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1. Introduction
Intracerebral hemorrhage (ICH) is a devastating clinical event caused by rupture of blood vessels and accumulation of blood in the brain. Many disorders, including hypertensive arteriosclerosis, amyloid angiopathy, neoplasia, coagulation disorders and cerebrovascular malformations, directly or indirectly damage blood vessels in the brain and thus lead to ICH. The annual occurrence of ICH is estimated to be approximately 0.12 million in the USA and 2 million in the world. These numbers are expected to increase due to the aging of populations. Although accounting for only 15-20% of all strokes, ICH has severe clinical symptoms and poor prognosis. The 1-year survival rate of ICH is estimated to be 38% and long-term physical and mental disability is found in more than 90% of the survivors. Sadly, there is no effective treatment for ICH. Currently, primary supportive care and risk factor control are the main therapy for ICH in clinics. Thus, research and development of effective reagents to treat ICH is extremely urgent. In this chapter, we first introduce the anatomy and biology of the blood brain barrier. Then the pathophysiology and animal models of ICH are reviewed. Furthermore, we summarize the potential therapeutic targets for ICH.
2. Blood brain barrier
One unique feature about the blood vessels in the brain is the presence of the blood-brain barrier (BBB). BBB is a natural barrier that separates the central nervous system (CNS) from the circulation [1]. Under physiological conditions, the BBB prevents the entrance of blood cells and large molecules into the brain, but allows the uptake of nutrients and hormones from the blood, maintaining the homeostasis of CNS microenvironment [1, 2]. Under pathological conditions, the integrity of BBB is compromised and blood components leak into the brain, contributing to the progress of diseases [3-12]. At the cellular level, the BBB consists of brain microvascular endothelial cells (BMECs), astrocytes, pericytes, neurons, microglia, and the non-cellular component-basement membrane [13] (Figure 1).
Figure 1.
Schematic illustration of BBB. The BBB is composed of cellular and non-cellular components. Cellular components include BMECs, perycites, astrocytic endfeet, neurons, and microglia. Non-cellular components includes the basement membrane.
BMECs
Endothelial cells in the CNS, BMECs, are different in many ways from the ones in the periphery. First, BMECs have more mitochondria, lower pinocytotic activity, and little-to-no fenestrations. Second, the endothelium in the brain and the spinal cord is 50-100 times tighter than that in the rest of the body [14]. In the CNS, BMECs connect to each other via tight junctions, which are unique structures that confer impermeability to the BBB. Two types of proteins are found at tight junctions: transmembrane proteins, including occludin and claudins, and cytoplasmic accessory proteins, including zonula occluden-1, 2, 3 (ZO-1, 2, 3) and cingulin [15, 16]. The transmembrane proteins seal gaps between adjacent cells, decreasing intercellular permeability [17, 18], whereas cytoplasmic accessory proteins link transmembrane proteins to cortical actin-based cytoskeleton, enabling strict regulation of the distribution of tight junction proteins (TJP) [19, 20].
Besides intercellular transportation, intracellular transportation is another way to regulate BBB permeability [11, 21-23]. Although small lipophilic molecules, such as oxygen and carbon dioxide, can diffuse across BMECs freely [24], the transport of large hydrophilic molecules is mediated by specific transporters or receptors. Based on their subcellular distribution and functions, these transporters and receptors are divided into three groups. Group I transporters are expressed on both luminal and abluminal sides of BMECs and function to transport nutrients between the blood and brain [25, 26]. For example, glucose transporter 1 (GLUT1) transports glucose; monocarboxylate transporter 1 (MCT1) transports lactate; the L1 and y+transporters transport large neutral and cationic essential amino acids to and from the brain. Group II transporters are also expressed on both sides of BMECs, but only transport materials in one direction [27-29]. For example, transferrin and insulin receptors (TFR and IR) are expressed on both sides of BMECs. The luminal and abluminal receptors mediate endocytosis of transferrin and insulin from the blood and brain, respectively. Group III transporters are expressed on only one side of BMECs and usually mediate one-way transportation of materials [26, 30-38]. For instance, in order to remove excitatory neurotransmitter glutamate from the brain, excitatory amino acid transporters (EAATs) are exclusively expressed on the abluminal side of BMECs. Similarly, to facilitate the removal of amyloid-β from the brain, low-density lipoprotein receptor related protein 1 (LRP1) is solely expressed on the abluminal side of BMECs. Another example of such transporters is (Na+-K+) ATPase, which is only found on the abluminal side to regulate ion homeostasis and thus proper neuronal & synaptic functions. Additionally, multidrug resistance related protein 1 (MRP1) and P-glycoprotein (P-gp) are primarily expressed on BMEC luminal side to efflux many types of drugs from the brain. The subcellular distribution of these transporters and receptors is summarized in Figure 2.
Figure 2.
Major transporters and receptors expressed by BMECs. Three groups of transporters are expressed in BMECs. Group I includes GLUT1, MCT1, L1 and y+transporters, which are expressed on both luminal and abluminal sides of BMECs and transport materials bi-directionally. Group II includes TRP and IR, which are expressed on both sides of BMRCs but transport materials in one direction. Group III includes EAATs, LRP1, (Na+-K+)ATPase, MRP1 and P-gp, wich are expressed on only one side of BMECs.
Astrocytes
More than 30 years ago Stewart and Wiley, using xenograft experiments, demonstrated that the unique properties of BMECs, including increased mitochondria number, few pinocytotic vesicles and presence of tight junctions [39], were induced by the microenvironment of the CNS. Astrocytes, which constitute the major glial cells in the brain that cover more than 99% of the vascular surface using their extended endfeet [40, 41], have been suggested to contribute to these unique features of BMECs as well as the impermeability of BBB. Consistent with this hypothesis, temporary focal loss of astrocytes positively correlates with the compromise of BBB integrity
Pericytes
Discovered in 1873, pericytes are perivascular cells sandwiched between endothelial cells and astrocytic endfeet [50]. They are embedded in the basement membrane under normal conditions [1]. Pericytes cover capillaries and the degree of coverage varies depending on the species and tissue type[51]. It has been shown that the pericyte-to-endothelial ratio is 1:5 in rats, 1:4 in mice, and 1:3-4 in humans [52, 53]. In mice, this ratio is 1:1 in retina, 1:3 in brain and 1:100 in skeletal muscle vasculature [54], representing how tightly the blood vessels and their contents are confined in different tissues. Pericytes have several different developmental origins, depending on the organs they cover [51]. In the brain and thymus, pericytes arise from ectoderm-derived neural crest, whereas they differentiate from the mesothelium in the lungs, liver, and gut [51]. So far, there are no pericyte-specific markers available [51], although many cellular markers, including α-smooth muscle actin (SMA), PDGFRβ, Desmin, CD13, NG2, and RGS-5, have been used to identify pericytes, primarily in combination, as none of these markers is exclusive for these cells (pericytes share markers with myofibroblasts, vascular smooth muscle cells and neuronal progenitors [51]). It should be noted that the expression of these markers is high dependent on the differentiation stage of pericytes.
The main functions of pericytes include BBB regulation, vascular development and injury repair [52, 55, 56]. Here we focus on BBB regulation. It has been shown that pericyte-deficient mice have compromised BBB and pericyte coverage positively correlates with the tightness of tight junction [11, 57, 58]. Additionally, pericytes migrate away from capillaries, decreasing their coverage, under pathological conditions, such as hypoxia and traumatic brain injury [59, 60]. These data suggest that pericytes play a critical role in BBB integrity and maintenance. Mechanistic studies demonstrate that BBB breakdown in pericyte-deficient mice is due to diminished expression of BBB-specific genes in endothelial cells and lack of polarity in astrocytic endfeet [58]. Consistent with these data, adding pericytes to BMEC-astrocyte co-culture system significantly enhanced TEER and decreased the leakage of tracers [61, 62]. Further studies showed that the function of pericytes on BBB integrity is also dependent on the differentiation stage of pericytes [63]. TGF-β treated pericytes, which are further differentiated SMA+pericytes, compromise BBB integrity. On the contrary, b-FGF treated pericytes, which are less differentiated SMA-pericytes, maintain impermeability of BBB. Altogether, these data suggest that pericytes is a key regulator of the BBB integrity. Nowadays, BMEC-pericyte-astrocyte triple-culture is becoming more and more popular in BBB research.
Neurons
In the human brain, the number of neurons and capillaries is estimated to be the same [64]. Both BMECs and astrocytic processes are directly innervated by noradrenergic, serotonergic, cholinergic, and GABA-ergic neurons [65-71]. The fact that local neuronal activity and metabolism regulate cerebral blood flow (neurovascular coupling) suggests that neurons may regulate BBB permeability through modulating BMEC and astrocyte function [72]. Consistent with these data, adding neurons to
Microglia
Microglia, the brain resident immune competent cells, account for 10-20% of glial cells in the brain [74, 75]. Fate mapping studies suggest that they originate from Myb-independent, FLT3-independent, but PU.1-dependent myeloid progenitors that express colony stimulating factor 1 receptor (Csf1R) at embryonic day 8.5 [76-80]. Under physiological conditions, microglia have a ramified morphology, characterized by a small cell body and many long/thin dynamic processes [75]. By extending and retracting these dynamic processes, microglia survey the changes of microenvironment in the brain [75]. Once an insult is identified, microglia quickly undergo a process collectively termed activation, which involves changes to ameboid morphology. Activated microglia migrate to the site of injury, proliferate locally, secrete pro-and anti-inflammatory cytokines, and remove cellular debris by phagocytosis [74, 81-83]. Microglia play a dual role in the brain. On one hand, they contribute to neurite growth and neuronal survival by clearing cell debris and releasing neurotrophic factors [84-86], such as neurotrophin-3 and brain-derived neurotrophic factor. On the other hand, microglia secrete high levels of pro-inflammatory cytokines, including TNF-α and IL-1β, promoting neuronal death. The former (neuroprotective microglia) display anti-inflammatory properties and are called M2 cells, similar to the nomenclature of macrophages. The latter, secreting pro-inflammatory cytokines, exhibit neurotoxic behaviors and are called M1 microglia. Which role they play is highly dependent on the timing after injury and the type of injury. Since microglia are close to other components of the BBB in the brain, they may regulate BBB integrity either by directly interacting with the blood vessels, or indirectly through interaction with BMECs, astrocyte endfeet, or pericytes [87]. Interestingly, microglial activation has been reported to both compromise and restore BBB integrity [88, 89]. This discrepancy could be explained by different injury models and different timing after injury. More work is needed to answer the question how microglia regulate BBB integrity.
Basement Membrane (BM)
BM is a 3-dimensional network composed of extracellular matrix (ECM) proteins, including collagens, laminins, heparin sulfate proteoglycans, and nidogens [47, 90]. The formation of this network involves polymerization and cross-link of these ECM proteins [90, 91]. At the BBB, BMECs generate a vascular BM and astrocytes generate a parenchymal BM [92, 93]. The vascular and parenchymal BM is usually indistinguishable at capillaries [1]. However, at the post-capillary venules, the two BMs are separated by perivascular space where cerebrospinal fluid drains, and where antigen-presenting cells can be found [1]. Both BM layers have the same composition except that in the vascular BM laminin-α4 and-α5 are predominantly present [93], whereas in the parenchymal BM laminins-α1 and-α2 are the main components [92-94].
Accumulating evidence suggests that loss of BM results in disruption of BBB, probably due to the loss of a physical barrier at the BMEC-astrocyte interface and/or lack of signaling from ECM molecules [95-99]. Individual ECM proteins, including laminin, collagen type IV, and fibronectin, have been shown to increase the TEER of BMECs
3. Pathophysiology
When ICH occurs, blood leaks into the brain parenchyma, leading to the formation of hematoma, which quickly increases intracranial pressure. The accumulated blood and high intracranial pressure cause immediate primary damage to the brain. This initial injury is followed by secondary damage mainly resulting from inflammatory responses [102, 103]. The exposure of brain parenchyma to blood proteins (e.g., proteases and hemoglobin) and cells (red blood cells and leukocytes) results in activation of microglia, and the secretion of pro-inflammatory cytokines/chemokines [104, 105], including TNF-α, IL-1β, and MCP1/CCL2. These inflammatory mediators, by forming a concentration gradient, activate and attract more microglia and other inflammatory cells to the injury site [106]. These cells then accumulate around the hematoma, forming a barrier to prevent the spread of injury to other sites. The released pro-inflammatory cytokines/chemokines and possibly activated microglia also act on BMECs, pericytes and astrocytes, leading to compromise of BBB integrity. Through the disrupted BBB, peripheral leukocytes infiltrate into the brain. The infiltrated leukocytes together with activated microglia produce more pro-inflammatory mediators, which induce cell death in the penumbra area [107, 108]. In addition, hemolysis of red blood cells causes iron deposition in the brain parenchyma and subsequent lipid peroxidation [109]. Free radicals generated during lipid peroxidation also lead to cell death and contribute to ICH-induced brain injury [110, 111]. With the progress of disease, microglia and infiltrated leukocytes change their gene expression profile from pro-inflammatory to anti-inflammatory and clear up the dead cells via phagocytosis [110, 112]. The clearance of cell debris finally leads to the resolution of the hematoma and repair of damaged tissue. At this stage, the activated inflammatory cells revert to a resting state again. Due to the limited regenerative ability of neurons, however, most neurological functions cannot be recovered, which explains the high extent of disability after ICH.
4. ICH animal models
To study ICH and eventually cure this disease, several ICH animal models have been developed, including collagenase ICH model, whole blood ICH model, and the spontaneous ICH model. Although these models have been widely used in ICH research, none of them fully replicates the pathology of ICH in human patients. Here we briefly discuss the advantages and disadvantages of these models.
Collagenase ICH Model
This model utilizes the enzymatic activity of collagenase, a bacterial enzyme. After injection into the brain, collagenase induces rupture of blood vessels by degrading collagen IV, a component of the blood vessel wall [103-105]. The rupture of blood vessels then induces the formation of hematoma and other pathological alterations. There are many advantages of this model. First, ICH induced by collagenase injection is very reliable and reproducible. The size and location of hematoma reported by different laboratories across the world are comparable [112-115]. Second, the location of hematoma can be controlled depending on the site of injection. Third, this model is very simple and fast. ICH can be induced within hours after collagenase injection. Due to these advantages, collagenase ICH model has become one of the most popular animal models for ICH research. This model, however, also has a few disadvantages. One of the most significant drawbacks is that it introduces collagenase, a bacterial enzyme, into the mammalian brain. This enzyme degrades ECM proteins in the brain, affects BBB integrity, and modifies inflammatory or immune responses, all of which may affect ICH progress [105, 116, 117]. Another disadvantage of this model is that it does not replicate the vascular challenges usually seen before the onset of ICH in patients, such as hypertension and atherosclerosis. Mice lacking these vascular injuries may have different disease progress and/or recovery patterns, which makes it difficult to interpret data generated using this ICH model.
Whole Blood ICH Model
The whole blood model involves injection of blood from the same animal or a donor into the brain. The injected blood induces secondary pathological changes observed in human patients. Unlike the collagenase ICH model, this model does not introduce exogenous enzymes. The application of this ICH model, however, is circumvented by its three major disadvantages. First, the whole blood ICH model lacks pathological changes in blood vessels. The vascular challenges and rupture of vasculature cannot be replicated in this model. Second, this model is less reproducible than collagenase ICH model. The size and location of hematoma vary depending on different laboratories. Third, the shape of hematoma is different from that found in human patients. Hematoma formed in whole blood ICH model is usually umbrella-shaped and narrower slit-like [118]. This unique shape is probably caused by high pressure-induced rapid distribution of blood along white matter tracts and/or corpus callosum after injection. A way to get around this problem is used in bigger animals, like pigs, where a space/balloon forming initial injection is followed by the injection of the homologous whole blood.
Spontaneous ICH Model
To better replicate the pathological changes observed in human patients, a spontaneous ICH model has been developed in rodents [119]. This new model induces ICH through acute hypertension, the most common etiology of hemorrhage in humans. In this model, animals are administered with NG-nitro-L-arginine methyl ester (L-NAME) and angiotensin II to induce hypertension. The injection of angiotensin II causes surges of blood pressure, which eventually lead to rupture of blood vessels and thus ICH. This spontaneous ICH model replicates most pathological alterations observed in human patients. However, the time it takes to induce ICH is relatively long (2-4 weeks), the location of the ICH varies, and the reproducibility still needs further investigation.
5. Targets for ICH treatments
ICH is a devastating clinical event. Sadly, no effective treatments are available at present. Current therapy is mainly supportive care [120, 121]. Due to the pivotal role of inflammatory responses in ICH development, anti-inflammatory strategies have been explored by many laboratories. Here we review a few anti-inflammatory targets with therapeutic potential in ICH: microglial activation, leukocyte infiltration, cytokines/chemokines, protease activation, and reactive oxygen species (ROS) production. In addition, stem cell therapy is also discussed briefly.
Microglial Activation
Microglia are one of the first cell types that respond to ICH. In collagenase ICH model, microglial activation starts at 1 hour [102, 122], peaks at 3-7 days [104, 105, 115, 123], and returns to a resting state again by 3-4 weeks after the onset of ICH [124, 125]. A similar time course of microglial activation is observed in whole blood ICH model [122, 124, 125]. Since activated microglia contribute to the amplification of inflammatory responses and cell death by secreting chemotactic cytokines and cytotoxic mediators, including proteases and ROS [102, 103, 112, 115], inhibition of microglial activation has been proposed as a therapeutic strategy for ICH. It has been shown that pre-or post-treatment with the tri-peptide microglia/macrophage inhibitory factor (MIF, Thr-Lys-Pro) significantly inhibited microglial activation, reduced injury size and improved neurological function [104, 105]. Consistently with this report, inhibiting microglial activation with neuroprotectant minocycline in both collagenase and whole blood ICH models protected BBB integrity, decreased brain edema, and improved functional recovery, although neuronal death remained changed [126-130]. These data support that inhibition of microglial activation is beneficial. However, there is also evidence suggesting that long-term inhibition of microglial activation is detrimental [104, 115]. Given that activated microglia also contribute to the clearance of cell debris and recovery at late stage, inhibition of microglial activation should be limited to the early stage. The question then becomes how to define early and late stages after ICH? Definition of these stages would significantly improve the outcome of ICH treatments.
Leukocyte Infiltration
Leukocytes infiltrate into the brain through the compromised BBB and modulate the progress and/or recovery of ICH [102, 112]. Among all the subtypes of leukocytes, neutrophils are the earliest ones to infiltrate into the brain after ICH. In both collagenase and whole blood ICH models in rodents, neutrophil infiltration starts at approximately 4 hours and peaks at 3 days after the onset of ICH [102, 115, 124, 131, 132]. These cells promote cell death and brain damage by producing ROS and pro-inflammatory mediators [107, 108], and usually die within 2 days in the brain. Mice deficient for CD18, a subunit of β2 integrin indispensable for leukocyte infiltration, demonstrated reduced brain edema and mortality as well as decreased leukocyte number in the brain after collagenase injection [133]. In human postmortem brains, leukocyte infiltration was also observed within hours after ICH [134, 135]. Furthermore, leukocyte counts in blood have been found to positively correlate with injury size in ICH patients [136]. Therefore, high leukocyte counts together with other factors have been used to predict early clinical outcome in ICH patients [137, 138]. Currently, no anti-leukocyte infiltration strategies have been investigated in ICH models. Obtaining such data may facilitate the research and development of novel reagents targeting leukocyte infiltration.
Cytokines/Chemokines
During ICH, activated microglia and infiltrated leukocytes produce high levels of inflammatory cytokines/chemokines, which mediate the secondary damage to the brain. In both rodents and humans, pro-inflammatory cytokines, including TNF-α and IL-1β, are transiently up-regulated in the peri-hematomal region [106, 139]. In addition, chemokines and chemokine receptors that mediate leukocyte extravasation, including CCL2-4, IL-8, CXCL5, and CCR1-2, are also increased/activated [139, 140]. These data suggest that targeting cytokine/chemokine signaling may be a therapeutic strategy for ICH. In collagenase ICH model, we have found that mice deficient for CCL2 or its receptor CCR2 have a mild but delayed disease progression [115]. In CCL2-/-or CCR2-/-mice, hematoma was smaller at day 1 post injury (dpi 1) but larger at subsequent times (dpi 7 and 14 [115]), indicating a delayed recovery. Consistent with the crucial role of CCL2-CCR2 system in microglial activation/migration, limited numbers of microglia were observed at dpi 1 in both knockout mice [115]. At dpi 3 and 7, however, the number of microglia in the knockout mice far exceeded those in control animals [115], suggesting that CCL2-CCR2 independent alternative signaling recruited microglia in the knockout mice. The infiltration of neutrophils was also ablated in both knockout mice at dpi 1 and 3, echoed by the smaller hematoma size early after injury [115]. In addition, at dpi 7 the expression of inducible nitric oxide synthase (iNOS) decreased in controls compared to earlier time-points, but remained high in the mutant mice, indicating that lack of CCL2-CCR2 signaling produces more ROS. Moreover, brain edema, neuronal loss and neurological function followed similar trends over time as that of hematoma size [115]. Altogether, these data suggest that inhibiting CCL2-CCR2 signaling early after ICH is neuroprotective, whereas long-term inhibition delays the recovery. Future work should focus on developing the best CCL2-CCR2 inhibition regimen for ICH patients.
Protease Activation
ICH activates many proteases, including matrix metalloproteinases (MMPs). MMPs are a group of zinc-dependent proteases actively involved in extracellular remodeling and neuroinflammation. Under physiological conditions, low levels of inactive MMPs are found in the brain. These MMPs, however, are dramatically up-regulated and activated when ICH occurs [112, 141]. We and others have demonstrated that collagenase quickly activates and up-regulates the expression of MMP-2,-3,-9, and-12 in rodents [112, 142]. Activation of MMP-9 has also been described in other ICH models [143-145]. In human ICH patients, blood MMP-9 level has been reported to correlate with BBB integrity, hematoma size, edema of the penumbra area, and neurological function [138, 146, 147], whereas blood MMP-3 levels have been found to associate with mortality [148]. Additionally, higher level of MMP-9 was detected in the peri-hematomal region in postmortem human brains [113, 149]. These data suggest that modulation of MMP activity may have therapeutic effect in ICH. Consistent with this hypothesis, mice lacking MMP-3,-9, or-12 are partially protected from ICH [141, 144, 150]. In addition, the therapeutic effect of MMP inhibitors has also been investigated. GM6001, a broad-spectrum MMP inhibitor, has been found to be neuroprotective in both collagenase and whole blood ICH models in mice [132, 151]. Similar results have been noted for BB-1101, another broad-spectrum MMP inhibitor [152]. However, both neuroprotective and detrimental roles have been reported for MMP inhibitor BB-94, depending on the animal models used [153-155]. Besides its inhibitory effect on microglial activation, minocycline also functions as a MMP inhibitor [126]. There is evidence suggesting that minocycline reduces TNF-α level and brain edema without affecting neuronal loss [127, 156], when administered 6 hours after ICH. Together, these data suggest that MMPs, especially MMP-9, play a detrimental role in ICH, and that MMP inhibitors may be used, alone or in combination with other medicine, to treat ICH.
ROS Production
One of the main pathological changes of ICH is the accumulation of blood in the brain. The hemolysis of extravasated red blood cells leads to degradation of hemoglobin and deposition of iron in the brain [109]. In rats, a 3-fold increase of non-heme iron was found after ICH [109]. Accumulated iron has been shown to induce oxidative stress by formation of free radicals, mediate secondary inflammatory injury, and contribute to brain atrophy and neurological deficits after ICH [157, 158]. In human patients with spontaneous ICH, blood ferritin level associates with brain edema in peri-hematomal region [159]. In addition, iron level in the hematoma also correlates with brain edema in peri-hematomal area [160]. These data suggest that iron deposition contributes to brain damage, and that removing the deposited iron may be an appropriate therapeutic approach. Consistent with this hypothesis, 2, 2'-dipyridyl, a lipid-soluble iron chelator, has been shown to be beneficial in both the collagenase and whole blood ICH models in mice [161]. Another iron chelator deferoxamine has shown neuroprotective effects in the whole blood ICH model in rats and piglets [162-165]. In collagenase ICH model, however, deferoxamine failed to show any beneficial effects [166], suggesting the effect of deferoxamine depends on ICH animal models. None-the-less high doses of deferoxamine are currently examined in clinical trials (starting in 2012) for the treatment of ICH.
An alternative way to treat iron-induced oxidative stress is to target antioxidant enzymes. To remove extra ROS, antioxidant enzymes, including glutathione S transferases, glutathione peroxidase, and glutamate-cysteine ligase, are up-regulated. The key transcription factor that controls the expression of these antioxidant enzymes is Nrf2 [167]. Nrf2 is expressed in neuronal and glial cells in the brain. Activation of Nrf2 has been shown to be neuroprotective both
Stem Cell Therapy
ICH induces neuronal death and loss of neurological function. Multipotent stem cells with the ability to differentiate into neurons are a potential therapy for ICH. It has been reported that human neural stem cells are able to differentiate into neurons and astrocytes, and thus improve neurological function after intravenous injection in collagenase ICH model [172]. Stem cell therapy is relatively new and more work is needed before it can be used in ICH patients. For example, the route, dose and timing of stem cell injection need to be optimized; the differentiation, proliferation and integration of stem cells
6. Summary
Accumulating evidence suggests that the secondary inflammatory responses play a critical role in the development of ICH, indicating that the molecular mechanism of inflammation is an ideal target for the therapy of ICH. As discussed, many pathways, including microglia activation, leukocyte infiltration, cytokine/chemokine secretion, protease activation, and ROS production, have been explored, and several compounds showed significant potential in the treatment of ICH. However, it should be noted that the animal models used in the studies are not perfect, which limits the interpretation of experimental data. Thus, other models and human samples should be used to confirm the results before they are used in patients.
References
- 1.
Engelhardt B, Ransohoff RM. Capture, crawl, cross: the T cell code to breach the blood-brain barriers. Trends Immunol 2012; 33:579-589. - 2.
Cestelli A, Catania C, D'Agostino S, Di Liegro I, Licata L, Schiera G, Pitarresi GL, Savettieri G, De Caro V, Giandalia G, Giannola LI. Functional feature of a novel model of blood brain barrier: studies on permeation of test compounds. J Control Release 2001; 76:139-147. - 3.
Garbuzova-Davis S, Rodrigues MC, Hernandez-Ontiveros DG, Louis MK, Willing AE, Borlongan CV, Sanberg PR. Amyotrophic lateral sclerosis: a neurovascular disease. Brain Res 2011; 1398:113-125. - 4.
Jain RK, di Tomaso E, Duda DG, Loeffler JS, Sorensen AG, Batchelor TT. Angiogenesis in brain tumours. Nat Rev Neurosci 2007; 8:610-622. - 5.
Zlokovic BV. Neurovascular mechanisms of Alzheimer's neurodegeneration. Trends Neurosci 2005; 28:202-208. - 6.
Selkoe DJ. Alzheimer disease: mechanistic understanding predicts novel therapies. Ann Intern Med 2004; 140:627-638. - 7.
Kortekaas R, Leenders KL, van Oostrom JC, Vaalburg W, Bart J, Willemsen AT, Hendrikse NH. Blood-brain barrier dysfunction in parkinsonian midbrain in vivo. Ann Neurol 2005; 57:176-179. - 8.
Benchenane K, Lopez-Atalaya JP, Fernandez-Monreal M, Touzani O, Vivien D. Equivocal roles of tissue-type plasminogen activator in stroke-induced injury. Trends Neurosci 2004; 27:155-160. - 9.
Moskowitz MA, Lo EH, Iadecola C. The science of stroke: mechanisms in search of treatments. Neuron 2010; 67:181-198. - 10.
Iadecola C. The overlap between neurodegenerative and vascular factors in the pathogenesis of dementia. Acta Neuropathol 2010; 120:287-296. - 11.
Bell RD, Winkler EA, Sagare AP, Singh I, LaRue B, Deane R, Zlokovic BV. Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron 2010; 68:409-427. - 12.
Shlosberg D, Benifla M, Kaufer D, Friedman A. Blood-brain barrier breakdown as a therapeutic target in traumatic brain injury. Nat Rev Neurol 2010; 6:393-403. - 13.
Guillemin GJ, Brew BJ. Microglia, macrophages, perivascular macrophages, and pericytes: a review of function and identification. J Leukoc Biol 2004; 75:388-397. - 14.
Abbott NJ. Astrocyte-endothelial interactions and blood-brain barrier permeability. J Anat 2002; 200:629-638. - 15.
Citi S, Cordenonsi M. Tight junction proteins. Biochim Biophys Acta 1998; 1448:1-11. - 16.
Huber JD, Egleton RD, Davis TP. Molecular physiology and pathophysiology of tight junctions in the blood-brain barrier. Trends Neurosci 2001; 24:719-725. - 17.
Forster C. Tight junctions and the modulation of barrier function in disease. Histochem Cell Biol 2008; 130:55-70. - 18.
Ogunrinade O, Kameya GT, Truskey GA. Effect of fluid shear stress on the permeability of the arterial endothelium. Ann Biomed Eng 2002; 30:430-446. - 19.
Brown RC, Davis TP. Hypoxia/aglycemia alters expression of occludin and actin in brain endothelial cells. Biochem Biophys Res Commun 2005; 327:1114-1123. - 20.
Huber JD, Hau VS, Borg L, Campos CR, Egleton RD, Davis TP. Blood-brain barrier tight junctions are altered during a 72-h exposure to lambda-carrageenan-induced inflammatory pain. Am J Physiol Heart Circ Physiol 2002; 283:H1531-1537. - 21.
MacAulay N, Zeuthen T. Water transport between CNS compartments: contributions of aquaporins and cotransporters. Neuroscience 2010; 168:941-956. - 22.
Madri JA. Modeling the neurovascular niche: implications for recovery from CNS injury. J Physiol Pharmacol 2009; 60 Suppl 4:95-104. - 23.
Miller DS. Regulation of P-glycoprotein and other ABC drug transporters at the blood-brain barrier. Trends Pharmacol Sci 2010; 31:246-254. - 24.
Ballabh P, Braun A, Nedergaard M. The blood-brain barrier: an overview: structure, regulation, and clinical implications. Neurobiol Dis 2004; 16:1-13. - 25.
Redzic Z. Molecular biology of the blood-brain and the blood-cerebrospinal fluid barriers: similarities and differences. Fluids Barriers CNS 2011; 8:3. - 26.
Zlokovic BV. Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nat Rev Neurosci 2011; 12:723-738. - 27.
Banks WA. Blood-brain barrier as a regulatory interface. Forum Nutr 2010; 63:102-110. - 28.
Nishijima T, Piriz J, Duflot S, Fernandez AM, Gaitan G, Gomez-Pinedo U, Verdugo JM, Leroy F, Soya H, Nunez A, Torres-Aleman I. Neuronal activity drives localized blood-brain-barrier transport of serum insulin-like growth factor-I into the CNS. Neuron 2010; 67:834-846. - 29.
Pardridge WM. Blood-brain barrier delivery. Drug Discov Today 2007; 12:54-61. - 30.
O'Kane RL, Martinez-Lopez I, DeJoseph MR, Vina JR, Hawkins RA. Na(+)-dependent glutamate transporters (EAAT1, EAAT2, and EAAT3) of the blood-brain barrier. A mechanism for glutamate removal. J Biol Chem 1999; 274:31891-31895. - 31.
Bell RD, Sagare AP, Friedman AE, Bedi GS, Holtzman DM, Deane R, Zlokovic BV. Transport pathways for clearance of human Alzheimer's amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system. J Cereb Blood Flow Metab 2007; 27:909-918. - 32.
Deane R, Wu Z, Sagare A, Davis J, Du Yan S, Hamm K, Xu F, Parisi M, LaRue B, Hu HW, et al. LRP/amyloid beta-peptide interaction mediates differential brain efflux of Abeta isoforms. Neuron 2004; 43:333-344. - 33.
Shibata M, Yamada S, Kumar SR, Calero M, Bading J, Frangione B, Holtzman DM, Miller CA, Strickland DK, Ghiso J, Zlokovic BV. Clearance of Alzheimer's amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J Clin Invest 2000; 106:1489-1499. - 34.
Neuwelt EA, Bauer B, Fahlke C, Fricker G, Iadecola C, Janigro D, Leybaert L, Molnar Z, O'Donnell ME, Povlishock JT, et al. Engaging neuroscience to advance translational research in brain barrier biology. Nat Rev Neurosci 2011; 12:169-182. - 35.
ElAli A, Hermann DM. ATP-binding cassette transporters and their roles in protecting the brain. Neuroscientist 2011; 17:423-436. - 36.
Abuznait AH, Kaddoumi A. Role of ABC transporters in the pathogenesis of Alzheimer's disease. ACS Chem Neurosci 2012; 3:820-831. - 37.
Soontornmalai A, Vlaming ML, Fritschy JM. Differential, strain-specific cellular and subcellular distribution of multidrug transporters in murine choroid plexus and blood-brain barrier. Neuroscience 2006; 138:159-169. - 38.
Miller DS, Bauer B, Hartz AM. Modulation of P-glycoprotein at the blood-brain barrier: opportunities to improve central nervous system pharmacotherapy. Pharmacol Rev 2008; 60:196-209. - 39.
Stewart PA, Wiley MJ. Developing nervous tissue induces formation of blood-brain barrier characteristics in invading endothelial cells: a study using quail--chick transplantation chimeras. Dev Biol 1981; 84:183-192. - 40.
Simard M, Arcuino G, Takano T, Liu QS, Nedergaard M. Signaling at the gliovascular interface. J Neurosci 2003; 23:9254-9262. - 41.
Kacem K, Lacombe P, Seylaz J, Bonvento G. Structural organization of the perivascular astrocyte endfeet and their relationship with the endothelial glucose transporter: a confocal microscopy study. Glia 1998; 23:1-10. - 42.
Willis CL, Nolan CC, Reith SN, Lister T, Prior MJ, Guerin CJ, Mavroudis G, Ray DE. Focal astrocyte loss is followed by microvascular damage, with subsequent repair of the blood-brain barrier in the apparent absence of direct astrocytic contact. Glia 2004; 45:325-337. - 43.
Janzer RC, Raff MC. Astrocytes induce blood-brain barrier properties in endothelial cells. Nature 1987; 325:253-257. - 44.
Cohen-Kashi Malina K, Cooper I, Teichberg VI. Closing the gap between the in-vivo and in-vitro blood-brain barrier tightness. Brain Res 2009; 1284:12-21. - 45.
Siddharthan V, Kim YV, Liu S, Kim KS. Human astrocytes/astrocyte-conditioned medium and shear stress enhance the barrier properties of human brain microvascular endothelial cells. Brain Res 2007; 1147:39-50. - 46.
Yao Y, Tsirka SE. Truncation of monocyte chemoattractant protein 1 by plasmin promotes blood-brain barrier disruption. J Cell Sci 2011; 124:1486-1495. - 47.
Cardoso FL, Brites D, Brito MA. Looking at the blood-brain barrier: molecular anatomy and possible investigation approaches. Brain Res Rev 2010; 64:328-363. - 48.
Persidsky Y, Ramirez SH, Haorah J, Kanmogne GD. Blood-brain barrier: structural components and function under physiologic and pathologic conditions. J Neuroimmune Pharmacol 2006; 1:223-236. - 49.
Quaegebeur A, Lange C, Carmeliet P. The neurovascular link in health and disease: molecular mechanisms and therapeutic implications. Neuron 2011; 71:406-424. - 50.
Sa-Pereira I, Brites D, Brito MA. Neurovascular Unit: a Focus on Pericytes. Mol Neurobiol 2012. - 51.
Armulik A, Genove G, Betsholtz C. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell 2011; 21:193-215. - 52.
Dore-Duffy P. Pericytes: pluripotent cells of the blood brain barrier. Curr Pharm Des 2008; 14:1581-1593. - 53.
Dore-Duffy P, Cleary K. Morphology and properties of pericytes. Methods Mol Biol 2011; 686:49-68. - 54.
Dalkara T, Gursoy-Ozdemir Y, Yemisci M. Brain microvascular pericytes in health and disease. Acta Neuropathol 2011; 122:1-9. - 55.
Dore-Duffy P, Katychev A, Wang X, Van Buren E. CNS microvascular pericytes exhibit multipotential stem cell activity. J Cereb Blood Flow Metab 2006; 26:613-624. - 56.
Fisher M. Pericyte signaling in the neurovascular unit. Stroke 2009; 40:S13-15. - 57.
Daneman R, Zhou L, Kebede AA, Barres BA. Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature 2010. - 58.
Armulik A, Genove G, Mae M, Nisancioglu MH, Wallgard E, Niaudet C, He L, Norlin J, Lindblom P, Strittmatter K, et al. Pericytes regulate the blood-brain barrier. Nature 2010. - 59.
Dore-Duffy P, Owen C, Balabanov R, Murphy S, Beaumont T, Rafols JA. Pericyte migration from the vascular wall in response to traumatic brain injury. Microvasc Res 2000; 60:55-69. - 60.
Gonul E, Duz B, Kahraman S, Kayali H, Kubar A, Timurkaynak E. Early pericyte response to brain hypoxia in cats: an ultrastructural study. Microvasc Res 2002; 64:116-119. - 61.
Dente CJ, Steffes CP, Speyer C, Tyburski JG. Pericytes augment the capillary barrier in in vitro cocultures. J Surg Res 2001; 97:85-91. - 62.
Nakagawa S, Deli MA, Kawaguchi H, Shimizudani T, Shimono T, Kittel A, Tanaka K, Niwa M. A new blood-brain barrier model using primary rat brain endothelial cells, pericytes and astrocytes. Neurochem Int 2009; 54:253-263. - 63.
Thanabalasundaram G, Schneidewind J, Pieper C, Galla HJ. The impact of pericytes on the blood-brain barrier integrity depends critically on the pericyte differentiation stage. Int J Biochem Cell Biol 2011; 43:1284-1293. - 64.
Zlokovic BV. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 2008; 57:178-201. - 65.
Ben-Menachem E, Johansson BB, Svensson TH. Increased vulnerability of the blood-brain barrier to acute hypertension following depletion of brain noradrenaline. J Neural Transm 1982; 53:159-167. - 66.
Cohen Z, Bonvento G, Lacombe P, Hamel E. Serotonin in the regulation of brain microcirculation. Prog Neurobiol 1996; 50:335-362. - 67.
Cohen Z, Molinatti G, Hamel E. Astroglial and vascular interactions of noradrenaline terminals in the rat cerebral cortex. J Cereb Blood Flow Metab 1997; 17:894-904. - 68.
Hawkins BT, Davis TP. The blood-brain barrier/neurovascular unit in health and disease. Pharmacol Rev 2005; 57:173-185. - 69.
Tong XK, Hamel E. Regional cholinergic denervation of cortical microvessels and nitric oxide synthase-containing neurons in Alzheimer's disease. Neuroscience 1999; 92:163-175. - 70.
Vaucher E, Hamel E. Cholinergic basal forebrain neurons project to cortical microvessels in the rat: electron microscopic study with anterogradely transported Phaseolus vulgaris leucoagglutinin and choline acetyltransferase immunocytochemistry. J Neurosci 1995; 15:7427-7441. - 71.
Vaucher E, Tong XK, Cholet N, Lantin S, Hamel E. GABA neurons provide a rich input to microvessels but not nitric oxide neurons in the rat cerebral cortex: a means for direct regulation of local cerebral blood flow. J Comp Neurol 2000; 421:161-171. - 72.
Iadecola C. Neurovascular regulation in the normal brain and in Alzheimer's disease. Nat Rev Neurosci 2004; 5:347-360. - 73.
Minami M. [Neuro-glio-vascular interaction in ischemic brains]. Yakugaku Zasshi 2011; 131:539-544. - 74.
Nakajima K, Kohsaka S. Microglia: neuroprotective and neurotrophic cells in the central nervous system. Curr Drug Targets Cardiovasc Haematol Disord 2004; 4:65-84. - 75.
Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 2005; 308:1314-1318. - 76.
Buza-Vidas N, Woll P, Hultquist A, Duarte S, Lutteropp M, Bouriez-Jones T, Ferry H, Luc S, Jacobsen SE. FLT3 expression initiates in fully multipotent mouse hematopoietic progenitor cells. Blood 2011; 118:1544-1548. - 77.
Schulz C, Gomez Perdiguero E, Chorro L, Szabo-Rogers H, Cagnard N, Kierdorf K, Prinz M, Wu B, Jacobsen SE, Pollard JW, et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 2012; 336:86-90. - 78.
Erblich B, Zhu L, Etgen AM, Dobrenis K, Pollard JW. Absence of colony stimulation factor-1 receptor results in loss of microglia, disrupted brain development and olfactory deficits. PLoS One 2011; 6:e26317. - 79.
Gomez Perdiguero E, Schulz C, Geissmann F. Development and homeostasis of "resident" myeloid cells: The case of the microglia. Glia 2013; 61:112-120. - 80.
Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, Mehler MF, Conway SJ, Ng LG, Stanley ER, et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 2010; 330:841-845. - 81.
Aloisi F. Immune function of microglia. Glia 2001; 36:165-179. - 82.
Hanisch UK, Kettenmann H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 2007; 10:1387-1394. - 83.
Kim SU, de Vellis J. Microglia in health and disease. J Neurosci Res 2005; 81:302-313. - 84.
Nakajima K, Tohyama Y, Kohsaka S, Kurihara T. Ceramide activates microglia to enhance the production/secretion of brain-derived neurotrophic factor (BDNF) without induction of deleterious factors in vitro. J Neurochem 2002; 80:697-705. - 85.
Rabchevsky AG, Streit WJ. Grafting of cultured microglial cells into the lesioned spinal cord of adult rats enhances neurite outgrowth. J Neurosci Res 1997; 47:34-48. - 86.
Elkabes S, DiCicco-Bloom EM, Black IB. Brain microglia/macrophages express neurotrophins that selectively regulate microglial proliferation and function. J Neurosci 1996; 16:2508-2521. - 87.
Choi YK, Kim KW. Blood-neural barrier: its diversity and coordinated cell-to-cell communication. BMB Rep 2008; 41:345-352. - 88.
Willis CL. Glia-induced reversible disruption of blood-brain barrier integrity and neuropathological response of the neurovascular unit. Toxicol Pathol 2011; 39:172-185. - 89.
Nishioku T, Matsumoto J, Dohgu S, Sumi N, Miyao K, Takata F, Shuto H, Yamauchi A, Kataoka Y. Tumor necrosis factor-alpha mediates the blood-brain barrier dysfunction induced by activated microglia in mouse brain microvascular endothelial cells. J Pharmacol Sci 2010; 112:251-254. - 90.
Yurchenco PD, Amenta PS, Patton BL. Basement membrane assembly, stability and activities observed through a developmental lens. Matrix Biol 2004; 22:521-538. - 91.
Yurchenco PD, Patton BL. Developmental and pathogenic mechanisms of basement membrane assembly. Curr Pharm Des 2009; 15:1277-1294. - 92.
Owens T, Bechmann I, Engelhardt B. Perivascular spaces and the two steps to neuroinflammation. J Neuropathol Exp Neurol 2008; 67:1113-1121. - 93.
Sixt M, Engelhardt B, Pausch F, Hallmann R, Wendler O, Sorokin LM. Endothelial cell laminin isoforms, laminins 8 and 10, play decisive roles in T cell recruitment across the blood-brain barrier in experimental autoimmune encephalomyelitis. J Cell Biol 2001; 153:933-946. - 94.
van Horssen J, Bo L, Vos CM, Virtanen I, de Vries HE. Basement membrane proteins in multiple sclerosis-associated inflammatory cuffs: potential role in influx and transport of leukocytes. J Neuropathol Exp Neurol 2005; 64:722-729. - 95.
del Zoppo GJ. Relationship of neurovascular elements to neuron injury during ischemia. Cerebrovasc Dis 2009; 27 Suppl 1:65-76. - 96.
Del Zoppo GJ, Milner R, Mabuchi T, Hung S, Wang X, Koziol JA. Vascular matrix adhesion and the blood-brain barrier. Biochem Soc Trans 2006; 34:1261-1266. - 97.
Kwon I, Kim EH, del Zoppo GJ, Heo JH. Ultrastructural and temporal changes of the microvascular basement membrane and astrocyte interface following focal cerebral ischemia. J Neurosci Res 2009; 87:668-676. - 98.
Lo EH, Rosenberg GA. The neurovascular unit in health and disease: introduction. Stroke 2009; 40:S2-3. - 99.
Wang CX, Shuaib A. Critical role of microvasculature basal lamina in ischemic brain injury. Prog Neurobiol 2007; 83:140-148. - 100.
Tilling T, Korte D, Hoheisel D, Galla HJ. Basement membrane proteins influence brain capillary endothelial barrier function in vitro. J Neurochem 1998; 71:1151-1157. - 101.
Yao Y, Chen ZL, Norris EH, Strickland S. Astrocytic laminin regulates pericyte differentiation and maintains blood brain barrier integrity. Nat Commun 2014; 5:3413. - 102.
Wang J, Dore S. Heme oxygenase-1 exacerbates early brain injury after intracerebral haemorrhage. Brain 2007; 130:1643-1652. - 103.
Wang J, Tsirka SE. Contribution of extracellular proteolysis and microglia to intracerebral hemorrhage. Neurocrit Care 2005; 3:77-85. - 104.
Wang J, Tsirka SE. Tuftsin fragment 1-3 is beneficial when delivered after the induction of intracerebral hemorrhage. Stroke 2005; 36:613-618. - 105.
Wang J, Rogove AD, Tsirka AE, Tsirka SE. Protective role of tuftsin fragment 1-3 in an animal model of intracerebral hemorrhage. Ann Neurol 2003; 54:655-664. - 106.
Keep RF, Xiang J, Ennis SR, Andjelkovic A, Hua Y, Xi G, Hoff JT. Blood-brain barrier function in intracerebral hemorrhage. Acta Neurochir Suppl 2008; 105:73-77. - 107.
Joice SL, Mydeen F, Couraud PO, Weksler BB, Romero IA, Fraser PA, Easton AS. Modulation of blood-brain barrier permeability by neutrophils: in vitro and in vivo studies. Brain Res 2009; 1298:13-23. - 108.
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; 102:900-912. - 109.
Wu J, Hua Y, Keep RF, Nakamura T, Hoff JT, Xi G. Iron and iron-handling proteins in the brain after intracerebral hemorrhage. Stroke 2003; 34:2964-2969. - 110.
Aronowski J, Hall CE. New horizons for primary intracerebral hemorrhage treatment: experience from preclinical studies. Neurol Res 2005; 27:268-279. - 111.
Xi G, Keep RF, Hoff JT. Mechanisms of brain injury after intracerebral haemorrhage. Lancet Neurol 2006; 5:53-63. - 112.
Wang J, Dore S. Inflammation after intracerebral hemorrhage. J Cereb Blood Flow Metab 2007; 27:894-908. - 113.
Tejima E, Zhao BQ, Tsuji K, Rosell A, van Leyen K, Gonzalez RG, Montaner J, Wang X, Lo EH. Astrocytic induction of matrix metalloproteinase-9 and edema in brain hemorrhage. J Cereb Blood Flow Metab 2007; 27:460-468. - 114.
Wagner KR. Modeling intracerebral hemorrhage: glutamate, nuclear factor-kappa B signaling and cytokines. Stroke 2007; 38:753-758. - 115.
Yao Y, Tsirka SE. The CCL2-CCR2 system affects the progression and clearance of intracerebral hemorrhage. Glia 2012; 60:908-918. - 116.
Matsushita K, Meng W, Wang X, Asahi M, Asahi K, Moskowitz MA, Lo EH. Evidence for apoptosis after intercerebral hemorrhage in rat striatum. J Cereb Blood Flow Metab 2000; 20:396-404. - 117.
Chu K, Jeong SW, Jung KH, Han SY, Lee ST, Kim M, Roh JK. Celecoxib induces functional recovery after intracerebral hemorrhage with reduction of brain edema and perihematomal cell death. J Cereb Blood Flow Metab 2004; 24:926-933. - 118.
MacLellan CL, Silasi G, Auriat AM, Colbourne F. Rodent models of intracerebral hemorrhage. Stroke 2010; 41:S95-98. - 119.
Wakisaka Y, Chu Y, Miller JD, Rosenberg GA, Heistad DD. Spontaneous intracerebral hemorrhage during acute and chronic hypertension in mice. J Cereb Blood Flow Metab 2010; 30:56-69. - 120.
Broderick JP, Adams HP, Jr., Barsan W, Feinberg W, Feldmann E, Grotta J, Kase C, Krieger D, Mayberg M, Tilley B, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: A statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke 1999; 30:905-915. - 121.
Morgenstern LB, Frankowski RF, Shedden P, Pasteur W, Grotta JC. Surgical treatment for intracerebral hemorrhage (STICH): a single-center, randomized clinical trial. Neurology 1998; 51:1359-1363. - 122.
Zhao X, Sun G, Zhang J, Strong R, Song W, Gonzales N, Grotta JC, Aronowski J. Hematoma resolution as a target for intracerebral hemorrhage treatment: role for peroxisome proliferator-activated receptor gamma in microglia/macrophages. Ann Neurol 2007; 61:352-362. - 123.
Wang J, Dore S. Heme oxygenase 2 deficiency increases brain swelling and inflammation after intracerebral hemorrhage. Neuroscience 2008; 155:1133-1141. - 124.
Xue M, Del Bigio MR. Intracerebral injection of autologous whole blood in rats: time course of inflammation and cell death. Neurosci Lett 2000; 283:230-232. - 125.
Gong C, Hoff JT, Keep RF. Acute inflammatory reaction following experimental intracerebral hemorrhage in rat. Brain Res 2000; 871:57-65. - 126.
Yong VW, Wells J, Giuliani F, Casha S, Power C, Metz LM. The promise of minocycline in neurology. Lancet Neurol 2004; 3:744-751. - 127.
Wasserman JK, Schlichter LC. Minocycline protects the blood-brain barrier and reduces edema following intracerebral hemorrhage in the rat. Exp Neurol 2007; 207:227-237. - 128.
Xue M, Mikliaeva EI, Casha S, Zygun D, Demchuk A, Yong VW. Improving outcomes of neuroprotection by minocycline: guides from cell culture and intracerebral hemorrhage in mice. Am J Pathol 2010; 176:1193-1202. - 129.
Wu J, Yang S, Xi G, Fu G, Keep RF, Hua Y. Minocycline reduces intracerebral hemorrhage-induced brain injury. Neurol Res 2009; 31:183-188. - 130.
Power C, Henry S, Del Bigio MR, Larsen PH, Corbett D, Imai Y, Yong VW, Peeling J. Intracerebral hemorrhage induces macrophage activation and matrix metalloproteinases. Ann Neurol 2003; 53:731-742. - 131.
Peeling J, Yan HJ, Corbett D, Xue M, Del Bigio MR. Effect of FK-506 on inflammation and behavioral outcome following intracerebral hemorrhage in rat. Exp Neurol 2001; 167:341-347. - 132.
Wang J, Tsirka SE. Neuroprotection by inhibition of matrix metalloproteinases in a mouse model of intracerebral haemorrhage. Brain 2005; 128:1622-1633. - 133.
Titova E, Ostrowski RP, Kevil CG, Tong W, Rojas H, Sowers LC, Zhang JH, Tang J. Reduced brain injury in CD18-deficient mice after experimental intracerebral hemorrhage. J Neurosci Res 2008; 86:3240-3245. - 134.
Mackenzie JM, Clayton JA. Early cellular events in the penumbra of human spontaneous intracerebral hemorrhage. J Stroke Cerebrovasc Dis 1999; 8:1-8. - 135.
Guo FQ, Li XJ, Chen LY, Yang H, Dai HY, Wei YS, Huang YL, Yang YS, Sun HB, Xu YC, Yang ZL. [Study of relationship between inflammatory response and apoptosis in perihematoma region in patients with intracerebral hemorrhage]. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 2006; 18:290-293. - 136.
Bestue-Cardiel M, Martin-Martinez J, Iturriaga-Heras C, Ara-Callizo JR, Oliveros-Juste A. [Leukocytes and primary intracerebral hemorrhage]. Rev Neurol 1999; 29:968-971. - 137.
Leira R, Davalos A, Silva Y, Gil-Peralta A, Tejada J, Garcia M, Castillo J. Early neurologic deterioration in intracerebral hemorrhage: predictors and associated factors. Neurology 2004; 63:461-467. - 138.
Silva Y, Leira R, Tejada J, Lainez JM, Castillo J, Davalos A. Molecular signatures of vascular injury are associated with early growth of intracerebral hemorrhage. Stroke 2005; 36:86-91. - 139.
Rosell A, Vilalta A, Garcia-Berrocoso T, Fernandez-Cadenas I, Domingues-Montanari S, Cuadrado E, Delgado P, Ribo M, Martinez-Saez E, Ortega-Aznar A, Montaner J. Brain perihematoma genomic profile following spontaneous human intracerebral hemorrhage. PLoS One 2011; 6:e16750. - 140.
Carmichael ST, Vespa PM, Saver JL, Coppola G, Geschwind DH, Starkman S, Miller CM, Kidwell CS, Liebeskind DS, Martin NA. Genomic profiles of damage and protection in human intracerebral hemorrhage. J Cereb Blood Flow Metab 2008; 28:1860-1875. - 141.
Xue M, Fan Y, Liu S, Zygun DA, Demchuk A, Yong VW. Contributions of multiple proteases to neurotoxicity in a mouse model of intracerebral haemorrhage. Brain 2009; 132:26-36. - 142.
Xue M, Yong VW. Matrix metalloproteinases in intracerebral hemorrhage. Neurol Res 2008; 30:775-782. - 143.
Lu A, Tang Y, Ran R, Ardizzone TL, Wagner KR, Sharp FR. Brain genomics of intracerebral hemorrhage. J Cereb Blood Flow Metab 2006; 26:230-252. - 144.
Xue M, Hollenberg MD, Yong VW. Combination of thrombin and matrix metalloproteinase-9 exacerbates neurotoxicity in cell culture and intracerebral hemorrhage in mice. J Neurosci 2006; 26:10281-10291. - 145.
Wu H, Zhang Z, Li Y, Zhao R, Li H, Song Y, Qi J, Wang J. Time course of upregulation of inflammatory mediators in the hemorrhagic brain in rats: correlation with brain edema. Neurochem Int 2010; 57:248-253. - 146.
Abilleira S, Montaner J, Molina CA, Monasterio J, Castillo J, Alvarez-Sabin J. Matrix metalloproteinase-9 concentration after spontaneous intracerebral hemorrhage. J Neurosurg 2003; 99:65-70. - 147.
Barr TL, Latour LL, Lee KY, Schaewe TJ, Luby M, Chang GS, El-Zammar Z, Alam S, Hallenbeck JM, Kidwell CS, Warach S. Blood-brain barrier disruption in humans is independently associated with increased matrix metalloproteinase-9. Stroke 2010; 41:e123-128. - 148.
Alvarez-Sabin J, Delgado P, Abilleira S, Molina CA, Arenillas J, Ribo M, Santamarina E, Quintana M, Monasterio J, Montaner J. Temporal profile of matrix metalloproteinases and their inhibitors after spontaneous intracerebral hemorrhage: relationship to clinical and radiological outcome. Stroke 2004; 35:1316-1322. - 149.
Rosell A, Ortega-Aznar A, Alvarez-Sabin J, Fernandez-Cadenas I, Ribo M, Molina CA, Lo EH, Montaner J. Increased brain expression of matrix metalloproteinase-9 after ischemic and hemorrhagic human stroke. Stroke 2006; 37:1399-1406. - 150.
Wells JE, Biernaskie J, Szymanska A, Larsen PH, Yong VW, Corbett D. Matrix metalloproteinase (MMP)-12 expression has a negative impact on sensorimotor function following intracerebral haemorrhage in mice. Eur J Neurosci 2005; 21:187-196. - 151.
Xue M, Hollenberg MD, Demchuk A, Yong VW. Relative importance of proteinase-activated receptor-1 versus matrix metalloproteinases in intracerebral hemorrhage-mediated neurotoxicity in mice. Stroke 2009; 40:2199-2204. - 152.
Rosenberg GA, Navratil M. Metalloproteinase inhibition blocks edema in intracerebral hemorrhage in the rat. Neurology 1997; 48:921-926. - 153.
Grossetete M, Rosenberg GA. Matrix metalloproteinase inhibition facilitates cell death in intracerebral hemorrhage in mouse. J Cereb Blood Flow Metab 2008; 28:752-763. - 154.
Lapchak PA, Chapman DF, Zivin JA. Metalloproteinase inhibition reduces thrombolytic (tissue plasminogen activator)-induced hemorrhage after thromboembolic stroke. Stroke 2000; 31:3034-3040. - 155.
Pfefferkorn T, Rosenberg GA. Closure of the blood-brain barrier by matrix metalloproteinase inhibition reduces rtPA-mediated mortality in cerebral ischemia with delayed reperfusion. Stroke 2003; 34:2025-2030. - 156.
Wasserman JK, Schlichter LC. Neuron death and inflammation in a rat model of intracerebral hemorrhage: effects of delayed minocycline treatment. Brain Res 2007; 1136:208-218. - 157.
Gutteridge JM. Hydroxyl radicals, iron, oxidative stress, and neurodegeneration. Ann N Y Acad Sci 1994; 738:201-213. - 158.
Zecca L, Youdim MB, Riederer P, Connor JR, Crichton RR. Iron, brain ageing and neurodegenerative disorders. Nat Rev Neurosci 2004; 5:863-873. - 159.
Mehdiratta M, Kumar S, Hackney D, Schlaug G, Selim M. Association between serum ferritin level and perihematoma edema volume in patients with spontaneous intracerebral hemorrhage. Stroke 2008; 39:1165-1170. - 160.
Lou M, Lieb K, Selim M. The relationship between hematoma iron content and perihematoma edema: an MRI study. Cerebrovasc Dis 2009; 27:266-271. - 161.
Wu H, Wu T, Li M, Wang J. Efficacy of the lipid-soluble iron chelator 2, 2'-dipyridyl against hemorrhagic brain injury. Neurobiol Dis 2012; 45:388-394. - 162.
Hua Y, Nakamura T, Keep RF, Wu J, Schallert T, Hoff JT, Xi G. Long-term effects of experimental intracerebral hemorrhage: the role of iron. J Neurosurg 2006; 104:305-312. - 163.
Okauchi M, Hua Y, Keep RF, Morgenstern LB, Xi G. Effects of deferoxamine on intracerebral hemorrhage-induced brain injury in aged rats. Stroke 2009; 40:1858-1863. - 164.
Song S, Hua Y, Keep RF, Hoff JT, Xi G. A new hippocampal model for examining intracerebral hemorrhage-related neuronal death: effects of deferoxamine on hemoglobin-induced neuronal death. Stroke 2007; 38:2861-2863. - 165.
Gu Y, Hua Y, Keep RF, Morgenstern LB, Xi G. Deferoxamine reduces intracerebral hematoma-induced iron accumulation and neuronal death in piglets. Stroke 2009; 40:2241-2243. - 166.
Warkentin LM, Auriat AM, Wowk S, Colbourne F. Failure of deferoxamine, an iron chelator, to improve outcome after collagenase-induced intracerebral hemorrhage in rats. Brain Res 2010; 1309:95-103. - 167.
Nguyen T, Nioi P, Pickett CB. The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem 2009; 284:13291-13295. - 168.
Shih AY, Li P, Murphy TH. A small-molecule-inducible Nrf2-mediated antioxidant response provides effective prophylaxis against cerebral ischemia in vivo. J Neurosci 2005; 25:10321-10335. - 169.
Zhao X, Zhang Y, Strong R, Grotta JC, Aronowski J. 15d-Prostaglandin J2 activates peroxisome proliferator-activated receptor-gamma, promotes expression of catalase, and reduces inflammation, behavioral dysfunction, and neuronal loss after intracerebral hemorrhage in rats. J Cereb Blood Flow Metab 2006; 26:811-820. - 170.
Zhao X, Sun G, Zhang J, Strong R, Dash PK, Kan YW, Grotta JC, Aronowski J. Transcription factor Nrf2 protects the brain from damage produced by intracerebral hemorrhage. Stroke 2007; 38:3280-3286. - 171.
Wang J, Fields J, Zhao C, Langer J, Thimmulappa RK, Kensler TW, Yamamoto M, Biswal S, Dore S. Role of Nrf2 in protection against intracerebral hemorrhage injury in mice. Free Radic Biol Med 2007; 43:408-414. - 172.
Jeong SW, Chu K, Jung KH, Kim SU, Kim M, Roh JK. Human neural stem cell transplantation promotes functional recovery in rats with experimental intracerebral hemorrhage. Stroke 2003; 34:2258-2263.