CMSolá SBrito MABrondino CDBrites DMoura JJ: Amyloid beta-peptide disrupts mitochondrial membrane lipid and protein structure: protective role of tauroursodeoxycholate. Biochem Biophys Res Commun 281:4684742001

    • Search Google Scholar
    • Export Citation
  • 105

    Rodrigues CMSola SNan ZCastro RERibeiro PSLow WC: Tauroursodeoxycholic acid reduces apoptosis and protects against neurological injury after acute hemorrhagic stroke in rats. Proc Natl Acad Sci U S A 100:608760922003

    • Search Google Scholar
    • Export Citation
  • 106

    Ropper AHZervas NT: Cerebral blood flow after experimental basal ganglia hemorrhage. Ann Neurol 11:2662711982

  • 107

    Rosamond WFlegal KFurie KGo AGreenlund KHaase N: Heart disease and stroke statistics—2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 117:e25e1462008. (Erratum in Circulation 122:e10 2010)

    • Search Google Scholar
    • Export Citation
  • 108

    Ryu JMin KJRhim TYKim THPyo HJin B: Prothrombin kringle-2 activates cultured rat brain microglia. J Immunol 168:580558102002

    • Search Google Scholar
    • Export Citation
  • 109

    Schellinger PDFiebach JBHoffmann KBecker KOrakcioglu BKollmar R: Stroke MRI in intracerebral hemorrhage: is there a perihemorrhagic penumbra?. Stroke 34:167416792003

    • Search Google Scholar
    • Export Citation
  • 110

    Secades JJAlvarez-Sabín JRubio FLozano RDávalos ACastillo J: Citicoline in intracerebral haemorrhage: a double-blind, randomized, placebo-controlled, multi-centre pilot study. Cerebrovasc Dis 21:3803852006

    • Search Google Scholar
    • Export Citation
  • 111

    Selim M: Deferoxamine mesylate: a new hope for intracerebral hemorrhage: from bench to clinical trials. Stroke 40:3 SupplS90S912009

    • Search Google Scholar
    • Export Citation
  • 112

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

    • Search Google Scholar
    • Export Citation
  • 113

    Sharp FLiu DZZhan XAnder BP: Intracerebral hemorrhage injury mechanisms: glutamate neurotoxicity, thrombin, and Src. Acta Neurochir Suppl 105:43462008

    • Search Google Scholar
    • Export Citation
  • 114

    Shimazu TInoue IAraki NAsano YSawada MFuruya D: A peroxisome proliferator-activated receptor-gamma agonist reduces infarct size in transient but not in permanent ischemia. Stroke 36:3533592005

    • Search Google Scholar
    • Export Citation
  • 115

    Silva RFRodrigues CMBrites D: Rat cultured neuronal and glial cells respond differently to toxicity of unconjugated bilirubin. Pediatr Res 51:5355412002

    • Search Google Scholar
    • Export Citation
  • 116

    Sinn DILee STChu KJung KHSong ECKim JM: Combined neuroprotective effects of celecoxib and memantine in experimental intracerebral hemorrhage. Neurosci Lett 411:2382422007

    • Search Google Scholar
    • Export Citation
  • 117

    Solomon SDMcMurray JJPfeffer MAWittes JFowler RFinn P: Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 352:107110802005

    • Search Google Scholar
    • Export Citation
  • 118

    Steiner TRosand JDiringer M: Intracerebral hemorrhage associated with oral anticoagulant therapy: current practices and unresolved questions. Stroke 37:2562622006

    • Search Google Scholar
    • Export Citation
  • 119

    Suidan HSStone SRHemmings BAMonard D: Thrombin causes neurite retraction in neuronal cells through activation of cell surface receptors. Neuron 8:3633751992

    • Search Google Scholar
    • Export Citation
  • 120

    Suo ZWu MAmeenuddin SAnderson HEZoloty JECitron BA: Participation of protease-activated receptor-1 in thrombin-induced microglial activation. J Neurochem 80:6556662002

    • Search Google Scholar
    • Export Citation
  • 121

    Suzuki MOgawa ASakurai YNishino AVenohara KMizoi K: Thrombin activity in cerebrospinal fluid after subarachnoid hemorrhage. Stroke 23:118111821992

    • Search Google Scholar
    • Export Citation
  • 122

    Suzuki RYamaguchi TKirino TOrzi FKlatzo I: The effects of 5-minute ischemia in Mongolian gerbils: I. Blood-brain barrier, cerebral blood flow, and local cerebral glucose utilization changes. Acta Neuropathol 60:2072161983

    • Search Google Scholar
    • Export Citation
  • 123

    Tanaka HUeda YHayashi MDate CBaba TYamashita H: Risk factors for cerebral hemorrhage and cerebral infarction in a Japanese rural community. Stroke 13:62731982

    • Search Google Scholar
    • Export Citation
  • 124

    Tapia-Perez HSanchez-Aguilar MTorres-Corzo JGRodriguez-Leyva IGonzalez-Aguirre DGordillo-Moscoso A: Use of statins for the treatment of spontaneous intracerebral hemorrhage: results of a pilot study. Cen Eur Neurosurg 70:15202009

    • Search Google Scholar
    • Export Citation
  • 125

    Tolosano EAltruda F: Hemopexin: structure, function, and regulation. DNA Cell Biol 21:2973062002

  • 126

    Traystman RJKirsch JRKoehler RC: Oxygen radical mechanisms of brain injury following ischemia and reperfusion. J Appl Physiol 71:118511951991

    • Search Google Scholar
    • Export Citation
  • 127

    Tseng MY: Summary of evidence on immediate statins therapy following aneurysmal subarachnoid hemorrhage. Neurocrit Care 15:2983012011

    • Search Google Scholar
    • Export Citation
  • 128

    Turgeon VLLloyd EDWang SFestoff BWHouenou LJ: Thrombin perturbs neurite outgrowth and induces apoptotic cell death in enriched chick spinal motoneuron cultures through caspase activation. J Neurosci 18:688268911998

    • Search Google Scholar
    • Export Citation
  • 129

    Turgeon VLMilligan CEHouenou LJ: Activation of the protease-activated thrombin receptor (PAR)-1 induces motoneuron degeneration in the developing avian embryo. J Neuropathol Exp Neurol 58:4995041999

    • Search Google Scholar
    • Export Citation
  • 130

    Vespa PPrins MRonne-Engstrom ECaron MShalmon EHovda DA: Increase in extracellular glutamate caused by reduced cerebral perfusion pressure and seizures after human traumatic brain injury: a microdialysis study. J Neurosurg 89:9719821998

    • Search Google Scholar
    • Export Citation
  • 131

    Vespa PMO'Phelan KShah MMirabelli JStarkman SKidwell C: Acute seizures after intracerebral hemorrhage: a factor in progressive midline shift and outcome. Neurology 60:144114462003

    • Search Google Scholar
    • Export Citation
  • 132

    Vu TKHung DTWheaton VICoughlin SR: Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 64:105710681991

    • Search Google Scholar
    • Export Citation
  • 133

    Wagner KRSharp FRArdizzone TDLu AClark JF: Heme and iron metabolism: role in cerebral hemorrhage. J Cereb Blood Flow Metab 23:6296522003

    • Search Google Scholar
    • Export Citation
  • 134

    Wagner KRXi GHua YKleinholz Mde Courten-Myers GMMyers RE: Lobar intracerebral hemorrhage model in pigs: rapid edema development in perihematomal white matter. Stroke 27:4904971996

    • Search Google Scholar
    • Export Citation
  • 135

    Wang XMori TSumii TLo EH: Hemoglobin-induced cytotoxicity in rat cerebral cortical neurons: caspase activation and oxidative stress. Stroke 33:188218882002

    • Search Google Scholar
    • Export Citation
  • 136

    Wells JEBiernaskie JSzymanska ALarsen PHYong VWCorbett D: Matrix metalloproteinase (MMP)-12 expression has a negative impact on sensorimotor function following intracerebral haemorrhage in mice. Eur J Neurosci 21:1871962005

    • Search Google Scholar
    • Export Citation
  • 137

    West KLAdamson CHoffman M: Prophylactic correction of the international normalized ratio in neurosurgery: a brief review of a brief literature. A review. J Neurosurg 114:9182011

    • Search Google Scholar
    • Export Citation
  • 138

    Wu GXi GHuang F: Spontaneous intracerebral hemorrhage in humans: hematoma enlargement, clot lysis, and brain edema. Acta Neurochir Suppl 96:78802006

    • Search Google Scholar
    • Export Citation
  • 139

    Wu JHua YKeep RFNakamura THoff JTXi G: Iron and iron-handling proteins in the brain after intracerebral hemorrhage. Stroke 34:296429692003

    • Search Google Scholar
    • Export Citation
  • 140

    Wu JHua YKeep RFSchallert THoff JTXi G: Oxidative brain injury from extravasated erythrocytes after intracerebral hemorrhage. Brain Res 953:45522002

    • Search Google Scholar
    • Export Citation
  • 141

    Wu JYang SXi GFu GKeep RFHua Y: Minocycline reduces intracerebral hemorrhage-induced brain injury. Neurol Res 31:1831882009

    • Search Google Scholar
    • Export Citation
  • 142

    Wu JYang SXi GSong SFu GKeep RF: Microglial activation and brain injury after intracerebral hemorrhage. Acta Neurochir Suppl 105:59652008

    • Search Google Scholar
    • Export Citation
  • 143

    Xi GHua YBhasin RREnnis SRKeep RFHoff JT: Mechanisms of edema formation after intracerebral hemorrhage: effects of extravasated red blood cells on blood flow and blood-brain barrier integrity. Stroke 32:293229382001

    • Search Google Scholar
    • Export Citation
  • 144

    Xi GHua YKeep RFHoff JT: Induction of colligin may attenuate brain edema following intracerebral hemorrhage. Acta Neurochir Suppl 76:5015052000

    • Search Google Scholar
    • Export Citation
  • 145

    Xi GKeep RFHoff JT: Erythrocytes and delayed brain edema formation following intracerebral hemorrhage in rats. J Neurosurg 89:9919961998

    • Search Google Scholar
    • Export Citation
  • 146

    Xi GKeep RFHoff JT: Mechanisms of brain injury after intracerebral haemorrhage. Lancet Neurol 5:53632006

  • 147

    Xi GKeep RFHua YXiang JHoff JT: Attenuation of thrombin-induced brain edema by cerebral thrombin preconditioning. Stroke 30:124712551999

    • Search Google Scholar
    • Export Citation
  • 148

    Xi GReiser GKeep RF: The role of thrombin and thrombin receptors in ischemic, hemorrhagic and traumatic brain injury: deleterious or protective?. J Neurochem 84:392003

    • Search Google Scholar
    • Export Citation
  • 149

    Xue MHollenberg MDDemchuk AYong VW: Relative importance of proteinase-activated receptor-1 versus matrix metalloproteinases in intracerebral hemorrhage-mediated neurotoxicity in mice. Stroke 40:219922042009

    • Search Google Scholar
    • Export Citation
  • 150

    Xue MHollenberg MDYong VW: Combination of thrombin and matrix metalloproteinase-9 exacerbates neurotoxicity in cell culture and intracerebral hemorrhage in mice. J Neurosci 26:10281102912006

    • Search Google Scholar
    • Export Citation
  • 151

    Yang GYBetz ALChenevert TLBrunberg JAHoff JT: Experimental intracerebral hemorrhage: relationship between brain edema, blood flow, and blood-brain barrier permeability in rats. J Neurosurg 81:931021994

    • Search Google Scholar
    • Export Citation
  • 152

    Yu YLKumana CRLauder IJCheung YKChan FLKou M: Treatment of acute cerebral hemorrhage with intravenous glycerol. A double-blind, placebo-controlled, randomized trial. Stroke 23:9679711992

    • Search Google Scholar
    • Export Citation
  • 153

    Zazulia ARDiringer MNVideen TOAdams REYundt KAiyagari V: Hypoperfusion without ischemia surrounding acute intracerebral hemorrhage. J Cereb Blood Flow Metab 21:8048102001

    • Search Google Scholar
    • Export Citation
  • 154

    Zazulia ARVideen TOPowers WJ: Transient focal increase in perihematomal glucose metabolism after acute human intracerebral hemorrhage. Stroke 40:163816432009

    • Search Google Scholar
    • Export Citation
  • 155

    Zhao FHua YHe YKeep RFXi G: Minocycline-induced attenuation of iron overload and brain injury after experimental intracerebral hemorrhage. Stroke 42:358735932011

    • Search Google Scholar
    • Export Citation
  • 156

    Zhao XGrotta JGonzales NAronowski J: Hematoma resolution as a therapeutic target: the role of microglia/macrophages. Stroke 40:3 SupplS92S942009

    • Search Google Scholar
    • Export Citation
  • 157

    Zhao XSong SSun GStrong RZhang JGrotta JC: Neuroprotective role of haptoglobin after intracerebral hemorrhage. J Neurosci 29:15819158272009

    • Search Google Scholar
    • Export Citation
  • 158

    Zhao XSun GZhang JStrong RDash PKKan YW: Transcription factor Nrf2 protects the brain from damage produced by intracerebral hemorrhage. Stroke 38:328032862007

    • Search Google Scholar
    • Export Citation
  • 159

    Zhao XSun GZhang JStrong RSong WGonzales N: Hematoma resolution as a target for intracerebral hemorrhage treatment: role for peroxisome proliferator-activated receptor gamma in microglia/macrophages. Ann Neurol 61:3523622007

    • Search Google Scholar
    • Export Citation
  • 160

    Zhao XZhang YStrong RGrotta JCAronowski J: 15d-Prostaglandin J2 activates peroxisome proliferator-activated receptor-gamma, promotes expression of catalase, and reduces inflammation, behavioral dysfunction, and neuronal loss after intracerebral hemorrhage in rats. J Cereb Blood Flow Metab 26:8118202006

    • Search Google Scholar
    • Export Citation
  • 161

    Zhao XZhang YStrong RZhang JGrotta JCAronowski J: Distinct patterns of intracerebral hemorrhage-induced alterations in NF-kappaB subunit, iNOS, and COX-2 expression. J Neurochem 101:6526632007

    • Search Google Scholar
    • Export Citation
  • 162

    Zheng GQWang XTWang XMGao RRZeng XLFu XL: Long-time course of protease-activated receptor-1 expression after intracerebral hemorrhage in rats. Neurosci Lett 459:62652009

    • Search Google Scholar
    • Export Citation
  • 163

    Zhou ZHQu FZhang CD: Systemic administration of argatroban inhibits protease-activated receptor-1 expression in perihematomal tissue in rats with intracerebral hemorrhage. Brain Res Bull 86:2352382011

    • Search Google Scholar
    • Export Citation
  • 164

    Zlotnik AGurevich BTkachov SMaoz IShapira YTeichberg VI: Brain neuroprotection by scavenging blood glutamate. Exp Neurol 203:2132202007

    • Search Google Scholar
    • Export Citation

If the inline PDF is not rendering correctly, you can download the PDF file here.

Article Information

Address correspondence to: Cory Adamson, M.D., Ph.D., M.P.H., M.H.Sc., DUMC Box 2624, Durham, North Carolina 27710. email: cory.adamson@duke.edu.

Please include this information when citing this paper: DOI: 10.3171/2012.1.FOCUS11366.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Mechanisms and potential treatments for primary and secondary brain injury following ICH.

  • View in gallery

    Once released after ICH, thrombin is able to activate the complement pathway and PARs. This leads to a variety of cytotoxic, excitotoxic, and inflammatory effects that all lead to secondary brain injury. MAPKs = mitogen-activated protein kinases.

  • View in gallery

    Hemolysis leads to the release of hemin into the extracellular space. Hemin may then intercalate into cell membranes or enter cells via the heme carrier protein 1 (HCP1). Intracellularly hemin may activate cytotoxic and inflammatory pathways. It is then degraded by heme oxygenases, producing prooxidative iron, carbon monoxide (CO), and bilirubin. Thus far, the role of CO and bilirubin in ICH-mediated injury is unclear. Hb = hemoglobin; HO-1 = heme oxygenase-1; ROS = reactive oxygen species.

References

  • 1

    Adibhatla RMHatcher JFDempsey RJ: Citicoline: neuroprotective mechanisms in cerebral ischemia. J Neurochem 80:12232002

  • 2

    Alvarez-Sabín JDelgado PAbilleira SMolina CAArenillas JRibó M: Temporal profile of matrix metalloproteinases and their inhibitors after spontaneous intracerebral hemorrhage: relationship to clinical and radiological outcome. Stroke 35:131613222004

    • Search Google Scholar
    • Export Citation
  • 3

    Aronowski JZhao X: Molecular pathophysiology of cerebral hemorrhage: secondary brain injury. Stroke 42:178117862011

  • 4

    Balla GJacob HSEaton JWBelcher JDVercellotti GM: Hemin: a possible physiological mediator of low density lipoprotein oxidation and endothelial injury. Arterioscler Thromb 11:170017111991

    • Search Google Scholar
    • Export Citation
  • 5

    Barnes PJKarin M: Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 336:106610711997

    • Search Google Scholar
    • Export Citation
  • 6

    Barone FCFeuerstein GZ: Inflammatory mediators and stroke: new opportunities for novel therapeutics. J Cereb Blood Flow Metab 19:8198341999

    • Search Google Scholar
    • Export Citation
  • 7

    Belayev LBusto RZhao WClemens JAGinsberg MD: Effect of delayed albumin hemodilution on infarction volume and brain edema after transient middle cerebral artery occlusion in rats. J Neurosurg 87:5956011997

    • Search Google Scholar
    • Export Citation
  • 8

    Belayev LLiu YZhao WBusto RGinsberg MD: Human albumin therapy of acute ischemic stroke: marked neuroprotective efficacy at moderate doses and with a broad therapeutic window. Stroke 32:5535602001

    • Search Google Scholar
    • Export Citation
  • 9

    Belayev LObenaus AZhao WSaul IBusto RWu C: Experimental intracerebral hematoma in the rat: characterization by sequential magnetic resonance imaging, behavior, and histopathology. Effect of albumin therapy. Brain Res 1157:1461552007

    • Search Google Scholar
    • Export Citation
  • 10

    Belayev LPinard ENallet HSeylaz JLiu YRiyamongkol P: Albumin therapy of transient focal cerebral ischemia: in vivo analysis of dynamic microvascular responses. Stroke 33:107710842002

    • Search Google Scholar
    • Export Citation
  • 11

    Belayev LSaul IBusto RDanielyan KVigdorchik AKhoutorova L: Albumin treatment reduces neurological deficit and protects blood-brain barrier integrity after acute intracortical hematoma in the rat. Stroke 36:3263312005

    • Search Google Scholar
    • Export Citation
  • 12

    Belayev LZhao WPattany PMWeaver RGHuh PWLin B: Diffusion-weighted magnetic resonance imaging confirms marked neuroprotective efficacy of albumin therapy in focal cerebral ischemia. Stroke 29:258725991998

    • Search Google Scholar
    • Export Citation
  • 13

    Bellander BMvon Holst HFredman PSvensson M: Activation of the complement cascade and increase of clusterin in the brain following a cortical contusion in the adult rat. J Neurosurg 85:4684751996

    • Search Google Scholar
    • Export Citation
  • 14

    Bergsneider MHovda DAShalmon EKelly DFVespa PMMartin NA: Cerebral hyperglycolysis following severe traumatic brain injury in humans: a positron emission tomography study. J Neurosurg 86:2412511997

    • Search Google Scholar
    • Export Citation
  • 15

    Bösel JGandor FHarms CSynowitz MHarms UDjoufack PC: Neuroprotective effects of atorvastatin against glutamate-induced excitotoxicity in primary cortical neurones. J Neurochem 92:138613982005

    • Search Google Scholar
    • Export Citation
  • 16

    Brito MARosa AIFalcão ASFernandes ASilva RFButterfield DA: Unconjugated bilirubin differentially affects the redox status of neuronal and astroglial cells. Neurobiol Dis 29:30402008

    • Search Google Scholar
    • Export Citation
  • 17

    Cai YCho GSJu CWang SLRyu JHShin CY: Activated microglia are less vulnerable to hemin toxicity due to nitric oxide-dependent inhibition of JNK and p38 MAPK activation. J Immunol 187:131413212011

    • Search Google Scholar
    • Export Citation
  • 18

    Carhuapoma JRWang PYBeauchamp NJKeyl PMHanley DFBarker PB: Diffusion-weighted MRI and proton MR spectroscopic imaging in the study of secondary neuronal injury after intracerebral hemorrhage. Stroke 31:7267322000

    • Search Google Scholar
    • Export Citation
  • 19

    Castillo JDávalos AAlvarez-Sabín JPumar JMLeira RSilva Y: Molecular signatures of brain injury after intracerebral hemorrhage. Neurology 58:6246292002

    • Search Google Scholar
    • Export Citation
  • 20

    Chapman AG: Glutamate receptors in epilepsy. Prog Brain Res 116:3713831998

  • 21

    Chen LZhang XChen-Roetling JRegan RF: Increased striatal injury and behavioral deficits after intracerebral hemorrhage in hemopexin knockout mice. Laboratory investigation. J Neurosurg 114:115911672011

    • Search Google Scholar
    • Export Citation
  • 22

    Chen-Roetling JChen LRegan RF: Minocycline attenuates iron neurotoxicity in cortical cell cultures. Biochem Biophys Res Commun 386:3223262009

    • Search Google Scholar
    • Export Citation
  • 23

    Chu KJeong SWJung KHHan SYLee STKim M: Celecoxib induces functional recovery after intracerebral hemorrhage with reduction of brain edema and perihematomal cell death. J Cereb Blood Flow Metab 24:9269332004

    • Search Google Scholar
    • Export Citation
  • 24

    Coughlin SR: How the protease thrombin talks to cells. Proc Natl Acad Sci U S A 96:11023110271999

  • 25

    Coughlin SR: Thrombin signalling and protease-activated receptors. Nature 407:2582642000

  • 26

    Déry OCorvera CUSteinhoff MBunnett NW: Proteinase-activated receptors: novel mechanisms of signaling by serine proteases. Am J Physiol 274:C1429C14521998

    • Search Google Scholar
    • Export Citation
  • 27

    Donovan FMPike CJCotman CWCunningham DD: Thrombin induces apoptosis in cultured neurons and astrocytes via a pathway requiring tyrosine kinase and RhoA activities. J Neurosci 17:531653261997

    • Search Google Scholar
    • Export Citation
  • 28

    Doyle KPSimon RPStenzel-Poore MP: Mechanisms of ischemic brain damage. Neuropharmacology 55:3103182008

  • 29

    Eastern Stroke and Coronary Heart Disease Collaborative Research Group: Blood pressure, cholesterol, and stroke in eastern Asia. Lancet 352:180118071998

    • Search Google Scholar
    • Export Citation
  • 30

    Elijovich LPatel PVHemphill JC III: Intracerebral hemorrhage. Semin Neurol 28:6576672008

  • 31

    Endres MLaufs UHuang ZNakamura THuang PMoskowitz MA: Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc Natl Acad Sci U S A 95:888088851998

    • Search Google Scholar
    • Export Citation
  • 32

    Fainardi EBorrelli MSaletti ASchivalocchi RAzzini CCavallo M: CT perfusion mapping of hemodynamic disturbances associated to acute spontaneous intracerebral hemorrhage. Neuroradiology 50:7297402008

    • Search Google Scholar
    • Export Citation
  • 33

    Fayad PBAwad IA: Surgery for intracerebral hemorrhage. Neurology 51:3 Suppl 3S69S731998

  • 34

    Fernandes AFalcão ASSilva RFBrito MABrites D: MAPKs are key players in mediating cytokine release and cell death induced by unconjugated bilirubin in cultured rat cortical astrocytes. Eur J Neurosci 25:105810682007

    • Search Google Scholar
    • Export Citation
  • 35

    Galis ZSKhatri JJ: Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ Res 90:2512622002

    • Search Google Scholar
    • Export Citation
  • 36

    Gass A: Is there a penumbra surrounding intracerebral hemorrhage?. Cerebrovasc Dis 23:452007

  • 37

    Gingrich MBJunge CELyuboslavsky PTraynelis SF: Potentiation of NMDA receptor function by the serine protease thrombin. J Neurosci 20:458245952000

    • Search Google Scholar
    • Export Citation
  • 38

    Gong YXi GHKeep RFHoff JTHua Y: Complement inhibition attenuates brain edema and neurological deficits induced by thrombin. Acta Neurochir Suppl 95:3893922005

    • Search Google Scholar
    • Export Citation
  • 39

    Gottlieb MWang YTeichberg VI: Blood-mediated scavenging of cerebrospinal fluid glutamate. J Neurochem 87:1191262003

  • 40

    Grysiewicz RAThomas KPandey DK: Epidemiology of ischemic and hemorrhagic stroke: incidence, prevalence, mortality, and risk factors. Neurol Clin 26:871895vii2008

    • Search Google Scholar
    • Export Citation
  • 41

    Gu YHua YKeep RFMorgenstern LBXi G: Deferoxamine reduces intracerebral hematoma-induced iron accumulation and neuronal death in piglets. Stroke 40:224122432009

    • Search Google Scholar
    • Export Citation
  • 42

    Haley EC JrThompson JLLevin BDavis SLees KRPittman JG: Gavestinel does not improve outcome after acute intracerebral hemorrhage: an analysis from the GAIN International and GAIN Americas studies. Stroke 36:100610102005