Mechanisms of Cerebral Hemorrhage

8 

Mechanisms of Cerebral Hemorrhage Jaroslaw Aronowski, Kenneth R. Wagner, Guohua Xi, John H. Zhang

KEY POINTS • The mechanisms triggering brain damage after intracerebral hemorrhage (ICH) are pleiotropic and are, in many respects, distinct from those contributing to ischemic brain injury. • The toxicity of extravasated blood toward all structural components of the neurovascular unit represents a unique feature of ICH-mediated brain damage. • Inflammation and oxidative stress appear to play prominent roles in the pathobiology of ICH. • The secondary injury after ICH develops over days suggesting the presence of a considerably long window for therapeutic intervention. • Approaches aimed at detoxification of blood-derived noxious components represent a promising target for the treatment of ICH. • Pre-clinical animal models provide useful guidance on the pathogenesis of ICH. However, better models to assess re-bleeding (hematoma enlargement) are urgently needed.

Intracerebral hemorrhage (ICH) is a devastating form of stroke with a high mortality and poor prognosis, for which no effective therapy is currently available.1–8 Rapid accumulation of blood within the brain parenchyma causes increased intracranial pressure and initial cell/tissue damage.9 Since only half of ICH-related deaths occur in the first 2 days after ICH,10,11 the contributions of toxic hematoma-derived products (e.g., hemolysis products12–22), oxidative stress and pro-inflammatory responses to secondary brain injury are clearly important.23–26 Indeed, as compared to ischemic stroke, ICH may have a long therapeutic time-window. This chapter will outline selected aspects of our current knowledge from experimental models of ICH, regarding cellular mechanisms of injury and experimental approaches to combat ICH-mediated brain injury (Fig. 8-1).

EXPERIMENTAL MODELS OF   INTRACEREBRAL HEMORRHAGE Over past two decades numerous animal models have been developed to study the pathobiology of ICH. However, most experimental studies of ICH have been conducted in two models, i.e., autologous blood infusion or collagenase injection (reviewed in27–30). In the blood infusion model, arterial blood is directly infused into a specific brain structure, e.g., basal ganglia in rodents or frontal white matter in pigs. In the collagenase model, the injected bacterial enzyme, collagenase,

102

degrades the basal lamina that surrounds cerebral blood vessels causing them to rupture and bleed.31 An additional model in swine involves the creation of a cavity in white matter by balloon inflation followed by infusion of blood into the cavity.32 All ICH models have their limitations.30,33 Direct autologous blood infusion does not capture blood vessel rupture that is the basis for bleeding in human ICH. In the collagenase model, the bacterial enzyme induces considerable inflammation and has a significantly different time course, extent and robustness of perihematomal blood–brain barrier (BBB) opening versus ICH in humans or in blood infusion models. Furthermore, collagenase also produces an injury volume that is considerably larger despite similar initial hematoma volumes.34 In the balloon inflation model, white matter tracts are “torn” and otherwise damaged in a manner different than that which occurs in blood infusion models and in human ICH. Lastly, unfortunately none of these models replicate the blood vessel pathologic changes that may be present with aging, e.g., amyloidosis.2 Despite their limitations, and as presented in this chapter, findings from these models (reviewed in2,5,35,36) have provided significant new understanding of ICH pathophysiology and pathochemistry. In addition, these models support potential pharmacologic and surgical treatments, including the recent development of a minimally invasive surgical approach using magnetic resonance-guided focused ultrasound.37 It is noteworthy that findings directly from ICH animal models have provided the basis for several ongoing clinical therapy trials including iron chelation with deferoxamine,38 pioglitazone for hematoma resolution (SHRINC),39 and minimally invasive surgery plus thrombolysis for clot evacuation (MISTIE).40

MECHANISM OF BRAIN INJURY AFTER INTRACEREBRAL HEMORRHAGE Inflammatory Responses after   Intracerebral Hemorrhage A considerable body of literature demonstrates the participation of inflammatory cells in the pathophysiologic processes following ICH, including blood-derived leukocytes and macrophages, resident microglia, astrocytes, and mast cells. These cells can aggravate ICH-induced secondary brain injury by releasing a variety of toxic factors, including cytokines, chemokines, free radicals and nitric oxide.41 Activated microglia, which are likely the first non-neuronal cells to acutely react to brain injury, are the main locus of cytokine production. Microglia are activated through a variety of different mechanisms, and undergo morphological and functional changes. Microglial cells classified as the activated phenotype (M1) are involved in pro-inflammatory processes following ICH, while the alternative phenotype (M2) may contribute to cell healing and repair. Microglial cells are activated within minutes after the onset of ICH.1 The activation



Mechanisms of Cerebral Hemorrhage

103

Hematoma evacuation and phagocytosis-mediated cleanup enhancement

8 Microglia activation Chemokine release

Tissue compression ischemia? Injury

Cytokine release PMN infiltration Iron toxicity Oxidative stress

Mass Effect

Excitotoxicity Spreading depression

ICH

Blood extravasation

Blood plasma components

Proteolytic enzymes Matrix degradation MF infiltration

Chemical injury

BBB disruption Edema

Products of hemolysis Figure 8-1.  In response to blood extravasation during ICH, brain tissue is subjected to physical injury associated with the mass effect and potentially to ischemia (in case of large hematomas), and also to chemical injury via toxicity of blood plasma component (e.g., coagulation factors, complement components or immunoglobulins) and product of hemolysis (e.g., hemoglobin, heme or iron). These deleterious events trigger proinflammatory responses comprised of activation of microglia, polymorphonuclear (PMN) leukocyte infiltration and entry of blood-borne monocytes. These responses together with the local brain cell death/damage amplify oxidative stress, cause excitotoxicity, ionic imbalance, spreading depression and promote proteolysis-mediated extracellular matrix damage leading to disintegration of neurovascular unit, blood brain damage and deadly edema.

of these cells, particularly the M1 phenotype, results in the production of pro-inflammatory cytokines, including tumor necrosis factors (TNF)-α, interleukin (IL)-1β, IL-65 and various chemokines,42 which triggers neuroinflammation and leukocyte brain infiltration.25 Several studies have shown that inhibition of microglia activation, for example by minocycline or tuftsin 1–3 fragment, reduces secondary brain injury and improves neurological function in rodents models of ICH.43,44 Timely clearance of the extravasated hematoma components and damaged tissue debris by activated microglia can reduce local damage from RBC lysis, thereby favoring a nurturing environment and promoting tissue recovery.19,45 The roles of other blood-borne inflammatory cells, such as leukocytes and macrophages, have increasingly gained attention in ICH-induced inflammation. In preclinical animal models, neutrophils (polymorphonuclear leukocytes, PMNs) are the earliest leukocyte subtype to infiltrate the hemorrhagic brain, occurring within 4–5 hours after the onset of ICH, and peaking at 3 days after hemorrhage induction.46–49 PMNs can occlude capillaries, release various proteolytic enzymes, generate NADPH-oxidase- and myeloperoxidasedependent oxidative stress, which can damage local cells and compromise the BBB.50–55 Apoptotic cell death of these infiltrating PMNs, without timely removal by phagocytes, may lead to secondary necrosis and further exacerbation of secondary brain injury by stimulating microglia/macrophages to release pro-inflammatory mediators. Recently, Rolland et al. found that fingolimod, an anti-inflammatory drug used as pharmacotherapy for multiple sclerosis, effectively reduced cerebral infiltration of T-lymphocytes, thereby inhibiting local inflammation and improving neurobehavioral and cognitive outcomes following experimental ICH.56 Activated astrocytes can secrete inflammatory mediators and increase production of glial fibrillary acidic protein (GFAP), causing so-called reactive gliosis, which can interfere with axonal regeneration. Astrocytes also express and release a variety of matrix metalloproteinases that participate in brain

inflammation. Thus, blocking microglia–astrocyte interactions might be a potentially effective strategy to minimize secondary brain damage following ICH.57 On the other hand, astrocytes may promote neuroprotection by modulating the production of microglial inflammatory mediators.58,59 Additionally, the inhibition of mast cells has been reported to reduce brain edema and hematoma volume, which was associated with ameliorated neurological deficits following experimental ICH.60 Hydrogen gas inhalation also diminished brain edema and enhanced BBB preservation by reducing mast cell activation and degranulation in an ICH mouse model.61 Accumulating evidence shows that cytokines exacerbate secondary injury after ICH. TNF-α and IL-1β are the two prominent mediators of pro-inflammatory responses in the progression of ICH-induced brain injury.1,43,62,63 IL-10 and transforming growth factor-β are anti-inflammatory cytokines, which act to eliminate inflammation. Following ICH, perihematomal levels of TNF-α are significantly increased,23,64,65 which contributes to brain edema and neurological deficits. Clinical evidence is consistent with animal studies, supporting the theory that TNF-α can aggravate ICH-induced brain injury.66 Similarly, IL-1β has been found to be upregulated after ICH; and increased IL-β expression is associated with severe brain edema and BBB disruption.43 Inhibition of IL-1β with the receptor antagonist, IL-1Rα, reduces ICH-mediated damage. In addition, IL-6 possesses both pro- and anti-inflammatory properties and may play a significant role in ICH pathophysiology. Toll-like receptor 4 (TLR4) recruits a specific set of adaptor molecules that interact with the TIR domain, such as MyD88 and TRIF, and subsequently activate a transcription factor, nuclear factor kappa B (NF-κB). The TLR4/NF-κB signaling pathway plays a major role in ICH-induced pathology.67,68 Heme degradation products lead to production of TNF-α, IL-1β, and IL-6 through activation of the TLR4 pathway. NF-κB is an important transcriptional regulator of pro-inflammatory cytokine production, including TNF-α and IL-1β. Activation of NF-κB occurs in the perihematoma within minutes, lasts

104

SECTION I  Pathophysiology

for at least 1 week after the onset of ICH,24,69 and is positively associated with perilesional cell death after ICH in rats. TLR4/ NF-κB inhibition, by significantly reducing the perihematomal inflammatory response and the infiltration of the peripheral inflammatory cells, is remarkably protective. In addition, treatment with peroxisome proliferator-activated receptor (PPAR)γ agonists, such as pioglitazone, rosiglitazone or 15d-PGJ2, promoted phagocytosis of RBCs by microglia/phagocytes, accelerated hematoma resolution and reduced neurological deficits in both in vitro and in vivo ICH models.19,45 A Phase 2 clinical study evaluating pioglitazone in ICH is currently being carried out.39 There are several shortcomings for studying ICH-induced inflammation in our current animal models. In both the collagenase and blood injection ICH models, inflammatory reactions are exacerbated by placing a needle into the animal’s brain. Moreover, collagenase itself may amplify inflammatory responses. Focused ultrasound or laser pulse-induced ICH via capillary rupture and endothelial damage might be necessary to improve the translatability of intracerebral injections of collagenase or blood products.70 Furthermore, establishing animals models of spontaneously occurring ICH, without the injection of foreign agents (such as collagenase), would be a substantial advancement in this field. Since preclinical ICH models are different from the human condition, human histopathologic studies are required to confirm their validity. A better understanding of the inflammation signaling pathways underlying ICH, especially newly identified pathways or molecules should facilitate the identification of therapeutic targets for this malady.

system. Nrf2 expression was significantly increased at 2 hours with a peak at 24 hours following intracerebral blood infusion, while Keap1 was decreased at 8 hours after ICH induction. The downstream antioxidative enzymes regulated by Nrf2, including hemeoxygenase-1 (HO-1), catalase, superoxide dismutase (SOD), glutathione (GSH), thioredoxin (TRX), and glutathione-S-transferase (GST-α1) increased to different degrees during the early stages of ICH.74,81,82 Nrf2−/− mice exhibited more severe neurologic damage than did wild-type mice subjected to the whole-blood injection model of ICH.74,81,83 Conversely, Nrf2 inducer sulforaphane exerted to reduce oxidative damage, increased haptoglobin production (to improve hemoglobin elimination), reduced neutrophil amount, and improved behavioral deficits.74,84 Drugs with antioxidant properties are promising candidates for ICH therapy. However, conventional antioxidants cannot neutralize ROS formed intracellularly, because the native enzymes cannot cross the membrane of neurons and astrocytes. Thus, different alternatives of enzyme delivery have been designed to improve fusion of enzymes, such as: nanoparticles, PEGylation and lecithinization.85 More recently, mitochondrial ROS amplified the inflammatory response by triggering NLRP3 inflammasome activation after ICH.86 Thus, the inhibition of the NLRP3 inflammasome may effectively block the interactions between oxidative stress and inflammation following ICH. The novel free radical neutralizers with clear pharmacokinetics still need to be explored.

Oxidative Stress after Intracerebral Hemorrhage

As described below, studies have shown that red blood cell (RBC) lysis and coagulation cascade activation are major factors leading to brain edema, BBB disruption, neuronal death and neurological deficits following ICH.

Reactive oxygen species (ROS) levels dramatically increase following ICH. High levels of oxidative stress, as measured by protein carbonyl formation, have been found shortly after the intracerebral injection of autologous blood injection in pigs.71,72 High levels of the ROS marker, ethidium or 4-hydroxynonenal, have been observed in the perihematomal brain region on days 1 and 3 after ICH in the mouse model.73,74 ROS are produced as a natural byproduct of the oxygen metabolism. Iron and thrombin, released from the hematoma, can generate hydroxyl radicals.5 One of the ROS sources after ICH is peripheral immune cells, which start invading the brain shortly after the hemorrhage and participate in microglial activation. Subsequently, the activated microglia further enhance the generation of ROS. Excess generation of ROS is lethal to cells. Hemoglobin degradation products can directly injure DNA by means of oxidative strand breaks.75 ROS also cause lipid peroxidation, protein oxidation, mitochondrial dysfunction and altered signal transduction, eventually leading to cell death. Beneficial effects of free radical scavengers in preclinical ICH models have been recently demonstrated, including α-phenyl-N-tertbutyl nitrone (PBN), NXY-059 (a derivative of PBN), and edaravone.1,76–78 In addition, gp91phox KO mice with deleted NADPH oxidase, a key enzyme involved in ROS generation, showed milder damage than wild-type mice in response to ICH.79 Furthermore, given the potential sources of ROS production following ICH, other efforts targeting pro-oxidant heme or iron such as deferoxamine or porphyrin derivatives have gained increasing promise.75,80 In response to heme toxicity and the generation of free radicals, depletion/malfunction of the scavenging antioxidant system may further enhance the oxidative injury of ICH. The pathway involving Kelch-like ECH-associated protein 1 (Keap1) and nuclear factor erythroid 2-related factor 2 (Nrf2) is currently recognized as the central endogenous antioxidant

Blood Components and IntracerebralHemorrhage-induced Injury

Red Blood Cell Lysis and Hemoglobin Toxicity RBCs within a clot preserve their normal biconcave configuration for a few days after ICH.87 Thereafter, they lose their normal shape and start to lyse. RBC lysis appears to begin very early in the brain after hemorrhage. In rodent models of brain hemorrhage, for example, RBCs start to lyse within 24 hours.88–91 In ICH patients, hemoglobin levels in the CSF increase during the first few days after ictus.92 However, lysis of RBCs occurs mostly several days after ICH,18,93,94 which may result from either depletion of intracellular energy reserves or formation of membrane attack complex after activation of the complement system, or both.95,96 RBC lysis causes edema formation, oxidative stress and neuronal death following ICH.97,98 A clinical study of edema and ICH indicates that delayed brain edema is related to significant midline shift after ICH in humans.99 This delayed brain edema (in the second or third weeks after the onset in human) is probably due to hemoglobin and its degradation products.100 A recent study showed that haptoglobin, an acute response protein and a key hemoglobin neutralizing component, is neuroprotective against ICH-induced brain injury.101 In addition, carbonic anhydrase-1, one of 14 carbonic anhydrase isozymes, is present at high concentrations in RBCs. Extracellular carbonic anhydrase-1 also contributes to BBB disruption and ICH-induced brain injury.87,102 Hemoglobin-induced brain injury results from heme degradation products. Heme is degraded by heme oxygenases in the brain into iron, carbon monoxide and biliverdin.16 An intracerebral injection of hemoglobin or its degradation products caused brain damage.103 Studies have shown that heme oxygenase-1 protein levels are increased after



Mechanisms of Cerebral Hemorrhage

brain hemorrhage90,104 and heme oxygenase inhibitors, tinmesoporphyrin and zinc protoporphyrin, reduce perihematomal edema, neuronal loss and neurological deficits in ICH animal models.105–107

Brain Iron Overload Iron accumulates in the brain after ICH and results in brain injury.94,108–110 The release of iron from the degradation of hemoglobin during clot resolution leads to a build up in nonheme brain tissue iron. The high level of non-heme iron remains in the brain for a long time in experimental ICH models and ICH patients.90 By enhanced Perls’ reaction, ironpositive cells are found in the perihematomal zone as early as the first day.90,111 Studies also have shown that free iron levels in CSF increase significantly on the third day after ICH, and remain high for at least 1 month.16 Iron has a key role in brain edema formation following ICH.94,112 Perihematomal brain edema develops immediately after an ICH and peaks several days later.112–114 Edema formation following ICH elevates intracranial pressure and may result in herniation.115 In experimental ICH models, brain edema peaks around the third or fourth days after the hemorrhage, then declines slowly.98,116–118 In species with significant white matter, perihematomal edema is mainly located within that tissue.117,119 In humans perihematomal edema develops within 3 hours of symptom onset and peaks between 1 and 3 weeks after the ictus.99,120,121 Several studies show that the degree of brain edema around the hematoma correlates with poor outcome in patients.99,115,122 Recent studies have shown that iron chelation with deferoxamine reduces perihematomal brain edema and ICH-induced brain injury in aged rats and pigs (Fig. 8-2).18,123–125 Brain iron overload also contributes to neuronal death and brain atrophy after ICH. Clinical and experimental studies have demonstrated that brain atrophy occurs after ICH.9,126 A

ICH + Vehicle

105

recent study demonstrated that brain atrophy developed gradually and peaked between 1 and 2 months after ICH in the rat.126 Brain atrophy was associated with prolonged neurological deficits. Deferoxamine, an iron chelator, reduced brain atrophy, brain ferritin levels, and improved neurological deficits after rat ICH.122,124,126 These studies have led to a clinical trial to test use of deferoxamine, an iron chelator, for ICH patients.127

Thrombin Formation Thrombin is a serine protease and an essential component in the coagulation cascade. It is produced immediately in the hematoma after an ICH. Although thrombin formation is essential to stop bleeding, thrombin at high concentrations is neurotoxic. For example, direct intracerebral injection of thrombin causes inflammatory cell infiltration, BBB disruption, brain edema formation and neuronal death.38,94,128 Thrombin-induced brain injury is partially through activation of its receptors.128,129 Three protease-activated receptors (PARs), PAR-1, PAR-3 and PAR-4, are thrombin receptors.130 To examine whether there is a time window for systemic administration of a thrombin inhibitor could reduce ICHinduced injury, ICH rats were treated with argatroban. The systemic administration of argatroban starting 6 hours after ICH significantly reduced edema but did not increase collagenase-induced hematoma volume.131 Thrombin-induced brain injury may be mediated by the complement cascade.132 Intracerebral infusion of thrombin in rat resulted in a sevenfold increase in complement C9 and deposition of complement C9 on neuronal membranes. Clusterin, an inhibitor of the membrane attack complex formation, was also upregulated by the thrombin and found in neurons. The effects of coagulation cascade on complement activation are not well studied. However, studies suggest that there is a very close relationship between thrombin and

ICH + Deferoxamine

Figure 8-2.  Deferoxamine reduces reddish zone around hematoma at day 3 in a pig ICH model. Pigs were treated with deferoxamine (50 mg/ kg; administered intramuscularly every 12 hours for 3 days, starting 2 hours post-ICH) or vehicle.

8

106

SECTION I  Pathophysiology

complement. For example, thrombin-cleaved C3a-like fragments are chemotactic for leukocytes and induce enzyme release from neutrophils.133 Tumor necrosis factor alpha (TNF-α) is one of the major pro-inflammatory cytokines and it may contribute to brain injury after ICH. TNF-α levels in the brain are increased after intracerebral infusion of thrombin and ICH.134 ICH-induced brain edema was less in TNF-α knockout mice compared with wild-type mice.135 In addition, thrombin activates matrix metalloproteinase 2 in endothelial cells.136

MECHANISMS OF CELL DEATH AFTER INTRACEREBRAL HEMORRHAGE Apoptosis Cell death can be primarily divided into necrosis and apoptosis.137 Necrosis is a more “chaotic” way of dying, which is characterized by cellular edema and disruption of the plasma membrane, leading to release of cellular components and inflammatory tissue response. Apoptosis is a programmed cellular death that is characterized by morphologic changes such as cell shrinkage, nuclear condensation and scission of chromosomal DNA into internucleosomal fragments and formation of “apoptosis bodies”, which can be removed by phagocytic cells. Using TUNEL staining (to assess DNA fragmentation) and histological evaluation of sections from 12 patients who underwent a blood evacuation procedure after ICH, the abundance of apoptotic cells in the peri-hematoma brain were observed in ten of these patients. Although TUNEL staining is not selective in labeling apoptotic cells, since it may label necrotic and mitotic cells as well, the authors indicated that neither of the TUNEL-positive cells displayed necrotic morphology. In agreement with this human study, the presence of TUNEL-positive cells with appearance of apoptotic morphology, in the peri-hematoma areas of the brain, was also reported in animal models of ICH, suggesting the important role of apoptosis as a pathway contributing to brain cell death after intracerebral hemorrhage.69,138–140 It is worth emphasizing that IL-1β is normally translated as a proenzyme (proIL-1β) and requires proteolysis by caspase-1 (interleukin-1 converting enzyme, ICE) to generate the biologically active peptide.141,142 Therefore, the robust increase in IL-1β levels after ICH1,143 may represent additional evidence for caspase activation after ICH. IL-1β is one of the most potent activators for NF-κB, which consequently leads to amplification of the inflammatory response regulated by transcriptional activation of several proinflammatory genes including IL-1β itself144 positioning caspase-1 as a key regulator of ICH-induced inflammation. It is well documented that release of cytochrome c from mitochondria to cytosol activates the proteolytic pathway involving caspase-9 and -3 activation which initiates caspaseactivated DNase (CAD) and poly(ADP-ribose) polymerase (PARP), leading to apoptotic cell death.145–147 Analysis of rat brain at 24 hours post-ICH demonstrated the presence of cells with increased staining intensity for cytosolic cytochrome c in the peri-hematoma transition zone.9 Cytochrome c-positive cells were still present at 3 days, but not at 7 days, after ICH, suggesting that mitochondrial damage and cytochrome c-mediated caspase activation may play an important role in ICH-induced apoptosis. In agreement with this notion, injection of zVADfmk, a broad-spectrum caspase inhibitor, prior to ICH, significantly reduced the number of TUNEL-positive cells in the ICH-affected hemisphere.1,138 In addition to mitochondrial pathways the receptormediated pathway of apoptosis through activation of

death-inducing ligand/receptor systems such as Fas ligand (FasL)/Fas receptor (FasR) plays a pathological role in cerebrovascular pathologies.148,149 Increased Fas antigen after ICH was documented,150,151 suggesting that Fas-mediated death could also play a role in cell death after ICH. This receptormediated apoptosis pathway may exist independently from the mitochondrial pathway and lead to PARP cleavage and CAD activation, producing DNA damage and cell death.

Excitotoxicity and Cell Death after   Intracerebral Hemorrhage It is documented that excessive Ca++ influx through NMDAand AMPA-glutamate subtype receptors, in response to prolonged increase of extracellular excitatory amino acids (EAA) or upregulation of these receptors, causes damage to neurons, termed excitotoxicity.152–154 Glutamate level after ICH was shown to be robustly increased in the perihematoma brain region,155 suggesting a possible damaging effect. In agreement with this notion, memantine, a non-competitive blocker of NMDA-subtype of glutamate receptor, used at a very high 20 mg/kg dose, was demonstrated to reduce injury, including inflammation and neurological deficit, in the rat ICH model which uses intracerebral injection of bacterial collagenase to induce bleeding.156 In addition memantine induced the expression of anti-apoptotic mitochondrial protein Bcl-2 and ameliorated ICH-induced caspase-3 activation. Memantine reduced collagenase-induced hematoma volume and inhibited the ICH-induced expression of tPA, uPA and MMP-9, proteases that have been documented to affect vascular integrity and produce hemorrhagic transformation. In another study, MK-801, a different non-competitive NMDA antagonist when used in a pig model of ICH helped to reduce delayed perihematoma edema when used in combination with rt-PA.157 The role of EAA in ICH pathogenicity could also be inferred from the studies showing that the glucose hypermetabolism in perihematomal brain could be ameliorated with AMPA- or NMDA-receptor antagonists.158 Finally, overexcitation as a contributor to ICH-mediated damage could be further supported by the findings that neurological outcome after ICH (induced by collagenase) could be improved with the agonist of γ-aminobutyric acid-A receptor (GABA-A; a major inhibitory neurotransmitter receptor), muscimol.159 However, inconsistent with the earlier work the NMDA-receptor antagonist, MK-801, did not affect ICH outcome in the same study. One likely explanation for these negative results with MK-801 is that the drug was administered 4 hours after the onset of ICH, in contrast to studies with hypermetabolism that used MK-801 30 minutes prior to ICH.

Additional Caveats about the Apoptosis and Other Forms of Death after Intracerebral Hemorrhage Autophagy occurs at a low basal level in most cells and is involved in protein and organelle turnover. Amongst other catabolic functions, autophagy has been proposed as one of the forms of programmed cell death160 that involve formation of autophagosomes and degradation of the cell’s own components. The formation of which could have a role in catabolism during starvation. Recently, it was proposed that autophagy takes place after ICH.161,162 Specifically, conversion of microtubule-associated protein light chain-3 (LC3-I) to its phosphatidylethanolamine conjugate (LC3-II; ), cathepsin D expression, and vacuole formation were increased after ICH, and in particular in aged rats, and this process was mimicked by intracerebral infusion of iron and blocked by administration of the iron-chelating agent, deferoxamine. Finally, more



recent work with necrostatin-1 (RIPK kinase inhibitor), a compound that selectively inhibits a programmed cell death named regulated necrosis or necroptosis163 and being stimulated by exposure to damage-associated molecular patterns (DAMPs),164 was demonstrated to reduce damage after ICH.165

BLOOD–BRAIN BARRIER DISRUPTION The BBB is a physical barrier that maintains a separation between the brain’s interstitial compartment and the cerebral circulation.166 The tight junctions of the cerebral microvessel endothelial cells are the cellular basis of this physical barrier.167 Clinical studies suggest a pathogenetic association between BBB damage and hemorrhagic stroke through increased levels of matrix metalloproteinases (MMPs) which can cleave structural proteins of the BBB (reviewed in168). Following ICH, damage to the BBB through various mechanisms leads to the development of vasogenic brain edema.35 Animal studies demonstrate that during the early hours after ICH, Evans blue leakage is absent indicating that the BBB remains intact to large molecules.35,169 However, by 8–12 hours, BBB permeability is increased.35,170 Blood clot formation and the components of the clotting cascade, in particular thrombin, importantly contribute to BBB damage and perihematomal edema formation.120,134,171 In white matter, edema fluid accumulation along fiber tracts can be prominent after ICH and BBB disruption as evidenced by Evans blue staining distant from the hematoma36 and hyperintensities on T2-weighted imaging.13 Recent studies suggest that Src kinase signaling is involved in multiple mechanisms of thrombininduced BBB injury after ICH.8 The inflammatory response following ICH (described elsewhere) also contributes to BBB damage following ICH. Circulating neutrophils, a component of this response, rapidly enter the brain after ICH.25,172,173 Decreasing neutrophil numbers with an anti-polymorphonuclear leukocyte antibody, reduced BBB breakdown and dramatically spared white matter.25 MMPs which can modify the extracellular matrix and damage the BBB are also important components in ICHinduced inflammatory responses.23,174–176 This is seen with MMP gene expression which is generally low, but is upregulated after ICH.140 Pharmacologic MMP inhibition can reduce edema development, suggesting that MMPs play a role in BBB damage.1,177 Furthermore, in MMP-9 knockout mice, edema is reduced suggesting that astrocytic MMP-9 can contribute to BBB injury after ICH.23 Also, hemoglobin generation following red cell lysis after ICH can lead to oxidative stress, MMP upregulation and BBB injury.178 Minocycline, which can reduce TNF-alpha levels and MMP activity, protects the BBB and reduces edema following ICH.179 In addition, local hypothermia after ICH markedly down-regulates the pro-inflammatory cytokine, interleukin-1 beta, mRNA expression, and protects the BBB, thereby attenuating vasogenic edema in porcine white matter.180

Modifiers of Intracerebral-hemorrhage-  induced Injury Hypertension Hypertension is a major cause of spontaneous ICH. A recent study showed that moderate chronic hypertension (< 200 mm Hg SBP) did not enlarge the hematoma or exacerbate brain edema after ICH in spontaneously hypertensive rats. However, it did result in increased neuronal death and worse functional outcome, which may be associated with microglia activation and iron toxicity.181

Mechanisms of Cerebral Hemorrhage

107

Gender Female animals have a reduced susceptibility to ischemic and hemorrhagic brain injury.182,183 The greater neuroprotection afforded to females is likely due to the effects of circulating estrogens and progestins.184 Treatment of male but not female rats with exogenous estrogen reduced ICH-induced brain injury, suggesting that normal circulating levels of estrogen in the female rats are sufficient to induce neuroprotection.182 Estrogen can reduce hemoglobin- and iron-induced neurotoxicity185,186 and it is well known that hemoglobin and iron are two major players in the causation of brain damage following ICH.187 Therefore, estrogen-induced protection after ICH may result from less hemoglobin- and iron-toxicity.

Age ICH is mostly a disease of the elderly, but current experimental ICH models have primarily used young animals. Age is a significant factor determining brain injury after ICH in animals and humans.6,188 Experimental data showed that ICH results in more severe brain swelling, white matter injury and neurological deficits in aged animals compared to young animals.188,189 Severe brain injury in aged animals is associated with enhanced microglial activation. Animal behavioral data also showed that the temporal profiles of recovery in aging and young animals are identical. This result suggests that it is differences in acute injury that cause the greater brain swelling and neurological deficits in aged rats rather than less plasticity.

THERAPEUTIC APPROACHES TARGETING INTRACEREBRAL HEMORRHAGE   PATHOGENESIS IN ANIMAL RESEARCH Surgical Treatment for Intracerebral Hemorrhage Experimental studies of clot removal surgery in ICH animal models have been relatively limited. Two reports described the use of thrombolytics to liquefy intracerebral clots that are notoriously difficult to aspirate. One study in the 1980s showed that tPA rapidly liquefied clots and induced resorption.190 A study in the late 1990s in a pig lobar ICH model demonstrated that early (3.5 hours) tPA-induced clot lysis plus aspiration was highly effective in reducing clot and white matter edema volumes by >70% and in preventing BBB opening.191 In contrast, other experimental studies conducted in a porcine balloon inflation hematoma model have suggested that tPA use for clot lysis and removal enhances delayed edema development.192 However, it is noteworthy that traumatic injury to white matter produced by balloon inflation is a different insult than the white matter tract dissection that occurs in blood infusion models. Interestingly, a new methodology for hematoma liquification has been recently reported in a swine ICH model in which transcranial MR-guided focused ultrasound (MRgFUS) sonothrombolysis facilitated minimally invasive clot evacuation via craniostomy and an aspiration tube.37 Findings in animal models plus results demonstrating that tPA could be used to liquefy hematomas in ICH patients,193–195 have provided support for the ongoing multicenter Minimally Invasive Surgery plus rt-PA for ICH Evacuation (MISTIE) trial. Hanley and colleagues40 recently reported that successful hematoma evacuation with a minimally invasive approach after tPA-induced clot lysis, led to significant edema volume reduction. Furthermore, in ICH patients with intraventricular extension of their hematomas, the instillation of rtPA into the ventricles resulted in faster clearance of blood and a reduction in perihematomal edema.196 At the 2013 International Stroke Meeting, Dr. Hanley presented the trial’s 365-day results that

8

108

SECTION I  Pathophysiology

TABLE 8-1  Intervention/target

Proposed mechanism

ICH model

Outcome tested

Porphyrin analogs110–112

HO-1 inhibition

Rat and pig AB

Edema, behavior, atrophy

NS-398204

COX-2 inhibitor

Rat AB

Edema

Erythropoietin205–208

Pleotropic

Rat, Mouse, AB, C

Behavior, tissue loss, inflammation

Sulforaphane/Nrf2

Antioxidative

Rat, mouse, AB, C

Behavior, inflammation

Statins209–212

HMG-CoA reductase inhibitor/ Pleiotropic

Rat, AB, C

Behavior, tissue loss, neurogenesis, inflammation

G-CSF213–215

Growth factor, Pleotropic

Rat, C

Behavior, edema, inflammation, neurogenesis, astrogliosis

Minocycline147, 216–219

Antiinflammatory, Pleiotropic

Rat, mouse, AB, C

Behavior, inflammation, edema, brain tissue loss, BBB integrity

Rosiglitazone, Pioglitazone5,19,45

PPARγ agonist

Rat, Mouse, AC

Behavior, edema, hematoma resolution, inflammation

Deferoxamine94,117,220–223

Iron chelator

Rat, mouse, piglet,C, AC,

Behavior, edema, inflammation

Memantine

NMDA receptor antagonist

Rat, C

Cell loss, inflammation, behavior

Argatroban138,224–227

Thrombin inhibitor

Rat, mouse, AC, C

Edema, inflammation

Citocoline

Cell membranes precursor

Mouse, C

Behavior

Hyperbaric oxygen229

Oxygenation, HIF 1α

Rat, AB

Edema

Glucocorticoid receptor

Rat, C

Behavior, edema, hematoma volume, inflammation

Estrogen receptor

Rat, AB,

Edema, Behavior

Cell therapy

Pleotropic

Rat, mouse, C, AB

Behavior, hematoma volume,

Glycyrrhizin248

HMGB1 inhibitor

Rat, C

Edema, behavior, neuronal loss

CP-1

Cathepsin B and L inhibitor

Rat, AB

Behavior, cytoprotection

Hypothermia250

Pleotropic

Rat, AB

Behavior, edema, inflammation, oxidative damage

Telmisartan251

Angiotensin II receptor (AT1) inhibitor

Rat, C

Edema, hematoma volume, inflammation, cytoprotection

Valproic Acid252

Histone deacetylase inhibitor

Rat C

Behavior, neuroprotection markers

PP1253

Src kinase inhibitor

Rat, AB

Glucose hypermetabolism, cell death, behavior

Bortezomib254, PS-519255

Proteasome inhibitor

Rat, AB, C

Inflammation, behavior, hematoma volume, edema

15d-Prostaglandin J2256

PPARγ agonist/NF-κB antagonist

Rat, AB

Behavior, oxidative stress

CGS 21680257

Adenosine 2A receptor agonist

Rat, C

Inflammation, cell death

NXY-059

Free radical trapping agent

Rat, C

Behavior, inflammation

Xenon259

NMDA antagonist, pleotropic

Mouse C

Inflammation, behavior, edema

PDGF receptor antagonist

Mouse, AB

Edema, behavior, BBB

77,84,86,87

163

228

Dexamethasone

230–232

Estrogen195,233–235 236–247

249

258

260

Gleevec

AB: an autologous blood injection model; C: collagenase model.

demonstrated an improving long-term beneficial clinical outcome versus 180 days and a 14% upward shift across all modified Rankin Score levels. Fewer MISTIE-treated subjects were in long-term care facilities and these had shorter hospital stays with significant cost savings (Hanley: Stroke Meeting Website Reference). These latter results are in contrast to the randomized clinical trials of surgical clot removal without clot thrombolytic treatment (n = 7) that have been conducted for more than 50 years (reviewed in197). The largest of these, the Surgical Trial in IntraCerebral Hemorrhage (STICH), was reported in 2005 and demonstrated that surgical and medical management of ICH were equivocal.198,199 Various reasons for this outcome have been discussed including the late timing of surgery,

operative techniques that induced damage and the presence of intraventricular hemorrhage, among others.197,200,201 Most recently, STICH II, a randomized controlled trial in 601 patients with superficial lobar ICH of early (within 48 hour of ictus), open craniotomy surgery and no IVH versus conservative management demonstrated that surgery might have a small but clinically relevant advantage without increasing death or disability rates at 6 months.202,203 In summary, clot removal in experimental animals as well as human ICH studies support the conclusion that surgery can improve outcome and that liquefying the hematoma especially facilitates evacuation and reduces perihematomal edema. The comprehensive description of surgical treatments is addressed more thoroughly in Chapter 3.



Mechanisms of Cerebral Hemorrhage

Pharmacologic and other Experimental   Treatment for Intracerebral Hemorrhage Besides surgical approaches aiming at blood evacuation, numerous experimental pharmacologic or physical (e.g., hypothermia) strategies have been evaluated in animal models of ICH over many years. It appears that in addition to the mechanical damage caused to the brain by tissue displacement with extravasating blood (hematoma), which could theoretically be medically addressed by the hematoma evacuation procedure or by blocking the subsequent hematoma enlargement, neutralization of blood toxicity in the brain parenchyma represents an important and promising target for ICH therapy. As mentioned elsewhere in this chapter, the components damaging brain tissue after ICH include products of hemolysis. Since red blood cell lysis and release of cytotoxic hemoglobin and iron including oxidative stress and inflammation progress over days after the ictus, it is likely that the therapy aiming at neutralization of blood-derived injury may have a longer window of opportunity, as compared to ischemic stroke. Many therapeutic approaches have been evaluated in animal ICH models with many of them showing significant benefit regarding edema or behavioral dysfunction. The following table lists selected experimental approaches targeting various aspects of ICH pathogenesis that have demonstrated beneficial effects in pre-clinical testing (Table 8-1).

CONCLUSION The most notable conclusion derived from pre-clinical research with ICH is that the pathobiology of ICH is highly complex and in many ways distinct from that of ischemic stroke. These differences primarily pertain to a limited contribution of ischemia (in the majority of cases) and presence of chemical insults associated with toxicity of extravasated blood cells and molecular mediators. Experimental models may also suggest that brain damage after ICH (at least those involving cascades of secondary injury) progresses slower and as such may offer a longer time window for the successful intervention, as compared to ischemic stroke. This extended window may provide therapeutic opportunities for not only surgical and cytoprotective approaches, but also open doors to novel approaches using pre- and post-conditioning paradigms. Finally, it is important to note that, although pre-clinical ICH models have not yet provided ultimate validation of their translational value, it appears that the existing spectrum of models can recapitulate many of ICH-induced pathological events and hopefully serve as meaningful tools to evaluate and develop future therapeutic opportunities. The complete reference list can be found on the companion Expert Consult website at www.expertconsult.inkling.com. KEY REFERENCES 1. Aronowski J, Hall CE. New horizons for primary intracerebral hemorrhage treatment: Experience from preclinical studies. Neurol Res 2005;27:268–79. 2. Qureshi AI, Mendelow AD, Hanley DF. Intracerebral haemorrhage. Lancet 2009;373:1632–44. 3. Adeoye O, Broderick JP. Advances in the management of intracerebral hemorrhage. Nat Rev Neurol 2010;6:593–601. 5. Aronowski J, Zhao X. Molecular pathophysiology of cerebral hemorrhage: Secondary brain injury. Stroke 2011;42:1781–6. 6. Keep RF, Hua Y, Xi G. Intracerebral haemorrhage: Mechanisms of injury and therapeutic targets. Lancet Neurol 2012;11:720–31. 8. Xi G, Keep RF, Hoff JT. Mechanisms of brain injury after intracerebral haemorrhage. Lancet Neurol 2006;5:53–63. 9. Felberg RA, Grotta JC, Shirzadi AL, et al. Cell death in experimental intracerebral hemorrhage: The “black hole” model of hemorrhagic damage. Ann Neurol 2002;51:517–24.

109

11. Broderick J, Connolly S, Feldmann E, et al. Guidelines for the management of spontaneous intracerebral hemorrhage in adults: 2007 update: A guideline from the American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group. Stroke 2007;38:2001–23. 12. Koeppen AH. The history of iron in the brain. J Neurol Sci 1995;134(Suppl.):1–9. 13. Xi G, Wagner KR, Keep RF, et al. Role of blood clot formation on early edema development after experimental intracerebral hemorrhage. Stroke 1998;29:2580–6. 14. Belayev L, Saul I, Curbelo K, et al. Experimental intracerebral hemorrhage in the mouse: Histological, behavioral, and hemodynamic characterization of a double-injection model. Stroke 2003;34:2221–7. 16. Wagner KR, Sharp FR, Ardizzone TD, et al. Heme and iron metabolism: Role in cerebral hemorrhage. J Cereb Blood Flow Metab 2003;23:629–52. 18. Xi G, Fewel ME, Hua Y, et al. Intracerebral hemorrhage: Pathophysiology and therapy. Neurocrit Care 2004;1:5–18. 19. Zhao X, Sun G, Zhang J, et al. Hematoma resolution as a target for intracerebral hemorrhage treatment: Role for peroxisome proliferator-activated receptor gamma in microglia/macrophages. Ann Neurol 2007;61:352–62. 22. Chen-Roetling J, Sinanan J, Regan RF. Effect of iron chelators on methemoglobin and thrombin preconditioning. Transl Stroke Res 2012;3:452–9. 23. Wang J, Dore S. Inflammation after intracerebral hemorrhage. J Cereb Blood Flow Metab 2007;27:894–908. 24. Zhao X, Zhang Y, Strong R, et  al. Distinct patterns of intra­cerebral hemorrhage-induced alterations in NF-kappaB subunit, iNOS, and COX-2 expression. J Neurochem 2007;101: 652–63. 25. Wang J. Preclinical and clinical research on inflammation after intracerebral hemorrhage. Prog Neurobiol 2010;92: 463–77. 27. Andaluz N, Zuccarello M, Wagner KR. Experimental animal models of intracerebral hemorrhage. Neurosurg Clin N Am 2002;13:385–93. 28. James ML, Warner DS, Laskowitz DT. Preclinical models of intracerebral hemorrhage: A translational perspective. Neurocrit Care 2008;9:139–52. 30. MacLellan CL, Paquette R, Colbourne F. A critical appraisal of experimental intracerebral hemorrhage research. J Cereb Blood Flow Metab 2012;32:612–27. 31. Rosenberg GA, Mun-Bryce S, Wesley M, et al. Collagenase-induced intracerebral hemorrhage in rats. Stroke 1990;21:801–7. 33. Adeoye O, Clark JF, Khatri P, et al. Animal models of hemorrhagic stroke: Do current models mirror the human pathologies? Transl Stroke Res 2011;2:17–25. 34. MacLellan CL, Silasi G, Poon CC, et al. Intracerebral hemorrhage models in rat: Comparing collagenase to blood infusion. J Cereb Blood Flow Metab 2008;28:516–25. 36. Wagner KR. White matter injury after experimental intracerebral hemorrhage. In: Baltan S, Carmichael ST, Matute C, et al., editors. White matter injury in stroke and CNS diseases. Springer; 2014 in press. 37. Monteith SJ, Harnof S, Medel R, et al. Minimally invasive treatment of intracerebral hemorrhage with magnetic resonanceguided focused ultrasound. J Neurosurg 2013;118:1035–45. 38. Selim M, Yeatts S, Goldstein JN, et al. Safety and tolerability of deferoxamine mesylate in patients with acute intracerebral hemorrhage. Stroke 2011;42:3067–74. 39. Gonzales NR, Shah J, Sangha N, et al. Design of a prospective, dose-escalation study evaluating the safety of pioglitazone for hematoma resolution in intracerebral hemorrhage (SCHRINC). Int J Stroke 2013;8:388–96. 40. Mould WA, Carhuapoma JR, Muschelli J, et al. Minimally invasive surgery plus recombinant tissue-type plasminogen activator for intracerebral hemorrhage evacuation decreases perihematomal edema. Stroke 2013;44:627–34. 42. Taylor RA, Sansing LH. Microglial responses after ischemic stroke and intracerebral hemorrhage. Clin Dev Immunol 2013;2013: 746068.

8

110

SECTION I  Pathophysiology

43. Wu J, Yang S, Xi G, et al. Microglial activation and brain injury after intracerebral hemorrhage. Acta Neurochir Suppl 2008;105: 59–65. 44. Wang J, Rogove AD, Tsirka AE, et al. Protective role of tuftsin fragment 1-3 in an animal model of intracerebral hemorrhage. Ann Neurol 2003;54:655–64. 45. Zhao X, Grotta J, Gonzales N, et al. Hematoma resolution as a therapeutic target: The role of microglia/macrophages. Stroke 2009;40:S92–4. 46. Del Bigio MR, Yan HJ, Buist R, et al. Experimental intracerebral hemorrhage in rats. Magnetic resonance imaging and histopathological correlates. Stroke 1996;27:2312–19, discussion 2319–20. 48. Wang J, Dore S. Heme oxygenase-1 exacerbates early brain injury after intracerebral haemorrhage. Brain 2007;130: 1643–52. 49. Zhao X, Sun G, Zhang H, et al. Polymorphonuclear neutrophil in brain parenchyma after experimental intracerebral hemorrhage. Trans Stroke Res 2014;5:554–61. 51. Garcia JH, Liu KF, Yoshida Y, et al. Influx of leukocytes and platelets in an evolving brain infarct (wistar rat). Am J Pathol 1994;144:188–99. 52. Hallenbeck JM, Dutka AJ, Tanishima T, et al. Polymorphonuclear leukocyte accumulation in brain regions with low blood flow during the early postischemic period. Stroke 1986;17: 246–53. 54. Sansing LH, Harris TH, Kasner SE, et al. Neutrophil depletion diminishes monocyte infiltration and improves functional outcome after experimental intracerebral hemorrhage. Acta Neurochir Suppl 2011;111:173–8. 56. Rolland WB, Lekic T, Krafft PR, et al. Fingolimod reduces cerebral lymphocyte infiltration in experimental models of rodent intracerebral hemorrhage. Exp Neurol 2013;241:45–55. 57. Wang J, Tsirka SE. Neuroprotection by inhibition of matrix metalloproteinases in a mouse model of intracerebral haemorrhage. Brain 2005;128:1622–33. 59. Brahmachari S, Fung YK, Pahan K. Induction of glial fibrillary acidic protein expression in astrocytes by nitric oxide. J Neurosci 2006;26:4930–9. 60. Lindsberg PJ, Strbian D, Karjalainen-Lindsberg ML. Mast cells as early responders in the regulation of acute blood-brain barrier changes after cerebral ischemia and hemorrhage. J Cereb Blood Flow Metab 2010;30:689–702. 61. Manaenko A, Lekic T, Ma Q, et al. Hydrogen inhalation ameliorated mast cell-mediated brain injury after intracerebral hemorrhage in mice. Crit Care Med 2013;41:1266–75. 62. Mayne M, Ni W, Yan HJ, et al. Antisense oligodeoxynucleotide inhibition of tumor necrosis factor- alpha expression is neuroprotective after intracerebral hemorrhage. Stroke 2001;32: 240–8. 63. Masada T, Hua Y, Xi G, et al. Overexpression of interleukin-1 receptor antagonist reduces brain edema induced by intracerebral hemorrhage and thrombin. Acta Neurochir Suppl 2003;86: 463–7. 65. Hua Y, Wu J, Keep RF, et al. Tumor necrosis factor-alpha increases in the brain after intracerebral hemorrhage and thrombin stimulation. Neurosurgery 2006;58(3):542–50, discussion 542–50. 67. Sansing LH, Harris TH, Welsh FA, et al. Toll-like receptor 4 contributes to poor outcome after intracerebral hemorrhage. Ann Neurol 2011;70:646–56. 69. Hickenbottom SL, Grotta JC, Strong R, et al. Nuclear factorkappab and cell death after experimental intracerebral hemorrhage in rats. Stroke 1999;30:2472–7, discussion 2477–8. 70. Morgan T, Zuccarello M, Narayan R, et al. Preliminary findings of the minimally-invasive surgery plus rtPA for intracerebral hemorrhage evacuation (MISTIE) clinical trial. Acta Neurochir Suppl 2008;105:147–51. 71. Arima H, Huang Y, Wang JG, et al. Earlier blood pressurelowering and greater attenuation of hematoma growth in acute intracerebral hemorrhage: Interact pilot phase. Stroke 2012;43: 2236–8. 74. Wagner KR, Packard BA, Hall CL, et al. Protein oxidation and heme oxygenase-1 induction in porcine white matter following intracerebral infusions of whole blood or plasma. Dev Neurosci 2002;24:154–60.

75. Wang J, Tsirka SE. Tuftsin fragment 1-3 is beneficial when delivered after the induction of intracerebral hemorrhage. Stroke 2005;36:613–18. 76. Zhao X, Sun G, Zhang J, et al. Transcription factor nrf2 protects the brain from damage produced by intracerebral hemorrhage. Stroke 2007;38:3280–6. 79. Lyden PD, Shuaib A, Lees KR, et al. Safety and tolerability of NXY-059 for acute intracerebral hemorrhage: The CHANT trial. Stroke 2007;38:2262–9. 80. Nakamura T, Kuroda Y, Yamashita S, et al. Edaravone attenuates brain edema and neurologic deficits in a rat model of acute intracerebral hemorrhage. Stroke 2008;39:463–9. 81. Tang J, Liu J, Zhou C, et al. Role of nadph oxidase in the brain injury of intracerebral hemorrhage. J Neurochem 2005;94: 1342–50. 82. Hatakeyama T, Okauchi M, Hua Y, et al. Deferoxamine reduces neuronal death and hematoma lysis after intracerebral hemorrhage in aged rats. Trans Stroke Res 2013;4. 83. Zhao X, Aronowski J. Nrf2 to pre-condition the brain against injury caused by products of hemolysis after ich. Trans Stroke Res 2013;4:71–5. 84. Shang H, Yang D, Zhang W, et al. Time course of Keap1-Nrf2 pathway expression after experimental intracerebral haemorrhage: Correlation with brain oedema and neurological deficit. Free Radic Res 2013;47:368–75. 85. Wang J, Fields J, Zhao C, et al. Role of nrf2 in protection against intracerebral hemorrhage injury in mice. Free Radic Biol Med 2007;43:408–14. 86. Zhao X, Song S, Sun G, et al. Neuroprotective role of haptoglobin after intracerebral hemorrhage. J Neurosci 2009;29: 15819–27. 88. Ma Q, Chen S, Hu Q, et al. Nlrp3 inflammasome contributes to inflammation after intracerebral hemorrhage. Ann Neurol 2014;75(2):209-19. 91. Koeppen AH, Dickson AC, McEvoy JA. The cellular reactions to experimental intracerebral hemorrhage. J Neurol Sci 1995; 134(Suppl.):102–12. 92. Wu J, Hua Y, Keep RF, et al. Iron and iron-handling proteins in the brain after intracerebral hemorrhage. Stroke 2003;34: 2964–9. 93. Nakamura T, Keep R, Hua Y, et al. Deferoxamine-induced attenuation of brain edema and neurological deficits in a rat model of intracerebral hemorrhage. J Neurosurg 2004;100:672–8. 95. Xi G, Keep RF, Hoff JT. Mechanisms of brain injury after intracerebral hemorrhage. Lancet Neurol 2006;5:53–63. 96. Gu Y, Hua Y, Keep RF, et al. Deferoxamine reduces intracerebral hematoma-induced iron accumulation and neuronal death in piglets. Stroke 2009;40:2241–3. 99. Wu J, Hua Y, Keep RF, et al. Oxidative brain injury from extra­ vasated erythrocytes after intracerebral hemorrhage. Brain Res 2002;953:45–52. 101. Zazulia AR, Diringer MN, Derdeyn CP, et al. Progression of mass effect after intracerebral hemorrhage. Stroke 1999;30:1167–73. 102. Wu G, Xi G, Huang F. Spontaneous intracerebral hemorrhage in humans: Hematoma enlargement, clot lysis, and brain edema. Acta Neurochir Suppl 2006;96:78–80. 103. Gao BB, Clermont A, Rook S, et al. Extracellular carbonic anhydrase mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation. Nat Med 2007;13:181–8. 104. Guo F, Hua Y, Wang J, et al. Inhibition of carbonic anhydrase reduces brain injury after intracerebral hemorrhage. Trans Stroke Res 2012;3:130–7. 107. Wagner KR, Hua Y, de Courten-Myers GM, et al. Tinmesoporphyrin, a potent heme oxygenase inhibitor, for treatment of intracerebral hemorrhage: In vivo and in vitro studies. Cell Mol Biol 2000;46:597–608. 109. Gong Y, Tian H, Xi G, et al. Systemic zinc protoporphyrin administration reduces intracerebral hemorrhage-induced brain injury. Acta Neurochir (Wien) 2006;96(Suppl.):232–6. 110. Perez de la Ossa N, Sobrino T, Silva Y, et al. Iron-related brain damage in patients with intracerebral hemorrhage. Stroke 2010; 41:810–13. 111. Selim M. Deferoxamine mesylate: A new hope for intracerebral hemorrhage: From bench to clinical trials. Stroke 2009;40: S90–1.

113. Wan S, Hua Y, Keep RF, et al. Deferoxamine reduces CSF free iron levels following intracerebral hemorrhage. Acta Neurochir (Wien) Acta Neurochir Suppl 2006;96:199–202. 114. Xi G, Keep RF, Hoff JT. Pathophysiology of brain edema formation. Neurosurg Clin North Am 2002;13:371–83. 116. Wagner KR, Xi G, Hua Y, et al. Lobar intracerebral hemorrhage model in pigs: Rapid edema development in perihematomal white matter. Stroke 1996;27:490–7. 117. Ropper AH. Lateral displacement of the brain and level of consciousness in patients with an acute hemispheral mass. New Engl J Med 1986;314:953–8. 120. Yang GY, Betz AL, Chenevert TL, et al. Experimental intracerebral hemorrhage: Relationship between brain edema, blood flow, and blood-brain barrier permeability in rats. J Neurosurg 1994; 81:93–102. 121. Garcia JH, Ho KL, Caccamo D. Intracerebral hemorrhage: Pathology of selected topics. In: Kase CS, Caplan LR, editors. Intracerebral hemorrhage. Boston: Butterworths; 1994. p. 45–72. 122. Broderick J, Brott T, Kothari R. Very early edema growth with ich. Stroke 1995;26:184. 125. Okauchi M, Hua Y, Keep RF, et al. Deferoxamine treatment for intracerebral hemorrhage in aged rats: Therapeutic time window and optimal duration. Stroke 2010;41:375–82. 127. Xie Q, Gu Y, Hua Y, et al. Deferoxamine attenuates white matter injury in a piglet intracerebral hemorrhage model. Stroke 2014; 45(1):290-2. 129. Xi G, Reiser G, Keep RF. The role of thrombin and thrombin receptors in ischemic, hemorrhagic and traumatic brain injury: Deleterious or protective? J Neurochem 2003;84:3–9. 131. Xue M, Hollenberg MD, Demchuk A, et al. Relative importance of proteinase-activated receptor-1 versus matrix metalloproteinases in intracerebral hemorrhage-mediated neurotoxicity in mice. Stroke 2009;40:2199–204. 132. Coughlin SR. Thrombin signalling and protease-activated receptors. Nature 2000;407:258–64. 134. Gong Y, Xi G, Keep R, et al. Complement inhibition attenuates brain edema and neurological deficits induced by thrombin. Acta Neurochir (Wien) 2005;95(Suppl.):389–92. 137. Hua Y, Keep R, Hoff J, et al. Brain injury after intracerebral hemorrhage: The role of thrombin and iron. Stroke 2007;38: 759–62. 138. Nguyen M, Arkell J, Jackson CJ. Thrombin rapidly and efficiently activates gelatinase A in human microvascular endothelial cells via a mechanism independent of active MT1 matrix metalloproteinase. Lab Invest 1999;79:467–75. 139. Bonfoco E, Krainc D, Ankarcrona M, et al. Apoptosis and necrosis: Two distinct events induced, respectively, by mild and intense insults with N-methyl-D-aspartate or nitric oxide/superoxide in cortical cell cultures. Proc Natl Acad Sci U S A 1995;92: 7162–6. 140. Matsushita K, Meng W, Wang X, et al. Evidence for apoptosis after intercerebral hemorrhage in rat striatum. J Cereb Blood Flow Metab 2000;20:396–404. 142. Power C, Henry S, Del Bigio MR, et al. Intracerebral hemorrhage induces macrophage activation and matrix metalloproteinases. Ann Neurol 2003;53:731–42. 143. Kuida K, Lippke JA, Ku G, et al. Altered cytokine export and apoptosis in mice deficient in interleukin- 1 beta converting enzyme. Science 1995;267:2000–3. 144. Hara H, Friedlander RM, Gagliardini V, et al. Inhibition of interleukin 1beta converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage. Proc Natl Acad Sci U S A 1997;94:2007–12. 145. Lu A, Tang Y, Ran R, et al. Brain genomics of intracerebral hemorrhage. J Cereb Blood Flow Metab 2006;26:230–52. 150. Rosenbaum DM, Gupta G, D’Amore J, et al. Fas (cd95/apo-1) plays a role in the pathophysiology of focal cerebral ischemia. J Neurosci Res 2000;61:686–92. 154. Choi DW. Calcium and excitotoxic neuronal injury. Ann N Y Acad Sci 1994;747:162–71. 157. Qureshi AI, Ali Z, Suri MF, et al. Extracellular glutamate and other amino acids in experimental intracerebral hemorrhage: An in vivo microdialysis study. Crit Care Med 2003;31:1482–9. 158. Lee ST, Chu K, Jung KH, et al. Memantine reduces hematoma expansion in experimental intracerebral hemorrhage, resulting

Mechanisms of Cerebral Hemorrhage

111

in functional improvement. J Cereb Blood Flow Metab 2006;26: 536–44. 160. Ardizzone TD, Lu A, Wagner KR, et al. Glutamate receptor blockade attenuates glucose hypermetabolism in perihematomal brain after experimental intracerebral hemorrhage in rat. Stroke 2004;35:2587–91. 163. He Y, Wan S, Hua Y, et al. Autophagy after experimental intra­ cerebral hemorrhage. J Cereb Blood Flow Metab 2008;28: 897–905. 168. Betz AL, Iannotti F, Hoff JT. Brain edema: A classification based on blood-brain barrier integrity. Cerebrovasc Brain Metabol Rev 1989;1:133–54. 170. Florczak-Rzepka M, Grond-Ginsbach C, Montaner J, et al. Matrix metalloproteinases in human spontaneous intracerebral hemorrhage: An update. Cerebrovasc Dis 2012;34:249–62. 171. Yang GY, Betz AL, Hoff JT. The effects of blood or plasma clot on brain edema in the rat with intracerebral hemorrhage. Acta Neurochir Suppl (Wien) 1994;60:555–7. 172. Brown MS, Kornfeld M, Mun-Bryce S, et al. Comparison of magnetic resonance imaging and histology in collagenase-induced hemorrhage in the rat. J Neuroimaging 1995;5:23–33. 173. Liu DZ, Sharp FR. The dual role of src kinases in intracerebral hemorrhage. Acta Neurochir Suppl 2011;111:77–81. 174. Moxon-Emre I, Schlichter LC. Neutrophil depletion reduces blood-brain barrier breakdown, axon injury, and inflammation after intracerebral hemorrhage. J Neuropathol Exp Neurol 2011;70:218–35. 175. Tejima E, Zhao BQ, Tsuji K, et al. Astrocytic induction of matrix metalloproteinase-9 and edema in brain hemorrhage. J Cereb Blood Flow Metab 2007;27:460–8. 176. Wang X, Jung J, Asahi M, et al. Effects of matrix metalloproteinase-9 gene knock-out on morphological and motor outcomes after traumatic brain injury. J Neurosci 2000;20:7037–42. 177. Rosenberg GA. Matrix metalloproteinases in neuroinflammation. Glia 2002;39:279–91. 178. del Zoppo GJ, Milner R, Mabuchi T, et al. Microglial activation and matrix protease generation during focal cerebral ischemia. Stroke 2007;38:646–51. 179. Rosenberg GA, Navratil M. Metalloproteinase inhibition blocks edema in intracerebral hemorrhage in the rat. Neurology 1997;48:921–6. 180. Katsu M, Niizuma K, Yoshioka H, et al. Hemoglobin-induced oxidative stress contributes to matrix metalloproteinase activation and blood-brain barrier dysfunction in vivo. J Cereb Blood Flow Metab 2010;30:1939–50. 181. Wasserman JK, Schlichter LC. Minocycline protects the bloodbrain barrier and reduces edema following intracerebral hemorrhage in the rat. Exp Neurol 2007;207:227–37. 182. Wagner KR, Beiler S, Beiler C, et al. Delayed profound local brain hypothermia markedly reduces interleukin-1beta gene expression and vasogenic edema development in a porcine model of intracerebral hemorrhage. Acta Neurochir (Wien) Acta Neurochir Suppl 2006;96:177–82. 183. Wu G, Bao X, Xi G, et al. Brain injury after intracerebral hemorrhage in spontaneously hypertensive rats. J Neurosurg 2011;114: 1805–11. 184. Nakamura T, Hua Y, Keep R, et al. Estrogen therapy for experimental intracerebral hemorrhage. J Neurosurg 2005;103: 97–103. 185. Hurn PD, Macrae IM. Estrogen as a neuroprotectant in stroke. J Cereb Blood Flow Metab 2000;20:631–52. 186. Roof RL, Hall ED. Gender differences in acute CNS trauma and stroke: Neuroprotective effects of estrogen and progesterone. J Neurotrauma 2000;17:367–88. 187. Regan RF, Guo Y. Estrogens attenuate neuronal injury due to hemoglobin, chemical hypoxia, and excitatory amino acids in murine cortical cultures. Brain Res 1997;764:133–40. 188. Culmsee C, Vedder H, Ravati A, et al. Neuroprotection by estrogens in a mouse model of focal cerebral ischemia and in cultured neurons: Evidence for a receptor-independent antioxidative mechanism. J Cereb Blood Flow Metab 1999;19: 1263–9. 189. Gong Y, Hua Y, Keep RF, et al. Intracerebral hemorrhage: Effects of aging on brain edema and neurological deficits. Stroke 2004;35:2571–5.

8

112

SECTION I  Pathophysiology

190. Daverat P, Castel JP, Dartigues JF, et al. Death and functional outcome after spontaneous intracerebral hemorrhage. A prospective study of 166 cases using multivariate analysis. Stroke 1991;22:1–6. 191. Wasserman JK, Schlichter LC. White matter injury in young and aged rats after intracerebral hemorrhage. Exp Neurol 2008;214: 266–75. 192. Kaufman HH, Schochet S, Koss W, et al. Efficacy and safety of tissue plasminogen activator. Neurosurgery 1987;20:403–7. 193. Wagner KR, Xi G, Hua Y, et al. Ultra-early clot aspiration after lysis with tissue plasminogen activator in a porcine model of intracerebral hemorrhage: Edema reduction and blood-brain barrier protection. J Neurosurg 1999;90:491–8. 194. Thiex R, Kuker W, Muller HD, et al. The long-term effect of recombinant tissue-plasminogen-activator (rt-PA) on edema formation in a large-animal model of intracerebral hemorrhage. Neurol Res 2003;25:254–62. 195. Lippitz BE, Mayfrank L, Spetzger U, et al. Lysis of basal ganglia haematoma with recombinant tissue plasminogen activator (rtPA) after stereotactic aspiration: Initial results. Acta Neurochir (Wien) 1994;127:157–60. 196. Rohde V, Schaller C, Hassler WE. Intraventricular recombinant tissue plasminogen activator for lysis of intraventricular haemorrhage. J Neurol Neurosurg Psychiatry 1995;58:447–51.

197. Schaller C, Rohde V, Meyer B, et al. Stereotactic puncture and lysis of spontaneous intracerebral hemorrhage using recombinant tissue-plasminogen activator. Neurosurg 1995;36: 328–33. 198. Ziai W, Moullaali T, Nekoovaght-Tak S, et al. No exacerbation of perihematomal edema with intraventricular tissue plasminogen activator in patients with spontaneous intraventricular hemorrhage. Neurocrit Care 2013;18:354–61. 199. Vespa PM, Martin N, Zuccarello M, et al. Surgical trials in intracerebral hemorrhage. Stroke 2013;44:S79–82. 200. Mendelow AD, Gregson BA, Fernandes HM, et al. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the international surgical trial in intracerebral haemorrhage (STICH): A randomised trial. Lancet 2005;365:387–97. 201. Broderick JP. The STICH trial: What does it tell us and where do we go from here? Stroke 2005;36:1619–20. 202. Mendelow AD, Unterberg A. Surgical treatment of intracerebral haemorrhage. Curr Opin Crit Care 2007;13:169–74. 203. Mendelow AD, Gregson BA, Rowan EN, et al. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): A randomised trial. Lancet 2013;382:397–408.



Mechanisms of Cerebral Hemorrhage

REFERENCES 1. Aronowski J, Hall CE. New horizons for primary intracerebral hemorrhage treatment: Experience from preclinical studies. Neurol Res 2005;27:268–79. 2. Qureshi AI, Mendelow AD, Hanley DF. Intracerebral haemorrhage. Lancet 2009;373:1632–44. 3. Adeoye O, Broderick JP. Advances in the management of intracerebral hemorrhage. Nat Rev Neurol 2010;6:593–601. 4. Elliott J, Smith M. The acute management of intracerebral hemorrhage: A clinical review. Anesth Analg 2010;110:1419–27. 5. Aronowski J, Zhao X. Molecular pathophysiology of cerebral hemorrhage: Secondary brain injury. Stroke 2011;42:1781–6. 6. Keep RF, Hua Y, Xi G. Intracerebral haemorrhage: Mechanisms of injury and therapeutic targets. Lancet Neurol 2012;11: 720–31. 7. Manno EM. Update on intracerebral hemorrhage. Continuum (Minneap Minn) 2012;18:598–610. 8. Xi G, Keep RF, Hoff JT. Mechanisms of brain injury after intracerebral haemorrhage. Lancet Neurol 2006;5:53–63. 9. Felberg RA, Grotta JC, Shirzadi AL, et al. Cell death in experimental intracerebral hemorrhage: The “black hole” model of hemorrhagic damage. Ann Neurol 2002;51:517–24. 10. Broderick JP, Brott T, Tomsick T, et al. Intracerebral hemorrhage more than twice as common as subarachnoid hemorrhage. J Neurosurg 1993;78:188–91. 11. Broderick J, Connolly S, Feldmann E, et al. Guidelines for the management of spontaneous intracerebral hemorrhage in adults: 2007 update: A guideline from the American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group. Stroke 2007;38:2001–23. 12. Koeppen AH. The history of iron in the brain. J Neurol Sci 1995;134(Suppl.):1–9. 13. Xi G, Wagner KR, Keep RF, et al. Role of blood clot formation on early edema development after experimental intracerebral hemorrhage. Stroke 1998;29:2580–6. 14. Belayev L, Saul I, Curbelo K, et al. Experimental intracerebral hemorrhage in the mouse: Histological, behavioral, and hemodynamic characterization of a double-injection model. Stroke 2003;34:2221–7. 15. Hoff JT, Xi G. Brain edema from intracerebral hemorrhage. Acta Neurochir Suppl 2003;86:11–15. 16. Wagner KR, Sharp FR, Ardizzone TD, et al. Heme and iron metabolism: Role in cerebral hemorrhage. J Cereb Blood Flow Metab 2003;23:629–52. 17. Wagner KR, Dwyer BE. Hematoma removal, heme, and heme oxygenase following hemorrhagic stroke. Ann N Y Acad Sci 2004;1012:237–51. 18. Xi G, Fewel ME, Hua Y, et al. Intracerebral hemorrhage: Pathophysiology and therapy. Neurocrit Care 2004;1:5–18. 19. Zhao X, Sun G, Zhang J, et al. Hematoma resolution as a target for intracerebral hemorrhage treatment: Role for peroxisome proliferator-activated receptor gamma in microglia/macrophages. Ann Neurol 2007;61:352–62. 20. Keep RF, Xiang J, Ennis SR, et al. Blood-brain barrier function in intracerebral hemorrhage. Acta Neurochir Suppl 2008;105: 73–7. 21. Chen L, Zhang X, Chen-Roetling J, et al. Increased striatal injury and behavioral deficits after intracerebral hemorrhage in hemopexin knockout mice. J Neurosurg 2011;114:1159–67. 22. Chen-Roetling J, Sinanan J, Regan RF. Effect of iron chelators on methemoglobin and thrombin preconditioning. Transl Stroke Res 2012;3:452–9. 23. Wang J, Dore S. Inflammation after intracerebral hemorrhage. J Cereb Blood Flow Metab 2007;27:894–908. 24. Zhao X, Zhang Y, Strong R, et al. Distinct patterns of intracerebral hemorrhage-induced alterations in NF-kappaB subunit, iNOS, and COX-2 expression. J Neurochem 2007;101:652–63. 25. Wang J. Preclinical and clinical research on inflammation after intracerebral hemorrhage. Prog Neurobiol 2010;92:463–77. 26. Kuramatsu JB, Huttner HB, Schwab S. Advances in the management of intracerebral hemorrhage. J Neural Transm 2013; 120(Suppl. 1):S35–41.

112.e1

27. Andaluz N, Zuccarello M, Wagner KR. Experimental animal models of intracerebral hemorrhage. Neurosurg Clin N Am 2002;13:385–93. 28. James ML, Warner DS, Laskowitz DT. Preclinical models of intracerebral hemorrhage: A translational perspective. Neurocrit Care 2008;9:139–52. 29. Wagner KR, Zuccarello M. Intracerebral hemorrhage: Animal models and experimental treatments. In: Carhuapoma JR, Mayer SA, Hanley DF, editors. Intracerebral hemorrhage. NY: Cambridge University Press; 2010. p. 193–205. 30. MacLellan CL, Paquette R, Colbourne F. A critical appraisal of experimental intracerebral hemorrhage research. J Cereb Blood Flow Metab 2012;32:612–27. 31. Rosenberg GA, Mun-Bryce S, Wesley M, et al. Collagenase-induced intracerebral hemorrhage in rats. Stroke 1990;21:801–7. 32. Rohde V, Rohde I, Thiex R, et al. Fibrinolysis therapy achieved with tissue plasminogen activator and aspiration of the liquefied clot after experimental intracerebral hemorrhage: Rapid reduction in hematoma volume but intensification of delayed edema formation. J Neurosurg 2002;97:954–62. 33. Adeoye O, Clark JF, Khatri P, et al. Animal models of hemorrhagic stroke: Do current models mirror the human pathologies? Transl Stroke Res 2011;2:17–25. 34. MacLellan CL, Silasi G, Poon CC, et al. Intracerebral hemorrhage models in rat: Comparing collagenase to blood infusion. J Cereb Blood Flow Metab 2008;28:516–25. 35. Xi G, Strahle J, Hua Y, et al. Progress in translational research on intracerebral hemorrhage: Is there an end in sight? Prog Neurobiol 2014;115:45–63. 36. Wagner KR. White matter injury after experimental intracerebral hemorrhage. In: Baltan S, Carmichael ST, Matute C, et al., editors. White matter injury in stroke and CNS diseases. Springer; 2014 in press. 37. Monteith SJ, Harnof S, Medel R, et al. Minimally invasive treatment of intracerebral hemorrhage with magnetic resonanceguided focused ultrasound. J Neurosurg 2013;118:1035–45. 38. Selim M, Yeatts S, Goldstein JN, et al. Safety and tolerability of deferoxamine mesylate in patients with acute intracerebral hemorrhage. Stroke 2011;42:3067–74. 39. Gonzales NR, Shah J, Sangha N, et al. Design of a prospective, dose-escalation study evaluating the safety of pioglitazone for hematoma resolution in intracerebral hemorrhage (SCHRINC). Int J Stroke 2013;8:388–96. 40. Mould WA, Carhuapoma JR, Muschelli J, et al. Minimally invasive surgery plus recombinant tissue-type plasminogen activator for intracerebral hemorrhage evacuation decreases perihematomal edema. Stroke 2013;44:627–34. 41. Joice SL, Mydeen F, Couraud PO, et al. Modulation of bloodbrain barrier permeability by neutrophils: In vitro and in vivo studies. Brain Res 2009;1298:13–23. 42. Taylor RA, Sansing LH. Microglial responses after ischemic stroke and intracerebral hemorrhage. Clin Dev Immunol 2013;2013: 746068. 43. Wu J, Yang S, Xi G, et al. Microglial activation and brain injury after intracerebral hemorrhage. Acta Neurochir Suppl 2008;105: 59–65. 44. Wang J, Rogove AD, Tsirka AE, et al. Protective role of tuftsin fragment 1-3 in an animal model of intracerebral hemorrhage. Ann Neurol 2003;54:655–64. 45. Zhao X, Grotta J, Gonzales N, et al. Hematoma resolution as a therapeutic target: The role of microglia/macrophages. Stroke 2009;40:S92–4. 46. Del Bigio MR, Yan HJ, Buist R, et al. Experimental intracerebral hemorrhage in rats. Magnetic resonance imaging and histopathological correlates. Stroke 1996;27:2312–19, discussion 2319–20. 47. Nguyen HX, O’Barr TJ, Anderson AJ. Polymorphonuclear leukocytes promote neurotoxicity through release of matrix metalloproteinases, reactive oxygen species, and TNF-alpha. J Neurochem 2007;102:900–12. 48. Wang J, Dore S. Heme oxygenase-1 exacerbates early brain injury after intracerebral haemorrhage. Brain 2007;130:1643–52. 49. Zhao X, Sun G, Zhang H, et al. Polymorphonuclear neutrophil in brain parenchyma after experimental intracerebral hemorrhage. Trans Stroke Res 2014;5:554–61.

8

112.e2 SECTION I 

Pathophysiology

50. del Zoppo GJ, Schmid-Schonbein GW, Mori E, et al. Polymorphonuclear leukocytes occlude capillaries following middle cerebral artery occlusion and reperfusion in baboons. Stroke 1991; 22:1276–83. 51. Garcia JH, Liu KF, Yoshida Y, et al. Influx of leukocytes and platelets in an evolving brain infarct (wistar rat). Am J Pathol 1994;144:188–99. 52. Hallenbeck JM, Dutka AJ, Tanishima T, et al. Polymorphonuclear leukocyte accumulation in brain regions with low blood flow during the early postischemic period. Stroke 1986;17: 246–53. 53. Kalimo H, del Zoppo GJ, Paetau A, et al. Polymorphonuclear neutrophil infiltration into ischemic infarctions: Myth or truth? Acta Neuropathol 2013;125:313–16. 54. Sansing LH, Harris TH, Kasner SE, et al. Neutrophil depletion diminishes monocyte infiltration and improves functional outcome after experimental intracerebral hemorrhage. Acta Neurochir Suppl 2011;111:173–8. 55. Amulic B, Cazalet C, Hayes GL, et al. Neutrophil function: From mechanisms to disease. Ann Rev Immunol 2012;30:459–89. 56. Rolland WB, Lekic T, Krafft PR, et al. Fingolimod reduces cerebral lymphocyte infiltration in experimental models of rodent intracerebral hemorrhage. Exp Neurol 2013;241:45–55. 57. Wang J, Tsirka SE. Neuroprotection by inhibition of matrix metalloproteinases in a mouse model of intracerebral haemorrhage. Brain 2005;128:1622–33. 58. Wang J, Dore S. Heme oxygenase 2 deficiency increases brain swelling and inflammation after intracerebral hemorrhage. Neuroscience 2008;155:1133–41. 59. Brahmachari S, Fung YK, Pahan K. Induction of glial fibrillary acidic protein expression in astrocytes by nitric oxide. J Neurosci 2006;26:4930–9. 60. Lindsberg PJ, Strbian D, Karjalainen-Lindsberg ML. Mast cells as early responders in the regulation of acute blood-brain barrier changes after cerebral ischemia and hemorrhage. J Cereb Blood Flow Metab 2010;30:689–702. 61. Manaenko A, Lekic T, Ma Q, et al. Hydrogen inhalation ameliorated mast cell-mediated brain injury after intracerebral hemorrhage in mice. Crit Care Med 2013;41:1266–75. 62. Mayne M, Ni W, Yan HJ, et al. Antisense oligodeoxynucleotide inhibition of tumor necrosis factor- alpha expression is neuroprotective after intracerebral hemorrhage. Stroke 2001;32: 240–8. 63. Masada T, Hua Y, Xi G, et al. Overexpression of interleukin-1 receptor antagonist reduces brain edema induced by intracerebral hemorrhage and thrombin. Acta Neurochir Suppl 2003; 86:463–7. 64. Lin S, Yin Q, Zhong Q, et al. Heme activates tlr4-mediated inflammatory injury via myd88/trif signaling pathway in intracerebral hemorrhage. J Neuroinflammation 2012;9:46. 65. Hua Y, Wu J, Keep RF, et al. Tumor necrosis factor-alpha increases in the brain after intracerebral hemorrhage and thrombin stimulation. Neurosurgery 2006;58(3):542–50, discussion 542–50. 66. Castillo J, Davalos A, Alvarez-Sabin J, et al. Molecular signatures of brain injury after intracerebral hemorrhage. Neurology 2002; 58:624–9. 67. Sansing LH, Harris TH, Welsh FA, et al. Toll-like receptor 4 contributes to poor outcome after intracerebral hemorrhage. Ann Neurol 2011;70:646–56. 68. Teng W, Wang L, Xue W, et al. Activation of tlr4-mediated nfkappab signaling in hemorrhagic brain in rats. Mediators Inflamm 2009;473276:2009. 69. Hickenbottom SL, Grotta JC, Strong R, et al. Nuclear factorkappab and cell death after experimental intracerebral hemorrhage in rats. Stroke 1999;30:2472–7, discussion 2477–8. 70. Morgan T, Zuccarello M, Narayan R, et al. Preliminary findings of the minimally-invasive surgery plus rtPA for intracerebral hemorrhage evacuation (MISTIE) clinical trial. Acta Neurochir Suppl 2008;105:147–51. 71. Arima H, Huang Y, Wang JG, et al. Earlier blood pressurelowering and greater attenuation of hematoma growth in acute intracerebral hemorrhage: Interact pilot phase. Stroke 2012;43: 2236–8. 72. Chonpathompikunlert P, Fan CH, Ozaki Y, et al. Redox nanoparticle treatment protects against neurological deficit in focused

ultrasound-induced intracerebral hemorrhage. Nanomedicine (Lond) 2012;7:1029–43. 73. Hall NC, Packard BA, Hall CL, et al. Protein oxidation and enzyme susceptibility in white and gray matter with in vitro oxidative stress: Relevance to brain injury from intracerebral hemorrhage. Cell Mol Biol 2000;46:673–83. 74. Wagner KR, Packard BA, Hall CL, et al. Protein oxidation and heme oxygenase-1 induction in porcine white matter following intracerebral infusions of whole blood or plasma. Dev Neurosci 2002;24:154–60. 75. Wang J, Tsirka SE. Tuftsin fragment 1-3 is beneficial when delivered after the induction of intracerebral hemorrhage. Stroke 2005;36:613–18. 76. Zhao X, Sun G, Zhang J, et al. Transcription factor nrf2 protects the brain from damage produced by intracerebral hemorrhage. Stroke 2007;38:3280–6. 77. Nakamura T, Keep RF, Hua Y, et al. Oxidative DNA injury after experimental intracerebral hemorrhage. Brain Res 2005;1039: 30–6. 78. Rojas H, Lekic T, Chen W, et al. The antioxidant effects of melatonin after intracerebral hemorrhage in rats. Acta Neurochir Suppl 2008;105:19–21. 79. Lyden PD, Shuaib A, Lees KR, et al. Safety and tolerability of NXY-059 for acute intracerebral hemorrhage: The CHANT trial. Stroke 2007;38:2262–9. 80. Nakamura T, Kuroda Y, Yamashita S, et al. Edaravone attenuates brain edema and neurologic deficits in a rat model of acute intracerebral hemorrhage. Stroke 2008;39:463–9. 81. Tang J, Liu J, Zhou C, et al. Role of nadph oxidase in the brain injury of intracerebral hemorrhage. J Neurochem 2005;94: 1342–50. 82. Hatakeyama T, Okauchi M, Hua Y, et al. Deferoxamine reduces neuronal death and hematoma lysis after intracerebral hemorrhage in aged rats. Trans Stroke Res 2013;4. 83. Zhao X, Aronowski J. Nrf2 to pre-condition the brain against injury caused by products of hemolysis after ich. Trans Stroke Res 2013;4:71–5. 84. Shang H, Yang D, Zhang W, et al. Time course of Keap1-Nrf2 pathway expression after experimental intracerebral haemorrhage: Correlation with brain oedema and neurological deficit. Free Radic Res 2013;47:368–75. 85. Wang J, Fields J, Zhao C, et al. Role of nrf2 in protection against intracerebral hemorrhage injury in mice. Free Radic Biol Med 2007;43:408–14. 86. Zhao X, Song S, Sun G, et al. Neuroprotective role of haptoglobin after intracerebral hemorrhage. J Neurosci 2009;29: 15819–27. 87. Jaffer H, Morris VB, Stewart D, et al. Advances in stroke therapy. Drug Deliv Transl Res 2011;1:409–19. 88. Ma Q, Chen S, Hu Q, et al. Nlrp3 inflammasome contributes to inflammation after intracerebral hemorrhage. Ann Neurol 2014;75(2):209-19. 89. Hayman LA, Pagani JJ, Kirkpatrick JB, et al. Pathophysiology of acute intracerebral and subarachnoid hemorrhage: Applications to MR imaging. Am J Roentgenol 1989;153:135–9. 90. Marlet JM, Barreto Fonseca JdP. Experimental determination of time of intracranial hemorrhage by spectrophotometric analysis of cerebrospinal fluid. J Forensic Sci 1982;27:880–8. 91. Koeppen AH, Dickson AC, McEvoy JA. The cellular reactions to experimental intracerebral hemorrhage. J Neurol Sci 1995; 134(Suppl.):102–12. 92. Wu J, Hua Y, Keep RF, et al. Iron and iron-handling proteins in the brain after intracerebral hemorrhage. Stroke 2003;34: 2964–9. 93. Nakamura T, Keep R, Hua Y, et al. Deferoxamine-induced attenuation of brain edema and neurological deficits in a rat model of intracerebral hemorrhage. J Neurosurg 2004;100:672–8. 94. Wahlgren NG, Lindquist C. Haem derivatives in the cerebrospinal fluid after intracranial haemorrhage. Eur Neurol 1987;26: 216–21. 95. Xi G, Keep RF, Hoff JT. Mechanisms of brain injury after intracerebral hemorrhage. Lancet Neurol 2006;5:53–63. 96. Gu Y, Hua Y, Keep RF, et al. Deferoxamine reduces intracerebral hematoma-induced iron accumulation and neuronal death in piglets. Stroke 2009;40:2241–3.

97. Kase CS, Caplan LR. Intracerebral hemorrhage. Boston: Butterworth-Heinemann; 1994. 98. Hua Y, Xi G, Keep RF, et al. Complement activation in the brain after experimental intracerebral hemorrhage. J Neurosurg 2000; 92:1016–22. 99. Wu J, Hua Y, Keep RF, et al. Oxidative brain injury from extravasated erythrocytes after intracerebral hemorrhage. Brain Res 2002;953:45–52. 100. Xi G, Keep RF, Hoff JT. Erythrocytes and delayed brain edema formation following intracerebral hemorrhage in rats. J Neurosurg 1998;89:991–6. 101. Zazulia AR, Diringer MN, Derdeyn CP, et al. Progression of mass effect after intracerebral hemorrhage. Stroke 1999;30:1167–73. 102. Wu G, Xi G, Huang F. Spontaneous intracerebral hemorrhage in humans: Hematoma enlargement, clot lysis, and brain edema. Acta Neurochir Suppl 2006;96:78–80. 103. Gao BB, Clermont A, Rook S, et al. Extracellular carbonic anhydrase mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation. Nat Med 2007;13: 181–8. 104. Guo F, Hua Y, Wang J, et al. Inhibition of carbonic anhydrase reduces brain injury after intracerebral hemorrhage. Trans Stroke Res 2012;3:130–7. 105. Huang F, Xi G, Keep RF, et al. Brain edema after experimental intracerebral hemorrhage: Role of hemoglobin degradation products. J Neurosurg 2002;96:287–93. 106. Chen Z, Gao C, Hua Y, et al. Role of iron in brain injury after intraventricular hemorrhage. Stroke 2011;42:465–70. 107. Wagner KR, Hua Y, de Courten-Myers GM, et al. Tinmesoporphyrin, a potent heme oxygenase inhibitor, for treatment of intracerebral hemorrhage: In vivo and in vitro studies. Cell Mol Biol 2000;46:597–608. 108. Koeppen AH, Dickson AC, Smith J. Heme oxygenase in experimental intracerebral hemorrhage: The benefit of tinmesoporphyrin. J Neuropathol Exp Neurol 2004;63:587–97. 109. Gong Y, Tian H, Xi G, et al. Systemic zinc protoporphyrin administration reduces intracerebral hemorrhage-induced brain injury. Acta Neurochir (Wien) 2006;96(Suppl.):232–6. 110. Perez de la Ossa N, Sobrino T, Silva Y, et al. Iron-related brain damage in patients with intracerebral hemorrhage. Stroke 2010; 41:810–13. 111. Selim M. Deferoxamine mesylate: A new hope for intracerebral hemorrhage: From bench to clinical trials. Stroke 2009;40:S90–1. 112. Wu G, Xi G, Hua Y, et al. T2* magnetic resonance imaging sequences reflect brain tissue iron deposition following intracerebral hemorrhage. Trans Stroke Res 2010;1:31–4. 113. Wan S, Hua Y, Keep RF, et al. Deferoxamine reduces CSF free iron levels following intracerebral hemorrhage. Acta Neurochir (Wien) Acta Neurochir Suppl 2006;96:199–202. 114. Xi G, Keep RF, Hoff JT. Pathophysiology of brain edema formation. Neurosurg Clin North Am 2002;13:371–83. 115. Suzuki J, Ebina T. Sequential changes in tissue surrounding ICH. In: Pia HW, Longmaid C, Zierski J, editors. Spontaneous intracerebral hematomas. Berlin: Springer; 1980. p. 121–8. 116. Wagner KR, Xi G, Hua Y, et al. Lobar intracerebral hemorrhage model in pigs: Rapid edema development in perihematomal white matter. Stroke 1996;27:490–7. 117. Ropper AH. Lateral displacement of the brain and level of consciousness in patients with an acute hemispheral mass. New Engl J Med 1986;314:953–8. 118. Enzmann DR, Britt RH, Lyons BE, et al. Natural history of experimental intracerebral hemorrhage: Sonography, computed tomography and neuropathology. Am J Neuroradiol 1981;2: 517–26. 119. Tomita H, Ito U, Ohno K, et al. Chronological changes in brain edema induced by experimental intracerebral hematoma in cats. Acta Neurochir Suppl 1994;60:558–60. 120. Yang GY, Betz AL, Chenevert TL, et al. Experimental intracerebral hemorrhage: Relationship between brain edema, blood flow, and blood-brain barrier permeability in rats. J Neurosurg 1994; 81:93–102. 121. Garcia JH, Ho KL, Caccamo D. Intracerebral hemorrhage: Pathology of selected topics. In: Kase CS, Caplan LR, editors. Intracerebral hemorrhage. Boston: Butterworths; 1994. p. 45–72.

Mechanisms of Cerebral Hemorrhage

112.e3

122. Broderick J, Brott T, Kothari R. Very early edema growth with ich. Stroke 1995;26:184. 123. Suzuki R, Ohno K, Hiratsuka H, et al. Chronological changes in brain edema in hypertensive intracerebral hemorrhage observed by CT and xenon-enhanced CT. In: Inaba Y, Klatzo I, Spatz M, editors. Brain edema. Berlin Heidelbery, New York, Tokyo: Springer; 1985. p. 613–20. 124. Ropper AH, King RB. Intracranial pressure monitoring in comatose patients with cerebral hemorrhage. Arch Neurol 1984;41: 725–8. 125. Okauchi M, Hua Y, Keep RF, et al. Deferoxamine treatment for intracerebral hemorrhage in aged rats: Therapeutic time window and optimal duration. Stroke 2010;41:375–82. 126. Okauchi M, Hua Y, Keep RF, et al. Effects of deferoxamine on intracerebral hemorrhage-induced brain injury in aged rats. Stroke 2009;40:1858–63. 127. Xie Q, Gu Y, Hua Y, et al. Deferoxamine attenuates white matter injury in a piglet intracerebral hemorrhage model. Stroke 2014; 45(1):290-2. 128. Hua Y, Nakamura T, Keep RF, et al. Long-term effects of experimental intracerebral hemorrhage: The role of iron. J Neurosurg 2006;104:305–12. 129. Xi G, Reiser G, Keep RF. The role of thrombin and thrombin receptors in ischemic, hemorrhagic and traumatic brain injury: Deleterious or protective? J Neurochem 2003;84:3–9. 130. Lee KR, Kawai N, Kim S, et al. 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 1997;86:272–8. 131. Xue M, Hollenberg MD, Demchuk A, et al. Relative importance of proteinase-activated receptor-1 versus matrix metalloproteinases in intracerebral hemorrhage-mediated neurotoxicity in mice. Stroke 2009;40:2199–204. 132. Coughlin SR. Thrombin signalling and protease-activated receptors. Nature 2000;407:258–64. 133. Kitaoka T, Hua Y, Xi G, et al. Delayed argatroban treatment reduces edema in a rat model of intracerebral hemorrhage. Stroke 2002;33:3012–18. 134. Gong Y, Xi G, Keep R, et al. Complement inhibition attenuates brain edema and neurological deficits induced by thrombin. Acta Neurochir (Wien) 2005;95(Suppl.):389–92. 135. Hugli TE. Complement factors and inflammation: Effects of thrombin on components of c3 and c5. In: Lundblad RL, Fenton JW, Mann KG, editors. Chemistry and biology of thrombin. Ann Arbor: Ann Arbor Science Publishers; 1977. p. 345–60. 136. Hua Y, Wu J, Keep R, et al. Tumor necrosis factor-alpha increases in the brain following intracerebral hemorrhage and thrombin stimulation. Neurosurgery 2006;58:542–50. 137. Hua Y, Keep R, Hoff J, et al. Brain injury after intracerebral hemorrhage: The role of thrombin and iron. Stroke 2007;38: 759–62. 138. Nguyen M, Arkell J, Jackson CJ. Thrombin rapidly and efficiently activates gelatinase A in human microvascular endothelial cells via a mechanism independent of active MT1 matrix metalloproteinase. Lab Invest 1999;79:467–75. 139. Bonfoco E, Krainc D, Ankarcrona M, et al. Apoptosis and necrosis: Two distinct events induced, respectively, by mild and intense insults with N-methyl-D-aspartate or nitric oxide/superoxide in cortical cell cultures. Proc Natl Acad Sci U S A 1995;92:7162–6. 140. Matsushita K, Meng W, Wang X, et al. Evidence for apoptosis after intercerebral hemorrhage in rat striatum. J Cereb Blood Flow Metab 2000;20:396–404. 141. Gong C, Boulis N, Qian J, et al. Intracerebral hemorrhageinduced neuronal death. Neurosurgery 2001;48:875–82, discussion 882–3. 142. Power C, Henry S, Del Bigio MR, et al. Intracerebral hemorrhage induces macrophage activation and matrix metalloproteinases. Ann Neurol 2003;53:731–42. 143. Kuida K, Lippke JA, Ku G, et al. Altered cytokine export and apoptosis in mice deficient in interleukin- 1 beta converting enzyme. Science 1995;267:2000–3. 144. Hara H, Friedlander RM, Gagliardini V, et al. Inhibition of interleukin 1beta converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage. Proc Natl Acad Sci U S A 1997;94:2007–12.

8

112.e4 SECTION I 

Pathophysiology

145. Lu A, Tang Y, Ran R, et al. Brain genomics of intracerebral hemorrhage. J Cereb Blood Flow Metab 2006;26:230–52. 146. Barnes PJ, Karin M. Nuclear factor-kappab: A pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 1997;336:1066–71. 147. Slee EA, Harte MT, Kluck RM, et al. Ordering the cytochrome c-initiated caspase cascade: Hierarchical activation of caspases-2, -3, -6, -7, -8, and -10 in a caspase-9-dependent manner. J Cell Biol 1999;144:281–92. 148. Neame SJ, Rubin LL, Philpott KL. Blocking cytochrome c activity within intact neurons inhibits apoptosis. J Cell Biol 1998;142: 1583–93. 149. Kluck RM, Bossy-Wetzel E, Green DR, et al. The release of cytochrome c from mitochondria: A primary site for bcl-2 regulation of apoptosis. Science 1997;275:1132–6. 150. Rosenbaum DM, Gupta G, D’Amore J, et al. Fas (cd95/apo-1) plays a role in the pathophysiology of focal cerebral ischemia. J Neurosci Res 2000;61:686–92. 151. Sugawara T, Fujimura M, Noshita N, et al. Neuronal death/ survival signaling pathways in cerebral ischemia. NeuroRx 2004;1:17–25. 152. Nakashima K, Yamashita K, Uesugi S, et al. Temporal and spatial profile of apoptotic cell death in transient intracerebral mass lesion of the rat. J Neurotrauma 1999;16:143–51. 153. Li L, Ke K, Tan X, et al. Up-regulation of nfatc4 involves in neuronal apoptosis following intracerebral hemorrhage. Cell Mol Neurobiol 2013;33:893–905. 154. Choi DW. Calcium and excitotoxic neuronal injury. Ann N Y Acad Sci 1994;747:162–71. 155. Rothman SM, Olney JW. Excitotoxicity and the nmda receptor– still lethal after eight years. Trends Neurosci 1995;18:57–8. 156. Nakamura T, Keep RF, Hua Y, et al. Intracerebral hemorrhage induces edema and oxidative stress and alters N-methyl-Daspartate receptor subunits expression. Acta Neurochir (Wien) Acta Neurochir Suppl 2005;95:421–4. 157. Qureshi AI, Ali Z, Suri MF, et al. Extracellular glutamate and other amino acids in experimental intracerebral hemorrhage: An in vivo microdialysis study. Crit Care Med 2003;31:1482–9. 158. Lee ST, Chu K, Jung KH, et al. Memantine reduces hematoma expansion in experimental intracerebral hemorrhage, resulting in functional improvement. J Cereb Blood Flow Metab 2006; 26:536–44. 159. Thiex R, Weis J, Krings T, et al. Addition of intravenous N-methylD-aspartate receptor antagonists to local fibrinolytic therapy for the optimal treatment of experimental intracerebral hemorrhages. J Neurosurg 2007;106:314–20. 160. Ardizzone TD, Lu A, Wagner KR, et al. Glutamate receptor blockade attenuates glucose hypermetabolism in perihematomal brain after experimental intracerebral hemorrhage in rat. Stroke 2004;35:2587–91. 161. Lyden PD, Jackson-Friedman C, Lonzo-Doktor L. Medical therapy for intracerebral hematoma with the gammaaminobutyric acid-A agonist muscimol. Stroke 1997;28: 387–91. 162. Levine B, Yuan J. Autophagy in cell death: An innocent convict? J Clin Invest 2005;115:2679–88. 163. He Y, Wan S, Hua Y, et al. Autophagy after experimental intracerebral hemorrhage. J Cereb Blood Flow Metab 2008;28: 897–905. 164. Gong Y, He Y, Gu Y, et al. Effects of aging on autophagy after experimental intracerebral hemorrhage. Acta Neurochir (Wien) Acta Neurochir Suppl 2011;111:113–17. 165. Degterev A, Huang Z, Boyce M, et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol 2005;1:112–19. 166. Kaczmarek A, Vandenabeele P, Krysko DV. Necroptosis: The release of damage-associated molecular patterns and its physiological relevance. Immunity 2013;38:209–23. 167. Chang P, Dong W, Zhang M, et al. Anti-necroptosis chemical necrostatin-1 can also suppress apoptotic and autophagic pathway to exert neuroprotective effect in mice intracerebral hemorrhage model. J Mol Neurosci 2014;52:242–9. 168. Betz AL, Iannotti F, Hoff JT. Brain edema: A classification based on blood-brain barrier integrity. Cerebrovasc Brain Metabol Rev 1989;1:133–54.

169. Rubin LL, Staddon JM. The cell biology of the blood-brain barrier. Ann Rev Neurosci 1999;22:11–28. 170. Florczak-Rzepka M, Grond-Ginsbach C, Montaner J, et al. Matrix metalloproteinases in human spontaneous intracerebral hemorrhage: An update. Cerebrovasc Dis 2012;34:249–62. 171. Yang GY, Betz AL, Hoff JT. The effects of blood or plasma clot on brain edema in the rat with intracerebral hemorrhage. Acta Neurochir Suppl (Wien) 1994;60:555–7. 172. Brown MS, Kornfeld M, Mun-Bryce S, et al. Comparison of magnetic resonance imaging and histology in collagenase-induced hemorrhage in the rat. J Neuroimaging 1995;5:23–33. 173. Liu DZ, Sharp FR. The dual role of src kinases in intracerebral hemorrhage. Acta Neurochir Suppl 2011;111:77–81. 174. Moxon-Emre I, Schlichter LC. Neutrophil depletion reduces blood-brain barrier breakdown, axon injury, and inflammation after intracerebral hemorrhage. J Neuropathol Exp Neurol 2011;70:218–35. 175. Tejima E, Zhao BQ, Tsuji K, et al. Astrocytic induction of matrix metalloproteinase-9 and edema in brain hemorrhage. J Cereb Blood Flow Metab 2007;27:460–8. 176. Wang X, Jung J, Asahi M, et al. Effects of matrix metalloproteinase-9 gene knock-out on morphological and motor outcomes after traumatic brain injury. J Neurosci 2000;20:7037–42. 177. Rosenberg GA. Matrix metalloproteinases in neuroinflammation. Glia 2002;39:279–91. 178. del Zoppo GJ, Milner R, Mabuchi T, et al. Microglial activation and matrix protease generation during focal cerebral ischemia. Stroke 2007;38:646–51. 179. Rosenberg GA, Navratil M. Metalloproteinase inhibition blocks edema in intracerebral hemorrhage in the rat. Neurology 1997; 48:921–6. 180. Katsu M, Niizuma K, Yoshioka H, et al. Hemoglobin-induced oxidative stress contributes to matrix metalloproteinase activation and blood-brain barrier dysfunction in vivo. J Cereb Blood Flow Metab 2010;30:1939–50. 181. Wasserman JK, Schlichter LC. Minocycline protects the bloodbrain barrier and reduces edema following intracerebral hemorrhage in the rat. Exp Neurol 2007;207:227–37. 182. Wagner KR, Beiler S, Beiler C, et al. Delayed profound local brain hypothermia markedly reduces interleukin-1beta gene expression and vasogenic edema development in a porcine model of intracerebral hemorrhage. Acta Neurochir (Wien) Acta Neurochir Suppl 2006;96:177–82. 183. Wu G, Bao X, Xi G, et al. Brain injury after intracerebral hemorrhage in spontaneously hypertensive rats. J Neurosurg 2011;114: 1805–11. 184. Nakamura T, Hua Y, Keep R, et al. Estrogen therapy for experimental intracerebral hemorrhage. J Neurosurg 2005;103: 97–103. 185. Hurn PD, Macrae IM. Estrogen as a neuroprotectant in stroke. J Cereb Blood Flow Metab 2000;20:631–52. 186. Roof RL, Hall ED. Gender differences in acute CNS trauma and stroke: Neuroprotective effects of estrogen and progesterone. J Neurotrauma 2000;17:367–88. 187. Regan RF, Guo Y. Estrogens attenuate neuronal injury due to hemoglobin, chemical hypoxia, and excitatory amino acids in murine cortical cultures. Brain Res 1997;764:133–40. 188. Culmsee C, Vedder H, Ravati A, et al. Neuroprotection by estrogens in a mouse model of focal cerebral ischemia and in cultured neurons: Evidence for a receptor-independent antioxidative mechanism. J Cereb Blood Flow Metab 1999;19:1263–9. 189. Gong Y, Hua Y, Keep RF, et al. Intracerebral hemorrhage: Effects of aging on brain edema and neurological deficits. Stroke 2004;35:2571–5. 190. Daverat P, Castel JP, Dartigues JF, et al. Death and functional outcome after spontaneous intracerebral hemorrhage. A prospective study of 166 cases using multivariate analysis. Stroke 1991;22:1–6. 191. Wasserman JK, Schlichter LC. White matter injury in young and aged rats after intracerebral hemorrhage. Exp Neurol 2008;214: 266–75. 192. Kaufman HH, Schochet S, Koss W, et al. Efficacy and safety of tissue plasminogen activator. Neurosurgery 1987;20:403–7. 193. Wagner KR, Xi G, Hua Y, et al. Ultra-early clot aspiration after lysis with tissue plasminogen activator in a porcine model of

intracerebral hemorrhage: Edema reduction and blood-brain barrier protection. J Neurosurg 1999;90:491–8. 194. Thiex R, Kuker W, Muller HD, et al. The long-term effect of recombinant tissue-plasminogen-activator (rt-PA) on edema formation in a large-animal model of intracerebral hemorrhage. Neurol Res 2003;25:254–62. 195. Lippitz BE, Mayfrank L, Spetzger U, et al. Lysis of basal ganglia haematoma with recombinant tissue plasminogen activator (rtPA) after stereotactic aspiration: Initial results. Acta Neurochir (Wien) 1994;127:157–60. 196. Rohde V, Schaller C, Hassler WE. Intraventricular recombinant tissue plasminogen activator for lysis of intraventricular haemorrhage. J Neurol Neurosurg Psychiatry 1995;58:447–51. 197. Schaller C, Rohde V, Meyer B, et al. Stereotactic puncture and lysis of spontaneous intracerebral hemorrhage using recombinant tissue-plasminogen activator. Neurosurg 1995;36:328–33. 198. Ziai W, Moullaali T, Nekoovaght-Tak S, et al. No exacerbation of perihematomal edema with intraventricular tissue plasminogen activator in patients with spontaneous intraventricular hemorrhage. Neurocrit Care 2013;18:354–61. 199. Vespa PM, Martin N, Zuccarello M, et al. Surgical trials in intracerebral hemorrhage. Stroke 2013;44:S79–82. 200. Mendelow AD, Gregson BA, Fernandes HM, et al. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the international surgical trial in intracerebral haemorrhage (STICH): A randomised trial. Lancet 2005;365:387–97. 201. Broderick JP. The STICH trial: What does it tell us and where do we go from here? Stroke 2005;36:1619–20. 202. Mendelow AD, Unterberg A. Surgical treatment of intracerebral haemorrhage. Curr Opin Crit Care 2007;13:169–74. 203. Mendelow AD, Gregson BA, Rowan EN, et al. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): A randomised trial. Lancet 2013;382:397–408. 204. Gong C, Ennis SR, Hoff JT, et al. Inducible cyclooxygenase-2 expression after experimental intracerebral hemorrhage. Brain Res 2001;901:38–46. 205. Lee ST, Chu K, Sinn DI, et al. Erythropoietin reduces perihematomal inflammation and cell death with eNOS and STAT3 activations in experimental intracerebral hemorrhage. J Neurochem 2006;96:1728–39. 206. Seyfried DM, Han Y, Yang D, et al. Erythropoietin promotes neurological recovery after intracerebral haemorrhage in rats. Int J Stroke 2009;4:250–6. 207. Li Y, Ogle ME, Wallace GCt, et al. Erythropoietin attenuates intracerebral hemorrhage by diminishing matrix metallo­ proteinases and maintaining blood-brain barrier integrity in mice. Acta Neurochir (Wien) Acta Neurochir Suppl 2008;105: 105–12. 208. Chau M, Chen D, Wei L. Erythropoietin attenuates inflammatory factors and cell death in neonatal rats with intracerebral hemorrhage. Acta Neurochir (Wien) Acta Neurochir Suppl 2011;111: 299–305. 209. Karki K, Knight RA, Han Y, et al. Simvastatin and atorvastatin improve neurological outcome after experimental intracerebral hemorrhage. Stroke 2009;40:3384–9. 210. Seyfried D, Han Y, Lu D, et al. Improvement in neurological outcome after administration of atorvastatin following experimental intracerebral hemorrhage in rats. J Neurosurg 2004;101: 104–7. 211. Jung KH, Chu K, Jeong SW, et al. HMG-CoA reductase inhibitor, atorvastatin, promotes sensorimotor recovery, suppressing acute inflammatory reaction after experimental intracerebral hemorrhage. Stroke 2004;35:1744–9. 212. Ewen T, Qiuting L, Chaogang T, et al. Neuroprotective effect of atorvastatin involves suppression of TNF-α and upregulation of IL-10 in a rat model of intracerebral hemorrhage. Cell Biochem Biophys 2013;66:337–46. 213. Park HK, Chu K, Lee ST, et al. Granulocyte colony-stimulating factor induces sensorimotor recovery in intracerebral hemorrhage. Brain Res 2005;1041:125–31. 214. Zhang L, Shu XJ, Zhou HY, et al. Protective effect of granulocyte colony-stimulating factor on intracerebral hemorrhage in rat. Neurochem Res 2009;34:1317–23.

Mechanisms of Cerebral Hemorrhage

112.e5

215. Guo X, Bu X, Jiang J, et al. Enhanced neuroprotective effects of co-administration of G-CSF with simvastatin on intracerebral hemorrhage in rats. Turkish Neurosurg 2012;22:732–9. 216. Wu J, Yang S, Hua Y, et al. Minocycline attenuates brain edema, brain atrophy and neurological deficits after intracerebral hemorrhage. Acta Neurochir (Wien) Acta Neurochir Suppl 2010;106: 147–50. 217. Wu J, Yang S, Xi G, et al. Minocycline reduces intracerebral hemorrhage-induced brain injury. Neurol Res 2009;31:183–8. 218. Zhao F, Hua Y, He Y, et al. Minocycline-induced attenuation of iron overload and brain injury after experimental intracerebral hemorrhage. Stroke 2011;42:3587–93. 219. Xue M, Mikliaeva EI, Casha S, et al. Improving outcomes of neuroprotection by minocycline: Guides from cell culture and intracerebral hemorrhage in mice. Am J Pathol 2010;176: 1193–202. 220. Song S, Hua Y, Keep RF, et al. Deferoxamine reduces brain swelling in a rat model of hippocampal intracerebral hemorrhage. Acta Neurochir (Wien)Acta Neurochir Suppl 2008;105: 13–18. 221. Xing Y, Hua Y, Keep RF, et al. Effects of deferoxamine on brain injury after transient focal cerebral ischemia in rats with hyperglycemia. Brain Res 2009;1291:113–21. 222. Gu Y, Hua Y, He Y, et al. Iron accumulation and DNA damage in a pig model of intracerebral hemorrhage. Acta Neurochir (Wien) Acta Neurochir Suppl 2011;111:123–8. 223. Wu H, Wu T, Xu X, et al. Iron toxicity in mice with collagenaseinduced intracerebral hemorrhage. J Cereb Blood Flow Metab 2011;31:1243–50. 224. Nagatsuna T, Nomura S, Suehiro E, et al. Systemic administration of argatroban reduces secondary brain damage in a rat model of intracerebral hemorrhage: Histopathological assessment. Cerebrovasc Dis 2005;19:192–200. 225. Kitaoka T, Hua Y, Xi G, et al. Effect of delayed argatroban treatment on intracerebral hemorrhage-induced edema in the rat. Acta Neurochir (Wien) Acta Neurochir Suppl 2003;86:457–61. 226. Li G, Fan RM, Chen JL, et al. Neuroprotective effects of argatroban and c5a receptor antagonist (PMX53) following intracerebral hemorrhage. Clin Exp Immunol 2013. 227. Zhou ZH, Qu F, Zhang CD. Systemic administration of argatroban inhibits protease-activated receptor-1 expression in perihematomal tissue in rats with intracerebral hemorrhage. Brain Res Bull 2011;86:235–8. 228. Clark W, Gunion-Rinker L, Lessov N, et al. Citicoline treatment for experimental intracerebral hemorrhage in mice. Stroke 1998;29:2136–40. 229. Qin Z, Xi G, Keep RF, et al. Hyperbaric oxygen for experimental intracerebral hemorrhage. Acta Neurochir (Wien) Acta Neurochir Suppl 2008;105:113–17. 230. Lema PP, Girard C, Vachon P. Evaluation of dexamethasone for the treatment of intracerebral hemorrhage using a collagenaseinduced intracerebral hematoma model in rats. J Vet Pharmacol Therapeut 2004;27:321–8. 231. Vachon P, Moreau JP. Low doses of dexamethasone decrease brain water content of collagenase-induced cerebral hematoma. Can J Vet Res 2003;67:157–9. 232. Li ZQ, Liang GB, Xue YX, et al. Effects of combination treatment of dexamethasone and melatonin on brain injury in intracerebral hemorrhage model in rats. Brain Res 2009;1264:98–103. 233. Xie Q, Guan J, Wu G, et al. Tamoxifen treatment for intracerebral hemorrhage. Acta Neurochir (Wien) Acta Neurochir Suppl 2011;111:271–5. 234. Nakamura T, Xi G, Keep RF, et al. Effects of endogenous and exogenous estrogen on intracerebral hemorrhage-induced brain damage in rats. Acta Neurochir (Wien) Acta Neurochir Suppl 2006;96:218–21. 235. Auriat A, Plahta WC, McGie SC, et al. 17beta-estradiol pretreatment reduces bleeding and brain injury after intracerebral hemorrhagic stroke in male rats. J Cereb Blood Flow Metab 2005;25: 247–56. 236. Vaquero J, Otero L, Bonilla C, et al. Cell therapy with bone marrow stromal cells after intracerebral hemorrhage: Impact of platelet-rich plasma scaffolds. Cytotherapy 2013;15:33–43. 237. Wang SP, Wang ZH, Peng DY, et al. Therapeutic effect of mesenchymal stem cells in rats with intracerebral hemorrhage: Reduced

8

112.e6 SECTION I 

Pathophysiology

apoptosis and enhanced neuroprotection. Mol Med Rep 2012;6: 848–54. 238. Seghatoleslam M, Jalali M, Nikravesh MR, et al. Intravenous administration of human umbilical cord blood-mononuclear cells dose-dependently relieve neurologic deficits in rat intracerebral hemorrhage model. Ann Anat 2013;195:39–49. 239. Yang KL, Lee JT, Pang CY, et al. Human adipose-derived stem cells for the treatment of intracerebral hemorrhage in rats via femoral intravenous injection. Cell Mol Biol Lett 2012;17: 376–92. 240. Yang D, Han Y, Zhang J, et al. Therapeutic effect of human umbilical tissue-derived cell treatment in rats with experimental intracerebral hemorrhage. Brain Res 2012;1444:1–10. 241. Wang Z, Cui C, Li Q, et al. Intracerebral transplantation of foetal neural stem cells improves brain dysfunction induced by intracerebral haemorrhage stroke in mice. J Cell Mol Med 2011;15: 2624–33. 242. Otero L, Zurita M, Bonilla C, et al. Late transplantation of allogeneic bone marrow stromal cells improves neurologic deficits subsequent to intracerebral hemorrhage. Cytotherapy 2011;13: 562–71. 243. Liao W, Zhong J, Yu J, et al. Therapeutic benefit of human umbilical cord derived mesenchymal stromal cells in intracerebral hemorrhage rat: Implications of anti-inflammation and angiogenesis. Cell Physiol Biochem 2009;24:307–16. 244. Fatar M, Stroick M, Griebe M, et al. Lipoaspirate-derived adult mesenchymal stem cells improve functional outcome during intracerebral hemorrhage by proliferation of endogenous progenitor cells stem cells in intracerebral hemorrhages. Neurosci Lett 2008;443:174–8. 245. Kim JM, Lee ST, Chu K, et al. Systemic transplantation of human adipose stem cells attenuated cerebral inflammation and degeneration in a hemorrhagic stroke model. Brain Res 2007;1183: 43–50. 246. Lee HJ, Kim KS, Kim EJ, et al. Brain transplantation of immortalized human neural stem cells promotes functional recovery in mouse intracerebral hemorrhage stroke model. Stem Cells 2007; 25:1204–12. 247. Nonaka M, Yoshikawa M, Nishimura F, et al. Intraventricular transplantation of embryonic stem cell-derived neural stem cells in intracerebral hemorrhage rats. Neurol Res 2004;26:265–72. 248. Ohnishi M, Katsuki H, Fukutomi C, et al. Hmgb1 inhibitor glycyrrhizin attenuates intracerebral hemorrhage-induced injury in rats. Neuropharmacol 2011;61:975–80.

249. Yang D, Han Y, Zhang J, et al. Improvement in recovery after experimental intracerebral hemorrhage using a selective cathepsin b and l inhibitor. J Neurosurg 2011;114:1110–16. 250. Kawanishi M, Kawai N, Nakamura T, et al. Effect of delayed mild brain hypothermia on edema formation after intracerebral hemorrhage in rats. J Stroke Cerebrovasc Dis 2008;17:187–95. 251. Jung KH, Chu K, Lee ST, et al. Blockade of at1 receptor reduces apoptosis, inflammation, and oxidative stress in normotensive rats with intracerebral hemorrhage. J Pharmacol Experiment Therap 2007;322:1051–8. 252. Sinn DI, Kim SJ, Chu K, et al. Valproic acid-mediated neuroprotection in intracerebral hemorrhage via histone deacetylase inhibition and transcriptional activation. Neurobiol Dis 2007;26: 464–72. 253. Ardizzone TD, Zhan X, Ander BP, et al. SRC kinase inhibition improves acute outcomes after experimental intracerebral hemorrhage. Stroke 2007;38:1621–5. 254. Sinn DI, Lee ST, Chu K, et al. Proteasomal inhibition in intracerebral hemorrhage: Neuroprotective and anti-inflammatory effects of bortezomib. Neurosci Res 2007;58:12–18. 255. Al-Senani FM, Zhao X, Grotta JC, et al. Proteasome inhibitor reduces astrocytic iNOS expression and functional deficit after experimental intracerebral hemorrhage in rats. Trans Stroke Res 2012;3:146–53. 256. Zhao X, Zhang Y, Strong R, et al. 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 2006;26:811–20. 257. Mayne M, Fotheringham J, Yan HJ, et al. Adenosine a2a receptor activation reduces proinflammatory events and decreases cell death following intracerebral hemorrhage. Ann Neurol 2001;49: 727–35. 258. Peeling J, Del Bigio MR, Corbett D, et al. 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. Neuropharmacol 2001;40:433–9. 259. Sheng SP, Lei B, James ML, et al. Xenon neuroprotection in experimental stroke: Interactions with hypothermia and intracerebral hemorrhage. Anesthesiology 2012;117:1262–75. 260. Ma Q, Huang B, Khatibi N, et al. PDGFR-alpha inhibition preserves blood-brain barrier after intracerebral hemorrhage. Ann Neurol 2011;70:920–31.