doi: 10.1161/01.STR.0000255033.02904.db
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(Stroke. 2007;38:753.)
© 2007 American Heart Association, Inc.
Intracerebral Hemorrhage: Introduction |
Modeling Intracerebal Hemorrhage
Glutamate, Nuclear Factor-
B Signaling and Cytokines
From the Department of Neurology, University of Cincinnati College of Medicine, Cincinnati, Ohio and Medical Research Service, Department of Veterans Affairs Medical Center, Cincinnati, Ohio.
Correspondence to Kenneth R. Wagner, PhD, Research (151), Veterans Affairs Medical Center, 3200 Vine St, Cincinnati, OH 45220. E-mail wagnerkr{at}email.uc.edu
Abstract
A significant amount of new information has been generated in animal models of intracerebral hemorrhage during the past several years. These include findings on the pathophysiological, biochemical and molecular processes that underlie the development of brain tissue injury after intracerebral hemorrhage as well as potential new treatments. We review these various findings that include glutamate receptor activation, oxidative stress development, intracellular signaling through the transcription factor, nuclear factor-B, and markedly upregulated cytokine gene expression. We also briefly review the surgical treatment for intracerebral hemorrhage and list the pharmacological treatment studies that have recently appeared.
Key Words: blood-brain barrier • edema, brain • free radicals • inflammation • intracranial hemorrhage • treatment
Spontaneous intracerebral hemorrhage (ICH) is a devastating stroke subtype with high mortality and morbidity.1,2 Epidemiological studies have demonstrated that as many as 50% of patients die within the first 48 hours and as few as 20% of survivors return to normal activities of daily living.3 ICH can also occur after thrombolytic treatment for ischemic stroke and myocardial infarction.2 Bleeds into the cerebral white matter are an important cause of edema-related deaths4 and can also damage fiber tracts leading to permanent neurological deficits.5,6 At present, no pharamacological treatments are available in clinical practice, and studies of surgical treatment have demonstrated equivocal results. Thus, it is necessary to conduct experimental studies in ICH animal models to provide both new understanding of the pathophysiological and biochemical events leading to ICH-induced brain injury and to also examine potential ICH treatments.
The number of reports of ICH studies in animal models has markedly increased in recent years. In this review, we briefly describe the animal models used to study ICH, discuss the neuropathological similarities between these models and human ICH and summarize current findings in these models. Based on our recent cytokine expression data, we propose potential sites in intracellular signaling pathways where surgical treatment may be effective. We also describe several recent reports of new pharmacological therapies that have been successful in ICH animal models. This review is not exhaustive. The reader who seeks more information is referred to more comprehensive reviews.1,7–14
Modeling Intracerebral Hemorrhage in Animals
ICH has been classically induced in animals by directly infusing autologous arterial blood into a specific brain region, usually the basal ganglia. Although ICH has been studied in various species, generally the rat has been used.8,12,15 More recently, mouse ICH models have been developed thereby enabling the use of transgenic or knock-out (KO) animals to study specific pathways or injury processes.16–18 In our laboratory, we have developed a large animal (porcine) lobar ICH model that uses arterial blood infusion into the frontal hemispheric white matter.19 This model has been useful to study ICH-induced white matter pathophysiology and pathochemistry.9,19–22 We have also studied various treatments and surgical clot evacuation in this model.21,23,24
Another commonly used ICH model developed by Rosenberg and colleagues uses a local injection of bacterial collagenase usually into the basal ganglia.25 Collagenase dissolves the extracellular matrix and blood vessel basal lamina leading to blood vessel rupture and an intracerebral bleed. This model mimics the spontaneous rupture of an intraparenchymal vessel with bleeding into the tissue occurring over several hours.26 It should be noted, however, that currently there are no experimental animal models of arterial rupture with rapid intraparenchymal blood accumulation that occurs in sudden human ICH. All ICH animal models have certain artificialities which have been previously discussed.8,12
Based on the study design, desired hematoma volumes and costs, certain animal models have advantages in ICH research.12 The advantages of rodents include: (1) the most commonly used species; (2) well-developed paradigms for neurobehavioral testing; (3) extensive reagents for immunocytochemistry and molecular biology; (4) transgenic and knock-out animals are available. On the other hand, large species (eg, pigs) have gyrated brains with significant amounts of white matter. These animals enable the induction of hematoma volumes that are the human equivalent of a 50 mL bleed. With large clot volumes, surgical evacuation techniques and combined surgery and drug treatments can be carefully studied.
Overall, these models have provided new understanding of the pathophysiology underlying ICH-induced injury including information on the roles of mass effect and elevated intracranial pressure, alterations in blood flow and metabolism, and the impact of specific blood components on brain edema formation and blood-brain barrier (BBB) disruption. These models are also providing new details of ICH-induced biochemical and molecular events that have been detailed in recent reviews.9,11,13,27
Brain Pathological Response to ICH in Animal Models
The brain tissue responses to ICH appear similar in experimental animal models and in human ICH.8,12 Typical observations include edema development, astrogliosis, tissue necrosis, clot absorption and scar or cavity formations that are described in human ICH and are also present in animal models. Interestingly, we have observed that infusion of plasma alone into porcine white matter induces a brain pathological response that is similar to whole blood.22,28 These results demonstrate the significance of the blood’s plasma protein component in ICH-induced brain injury.9,13,22,27–30
The development of inflammation and cell death after ICH has been studied in detail31,32 and recently reviewed.11,14 These workers have characterized the cellular perihematomal inflammatory response, including the infiltration of immune cells and activation of microglia. Several workers, including ourselves, have examined the time course of DNA fragmentation.22,28,33,34 Felberg et al35 have proposed the "black hole" model of hemorrhagic damage based on their findings of prominent neuronal destruction adjacent to the hematoma and histological change in the immediate perihematomal region without significant distal injury after ICH.
Glutamate, Lactate and Hypermetabolism
In our porcine ICH model, edematous perihematomal white matter regions contain markedly increased lactate levels (by 10-fold) within 1 hour after induction of ICH.20 Because an energy deficit was not present, lactate accumulation in edematous white matter was not caused by stimulated anaerobic glycolysis. We hypothesized that blood glutamate that enters the brain’s extracellular space during ICH and is several-fold higher than normal levels stimulates ionotropic glutamate receptors and enhances aerobic glycolysis leading to lactate accumulation. Support for elevated extracellular glutamate after ICH was demonstrated using microdialysis by Qureshi and coworkers.36 Glutamate levels were elevated by 4-fold ipsilateral to the hematoma already at 30 minutes after ICH and remained elevated through 5 hours. Elevated glutamate levels have well-described detrimental effects on brain through excitotoxic mechanisms.37
Sharp and colleagues38 demonstrated an acute phase of increased [14C]-2-deoxyglucose uptake in the perihematomal region that peaked at 3 hours in a rat ICH model. This increased [14C]-2-deoxyglucose uptake produced by ICH was blocked by pretreatment with glutamate receptor antagonists. These data imply that glutamate receptor activation increases glucose metabolism in perihematomal brain at early times after ICH, which likely underlies the increased lactate production in the perihematomal white matter.
ICH-Induced Oxidative Stress
Oxidative stress is rapidly induced in perihematomal white matter after ICH as evidenced by protein carbonyl formation and upregulation of heme oxygenase-1 (HO-1) gene expression.30 Plasma infusions into the hemispheric white matter also induce protein carbonyl formation indicating that plasma components alone can induce oxidative stress.28 This may be attributable to several mechanisms including glutamate-induced receptor stimulation leading to increased intracellular calcium levels37 or possibly an interaction between holotransferrin and thrombin leading to intracellular iron deposition.39 Oxidative stress and HO-1 induction are also well described in gray matter after ICH.40 This oxidative stress likely contributes to well-described DNA damage after ICH.33,9,41,28 Zhang and coworkers18 showed that the total oxidative product was lower in NADPH oxidase KO mice after ICH. Brain edema, neurological deficit and a high mortality rate were observed in wild-type but not in KO mice indicating that oxidative stress resulting from NADPH oxidase activation contributes to ICH and promotes brain injury. Additional references to the role of oxidative stress in ICH-induced brain injury can be found in the recent comprehensive review by Aronowski and Hall.11
ICH-Induced Nuclear Factor-B Activation
Considerable evidence demonstrates that ICH induces alterations in gene expression that impact neuropathological processes and likely neuroprotective processes as well.9,42,43 An important transcription factor that is intimately involved in the processing extracellular "environmental" information for transmission to the nucleus is nuclear factor-B (NF-B; Figure 1). Details of the molecular biology of NF-B, its neuropathological as well as neurophysiological, neuroprotective and preconditioning/tolerance roles have been recently reviewed.44–48 Evidence demonstrates that activation of NF-B above physiological levels is observed in neuronal death in trauma, ischemia, Alzheimer and Parkinson diseases (references in Pizzi44). Besides the degree of activation, recent findings indicate that the specific subunit composition of the NF-B complex appears to be an important determiner of the cellular response to receptor activation (references in Pizzi44).
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NF-B is exquisitely sensitive to oxidative stress49,50 and is rapidly activated in perihematomal brain after ICH.9,11,22,50,51 Biochemical studies of NF-B activation in response to ICH have been carried out in other laboratories and by ourselves.11,22,50–52 NF-B is an important mediator for the rapid and coordinated induction of central nervous system genes including proinflammatory cytokines and HO-1.53,54
Recent studies by Aronowski and colleagues have demonstrated that after ICH, activation of peroxisome proliferator-activated receptor 
(PPAR-), a member of the nuclear hormone receptor superfamily, is associated with suppression of NF-B activation.55 Rosiglitazone, a PPAR- agonist, promoted hematoma resolution, decreased neuronal death, and improved functional recovery in a mouse ICH model. Interestingly, these workers have also reported that the prostaglandin, 15-deoxy-D12,14-prostaglandin J2 (15d-PGJ2) that acts as a physiological agonist for PPAR- is associated with activation of PPAR- and suppression of NF-B activity. Treatment with 15d-PGJ2 also reduced inflammation, behavioral dysfunction and neuronal damage produced by ICH.55 In other model systems, inhibition of NF-B activation is suggested to be a putative mechanism for the beneficial effects of PPAR- agonists.56,57
Intracerebral Plasma Infusions
The blood’s plasma component and coagulation cascade activation after ICH play an essential role in the development of perihematomal edema afte ICH.13,19,27,29 Interestingly, in support of animal study findings, an MRI study in human ICH suggested that this edema is plasma derived.58 These blood-derived plasma proteins can also activate microglia after ICH.59,60 In microglial cultures, serum stimulate superoxide production.61 We have observed early induction of HO-1 in perihematomal white matter after ICH possibly in microglia.30 Considerable evidence suggests that the edemogenic component in plasma is the coagulation protein, thrombin.13,27 Interestingly, thrombin potentiates NMDA receptor activity62 and may contribute to the early ICH induced hypermetabolism described above. Thrombin’s conversion of fibrinogen to fibrin and the resulting fibrin deposition along with its water retaining properties in the perihematomal interstitial space may also be important in early edema development.22,28
Proinflammatory Cytokines
Several reports have described upregulation of proinflammatory cytokines after ICH. A comprehensive review of inflammation after ICH has also been recently published.14 We demonstrated early (1- to 2-hour) upregulation of interleukin (IL)-1ß mRNA in perihematomal white matter.51,63 The proinflammatory contribution of IL-1ß in various brain injury models, in neurodegeneration and in increased blood-brain–barrier permeability and edema has been well-described.11,51,53,63,64 Interestingly, and in support of these observations, IL-1 receptor antagonist (IL-1ra) overexpression reduces edema induced by thrombin an important contributor to ICH-induced perihematomal edema.65 Our recent findings from gene expression studies using Affymetrix arrays in a rat ICH model demonstrates continued upregulation of IL-1ß gene expression through 24 hours.43 Contributing to this elevated IL-1ß gene expression is increased expression of its synthetic enzyme IL-1ß converting enzyme (caspase-1). IL-1ß protein in perihematomal white matter is localized to morphologically appearing astro- and microglial cells at 24 hours.51
Surgical Treatment for ICH
We reported that early (3.5-hour) tissue plasminogen activator (tPA)-induced clot lysis and aspiration was highly effective in reducing clot and edema volumes by >70% and preventing BBB opening at 24 hours in our pig ICH model.21 Early clot removal in human ICH is achievable and tPA has also been used successfully to treat human intracerebral hematomas.66 The effectiveness of early treatment, the use of tPA to facilitate clot removal and a stereotactic approach are currently being studied in the MISTIE trial (www.clinicaltrials.gov).
We recently reported that early surgery at 3 hours after ICH in our porcine model reduced increased proinflammatory cytokine expression to background levels when measured at 6 hours post-ICH.67 Thus, early clot removal effectively reduced cytokine expression that is linked to edema development and increased BBB permeability. As diagramed in Figure 2, we hypothesize that surgical hematoma removal and the potential removal of interstitial plasma proteins and fibrin deposition that contribute to edema (described above) may serve to decrease cytokine expression by reducing the stimulation of glutamate receptor activity and intracellular NF-B signaling pathways.
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Recent Findings in ICH Models and Treatments
During the past few years various reports have described ICH studies in mouse models and various treatments. Studies using KO mouse ICH models include the matrix metalloproteinase-9–deficient mouse68 and the tPA-deficient (tPA–/–) mouse.69 A new mouse ICH model uses embryos genetically null for all 
v-integrins which leads to ICH because of defective interactions between blood vessels and brain parenchymal cells.70
Several new ICH treatments have been examined including glutamate receptor antagonists,38,71 a statin,72 a cyclooxygenase-2 inhibitor,73 erythropoietin.74 and metalloporphyrin HO inhibitors.24,75–77 Recent studies of focal and global hypothermia treatment in ICH have shown positive effects on various pathophysiological and biochemical alterations including edema development, BBB permeability, inflammation and proinflmammatory cytokine expression.23,63,78,79
In the future it may be possible to use agents directed at NF-B activation as new approaches to treat ICH. Studies in culture and in mutant mice demonstrate that expression of the super-repressor form of NF-B’s inhibitory protein, IB, prevents overactivation of NF-B and neuronal protection after cerebral ischemia.80 Pizzi and Spano44 recently reported that selective inhibitors of NF-B factors, such as specific siRNAs targeting the p65 subunit, rescued neuronal cells from anoxic injury, whereas targeting the c-Rel factor enhanced neuronal susceptibility.
Nonaka et al81 described that intraventricular transplantation of embryonic stem cell–derived neural stem cells 7 days after ICH in rats generated embryonic stem cell–derived neurons and astrocytes around the hematoma cavities. Twenty-eight days later, embryonic stem cell–derived neurons and astrocytes could be detected in all rats receiving grafts.81 It has been recently shown that intravenous administration of human bone marrow stromal cells significantly improved neurological function in a rat ICH model. This treatment reduced tissue loss, mitotic activity, immature neurons, synaptogenesis, and neuronal migration.82
Summary
Results from several different ICH models demonstrate that components in the plasma (glutamate, thrombin, iron) and iron from the red cells themselves induce white and gray matter edema and injury after ICH. Rapid development of oxidative stress leading to downstream NF-B–dependent target gene expression including proinflammatory cytokines, especially the interleukin-1ß pathway appear to be important. Although proinflammatory cytokines also appear to participate in tissue recovery and repair, in the acute setting, these molecules are generally associated with central nervous system tissue injury. Because these important mediators of increased BBB permeability, leukocyte infiltration, and secondary lesion expansion and cell death are rapidly upregulated after ICH, early treatments aimed at interrupting these processes, including surgical clot removal after tPA-induced lysis possibly combined with pharmacological approaches aimed at suppressing NF-B activation, may reduce the morbidity of this devastating disease.
Acknowledgments
The author wishes to acknowledge the important contributions of his coinvestigators, research associates and students throughout this work.
Sources of Funding
These studies were supported by grants (R01NS-30652) from the National Institutes of Health and Merit Review funds from the Department of Veteran Affairs.
Disclosures
None.
accepted December 1, 2006.
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