**5. Inflammatory mediators [1-4]**

Whereas inflammatory mediators generated locally in response to brain injury have the capacity to augment damage caused by ICH (secondary injury), the involvement of inflam‐ matory cells, eg, microglia/macrophages, is vital for removal or cleanup of cellular debris from hematoma, the source of ongoing inflammation. The timely removal of damaged tissue is essential for reducing the length of deleterious pathological process and thereby allowing for faster and more efficient recovery.

Several lines of evidence showed that activation of innate immunity and inflammatory responses contributes to the pathogenesis of secondary injury after ICH. An inflammatory response occurs after ICH, which aggravates ICH-induced brain injury, leading to further tissue damage, blood–brain barrier disruption and edema. The inflammatory mechanisms involved in progression of ICH-induced brain injury include activation of microglial cells, infiltration of inflammatory cells and production of cytokines and chemokines.

#### **5.1. Microglias activation [1-4, 7]**

The brain-resident phagocytes, microglia, are highly abundant (10%–15% of total glial cells) in brain and become readily activated within minutes after ICH. Microglia are a type of glial cell that are the resident macrophages of the brain and spinal cord, and thus act as the first and main form of active immune defense in the central nervous system(CNS). Microglial cells fulfill a variety of different tasks within the CNS mainly related to both immune response and maintaining homeostasis.

Microglia constitute 10-15% of the total glial cell population within the brain. Microglia (and astrocytes) are distributed in large non-overlapping regions throughout the brain and spinal cord. Microglia are constantly scavenging the CNS for plaques, damaged neurons and infectious agents. The brain and spinal cord are considered "immune privileged" organs in that they are separated from the rest of the body by a series of endothelial cells known as the blood– brain barrier, which prevents most infections from reaching the vulnerable nervous tissue. In the case where infectious agents are directly introduced to the brain or cross the blood–brain barrier, microglial cells must react quickly to decrease inflammation and destroy the infectious agents before they damage the sensitive neural tissue. Due to the unavailability of antibodies from the rest of the body (few antibodies are small enough to cross the blood brain barrier), microglia must be able to recognize foreign bodies, swallow them, and act as antigen-present‐ ing cells activating T-cells. Since this process must be done quickly to prevent potentially fatal damage, microglia are extremely sensitive to even small pathological changes in the CNS.

astroglial end feet plays a key role in exchange of water between brain, blood, and cerebro‐ spinal fuid. Upregulation of AQP4 induced by iron overload may cause an increased perme‐ ability to water in astrocytic membranes. The faint positive immunoreactivity of AQP4 possibly prevent the astrocytes from swelling. So, AQP4 in the brain may be viewed as a final

Whereas inflammatory mediators generated locally in response to brain injury have the capacity to augment damage caused by ICH (secondary injury), the involvement of inflam‐ matory cells, eg, microglia/macrophages, is vital for removal or cleanup of cellular debris from hematoma, the source of ongoing inflammation. The timely removal of damaged tissue is essential for reducing the length of deleterious pathological process and thereby allowing for

Several lines of evidence showed that activation of innate immunity and inflammatory responses contributes to the pathogenesis of secondary injury after ICH. An inflammatory response occurs after ICH, which aggravates ICH-induced brain injury, leading to further tissue damage, blood–brain barrier disruption and edema. The inflammatory mechanisms involved in progression of ICH-induced brain injury include activation of microglial cells,

The brain-resident phagocytes, microglia, are highly abundant (10%–15% of total glial cells) in brain and become readily activated within minutes after ICH. Microglia are a type of glial cell that are the resident macrophages of the brain and spinal cord, and thus act as the first and main form of active immune defense in the central nervous system(CNS). Microglial cells fulfill a variety of different tasks within the CNS mainly related to both immune response and

Microglia constitute 10-15% of the total glial cell population within the brain. Microglia (and astrocytes) are distributed in large non-overlapping regions throughout the brain and spinal

infiltration of inflammatory cells and production of cytokines and chemokines.

common pathways of cerebral edema.

32 Intracerebral Hemorrhage

**5. Inflammatory mediators [1-4]**

faster and more efficient recovery.

**5.1. Microglias activation [1-4, 7]**

maintaining homeostasis.

**Figure 2.** Iron staining after ICH (Perl's staining) AQP4 positive staining in ICH rat

Microglia can be activated by a variety of factors including: glutamate receptor agonists, proinflammatory cytokines, cell necrosis factors, lipopolysaccharide, and changes in extracellular potassium (indicative of ruptured cells). Once activated the cells undergo several key mor‐ phological changes including the thickening and retraction of branches, uptake of major histocompatibility complex (MHC) class I/II proteins, expression of immunomolecules, secretion of cytotoxic factors, secretion of recruitment molecules, and secretion of proinflammatory signaling molecules (resulting in a pro-inflammation signal cascade). Activated non-phagocytic microglia generally appear as "bushy, " "rods, " or small ameboids depending on how far along the ramified to full phagocytic transformation continuum they are. In addition, the microglia also undergo rapid proliferation in order to increase their numbers. From a strictly morphological perspective, the variation in microglial form along the contin‐ uum is associated with changing morphological complexity and can be quantitated using the methods of fractal analysis, which have proven sensitive to even subtle, visually undetectable changes associated with different morphologies in different pathological states.

Microglial cells are activated within minutes after the onset of ICH. The activated microglia release proinflammatory cytokines and chemotactic factors, which help to recruit hemotoge‐ neous inflammatory cells to the ICH injury sites. Activated microglial cells undergo morpho‐ logical and functional changes that include enlargement and thickening of processes, upregulation of proinflammatory proteins, and behavioral changes, including proliferation, migration and phagocytosis. Timely clearance of the extravasated RBCs by activated micro‐ glia/macrophages can provide protection from local damage resulting from RBC lysis. The primary neuroprotective role of activated microglia is to clear the hematoma and damaged cell debris through phagocytosis, providing a nurturing environment for tissue recovery. This is characterized first by the transient (18 hours–4 days) infiltration of neutrophils and then a long-term (1 day–months) presence of hematogenous macrophages. However, accumulating evidence has shown that microglial activation contributes to ICH-induced secondary brain injury by releasing a variety of cytokines, chemokines, free radicals, nitric oxide and other potentially toxic chemicals. In addition, several studies have shown that inhibition of micro‐ glial activation reduces brain damages in animal models of ICH. Microglial inhibitors, such as minocycline and microglia/macrophage inhibitory factors (tuftsin fragment 1–3), reduce ICHinduced brain injury and improve neurological function in rodents. Clearly, microglial activation mediates ICH-mediated brain injury. Successful removal of injured cells can reduce secondary damage by preventing discharge of injurious proinflammatory cell contents. Resolution of hematoma and inhibition of inflammation are considered potential targets for ICH treatment.

Activated microglia can be stained via the marker ionized calcium-binding adapter molecule 1 (IBA1), which is upregulated during activation. Microglia are the only cells in the brain to express Iba1.

One way to control neuroinflammation is to inhibit microglial activation. Studies on microglia have shown that they are activated by diverse stimuli but they are dependent on activation of mitogen-activated protein kinase (MAPK). Previous approaches to down-regulate activated microglia focused on immunosuppressants. Recently, minocycline (a tetracycline derivative) has shown down-regulation of microglial MAPK. Another promising treatment is CPI-1189, which induces cell death in a tumor necrosis factor (TNF) α-inhibiting compound that also down-regulates MAPK. Recent study shows that nicergoline (Sermion) suppresses the production of proinflammatory cytokines and superoxide anion by activated microglia. Microglial activation can be inhibited by MIF (microglia/macrophage inhibitory factor, tuftsin fragment 1–3, Thr-Lys-Pro). MIF-treated mice showed reduced brain injury and improved neurologic function in a mouse model of collagenase-induced intracerebral hemorrhage.

**Figure 4.** Microglia/Macrophage - activated form from rat cortex after traumatic brain injury (lectin staining with HRP)

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Besides microglia, other blood-derived inflammatory cells, such as leukocytes and macro‐ phages, are also activated after ICH and contribute to ICH-induced brain injury Neutrophil infiltration occurs less than 1day after the onset of ICH, and the infiltrating neutrophils die by apoptosis within 2days . Neutrophils are believed to contribute to brain injury after ICH. Depletion of neutrophils reduced blood–brain barrier disruption, axon injury and inflamma‐ tion in a rat model of ICH and was found to prevent tissue plasminogen activator (tPA) induced ICH in a rat model of cerebral ischemia. Neutrophils may damage brain tissues by producing reactive oxygen species (ROS) and releasing proinflammatory cytokines and matrix metalloproteinases (MMPs). Dying leukocytes can cause further brain injury by stimulating microglia/macrophages to release proinflammatory factors. Activated macrophages are indistinguishable from resident microglia in morphology and function. Similar to activated microglia, activated leukocytes and macrophages release a variety of cytokines, chemokines,

Cytokines are well-known to be associated with inflammation and immune activation. Although cytokines are released by many cells, including microglia/macrophages, astrocytes

Many studies have shown that two major proinflammatory cytokines, TNF-α and interleu‐ kin1β (IL-1β), exacerbate ICH-induced brain injury. After ICH, TNF-α is significantly in‐ creased both *in vivo* and *in vitro*, which may contribute to brain edema formation and brain injury in animal models of ICH. Consistent with animal studies, clinical studies support the

and neurons, the major sources of cytokines are activated microglia/macrophages.

**5.2. Infiltration of inflammatory cells [1-3]**

free radicals and other potentially toxic chemicals.

**5.3. Production of cytokines**

*5.3.1. TNF-α and IL-1β [1-3]*

Albeit some inflammatory responses generated by microglia/macrophages after ICH may aggravate brain injury, microglia/macrophages-mediated phagocytosis is instrumental in conducting brain clean-up, the process that must occur to allow for tissue repair and functional recovery. A fast and efficient removal of apoptotic, dislocated (eg, extravascular erythrocytes), and damaged cells before the discharge of injurious and proinflammatory cell contents (damageassociated molecular patterns) occurs and may help to reduce secondary damage.

So, by inhibiting the activation of microglial cells, namely the inhibition of brain primary response to the timely removal of damaged tissue and self repairing systems, to reduce the amount of potential damages, the desirability of this way is still questionable .

**Figure 3.** Microglia - ramified form from rat cortex before traumatic brain injury (lectin staining with HRP)

**Figure 4.** Microglia/Macrophage - activated form from rat cortex after traumatic brain injury (lectin staining with HRP)

#### **5.2. Infiltration of inflammatory cells [1-3]**

secondary damage by preventing discharge of injurious proinflammatory cell contents. Resolution of hematoma and inhibition of inflammation are considered potential targets for

Activated microglia can be stained via the marker ionized calcium-binding adapter molecule 1 (IBA1), which is upregulated during activation. Microglia are the only cells in the brain to

One way to control neuroinflammation is to inhibit microglial activation. Studies on microglia have shown that they are activated by diverse stimuli but they are dependent on activation of mitogen-activated protein kinase (MAPK). Previous approaches to down-regulate activated microglia focused on immunosuppressants. Recently, minocycline (a tetracycline derivative) has shown down-regulation of microglial MAPK. Another promising treatment is CPI-1189, which induces cell death in a tumor necrosis factor (TNF) α-inhibiting compound that also down-regulates MAPK. Recent study shows that nicergoline (Sermion) suppresses the production of proinflammatory cytokines and superoxide anion by activated microglia. Microglial activation can be inhibited by MIF (microglia/macrophage inhibitory factor, tuftsin fragment 1–3, Thr-Lys-Pro). MIF-treated mice showed reduced brain injury and improved neurologic function in a mouse model of collagenase-induced intracerebral hemorrhage.

Albeit some inflammatory responses generated by microglia/macrophages after ICH may aggravate brain injury, microglia/macrophages-mediated phagocytosis is instrumental in conducting brain clean-up, the process that must occur to allow for tissue repair and functional recovery. A fast and efficient removal of apoptotic, dislocated (eg, extravascular erythrocytes), and damaged cells before the discharge of injurious and proinflammatory cell contents (damageassociated molecular patterns) occurs and may help to reduce secondary damage.

So, by inhibiting the activation of microglial cells, namely the inhibition of brain primary response to the timely removal of damaged tissue and self repairing systems, to reduce the

amount of potential damages, the desirability of this way is still questionable .

**Figure 3.** Microglia - ramified form from rat cortex before traumatic brain injury (lectin staining with HRP)

ICH treatment.

34 Intracerebral Hemorrhage

express Iba1.

Besides microglia, other blood-derived inflammatory cells, such as leukocytes and macro‐ phages, are also activated after ICH and contribute to ICH-induced brain injury Neutrophil infiltration occurs less than 1day after the onset of ICH, and the infiltrating neutrophils die by apoptosis within 2days . Neutrophils are believed to contribute to brain injury after ICH. Depletion of neutrophils reduced blood–brain barrier disruption, axon injury and inflamma‐ tion in a rat model of ICH and was found to prevent tissue plasminogen activator (tPA) induced ICH in a rat model of cerebral ischemia. Neutrophils may damage brain tissues by producing reactive oxygen species (ROS) and releasing proinflammatory cytokines and matrix metalloproteinases (MMPs). Dying leukocytes can cause further brain injury by stimulating microglia/macrophages to release proinflammatory factors. Activated macrophages are indistinguishable from resident microglia in morphology and function. Similar to activated microglia, activated leukocytes and macrophages release a variety of cytokines, chemokines, free radicals and other potentially toxic chemicals.

#### **5.3. Production of cytokines**

Cytokines are well-known to be associated with inflammation and immune activation. Although cytokines are released by many cells, including microglia/macrophages, astrocytes and neurons, the major sources of cytokines are activated microglia/macrophages.

#### *5.3.1. TNF-α and IL-1β [1-3]*

Many studies have shown that two major proinflammatory cytokines, TNF-α and interleu‐ kin1β (IL-1β), exacerbate ICH-induced brain injury. After ICH, TNF-α is significantly in‐ creased both *in vivo* and *in vitro*, which may contribute to brain edema formation and brain injury in animal models of ICH. Consistent with animal studies, clinical studies support the proposition that TNF-α contributes to ICH-induced brain injury. Plasma TNF-α has been shown to correlate with the magnitude of the perihematomal brain edema in patients with ICH. Single-nucleotide polymorphisms in the TNF-α gene promoter are associated with spontaneous deep ICH. Similarly, IL-1β has been found to be upregulated after ICH in an animal model and to produce detrimental effects, including brain edema and blood–brain barrier disruption.

after ICH. Our recent *in vivo* study shows that activation of TLR4 by heme causes ICH-induced inflammatory injury via the MyD88/TRIF signaling pathway and that effective blockade of TLR4 by its antibody suppresses ICH-induced inflammation. Thus, the TLR4 signaling

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The hemorrhage itself also induces the overexpression of matrix metalloproteinases(MMPs). Matrix metalloproteinases also promote BBB disruption and have been associated with increased edema volume via extracellular matrix proteolysis, basal lamina destruction, and

Matrix metalloproteinases (MMPs) are a large family of calcium-dependent zinc-containing endopeptidases, which are responsible for the tissue remodeling and degradation of the extracellular matrix (ECM), including collagens, elastins, gelatin, matrix glycoproteins, and proteoglycan. Matrix metalloproteinases are excreted by a variety of connective tissue and proinflammatory cells including fibroblasts, osteoblasts, endothelial cells, macrophages, neutro‐ phils, and lymphocytes. These enzymes are expressed as zymogens, which are subsequently processed by other proteolytic enzymes (such as serine proteases, furin, plasmin, and others) to generate the active forms. After hemorrhagic events in the brain, several members of the MMP family are recruited and involved in pathogenic processes. An early study on collagenase injection model reported that the MMP inhibitor BB-1101 could reduce brain edema when administered 6h after induction of ICH. In human ICH patients, expression of MMP-9 and MMP-3 increases after the incident. MMP-9 expression is induced in astrocytes and neurons in the perihematomal area, possibly by an action of hemoglobin. Increased MMP-9 is associated with the extent of perihematomal edema, whereas increased MMP-3 is associated with high mortality. Experiments using MMP-9–deficient mice demonstrated that MMP-9 derived from both blood and brain parenchyma contributes to edema formation after autologous blood injection. In addition, MMP-9–deficient mice displayed lower levels of neurodegeneration, neutrophil infiltration, and microglia/macrophage reactions than wild-type mice. In the collagenase injection model, MMP-9 expression was found mainly in neurons and vascular endothelial cells, and administration of the MMP inhibitor GM6001, beginning 2 h after induction of ICH, attenuated neutrophil infiltration, oxidative stress, brain edema, neurode‐ generation, and neurological impairment. With regard to MMP-3, early induction of this enzyme may contribute to brain damage in combination with other proteases such as MMP-9 and thrombin. Other lines of evidence indicate that MMP-12 may play a key role in the pathogenesis of ICH. That is, MMP-12 was induced most prominently among MMP isozymes in the collagenase-injection model in rats and mice, and MMP-12 deficient mice showed better functional recovery after ICH as well as reduced levels of recruitment of microglia/macro‐ phages in the perihematomal region.It should be noted that several studies reported conflicting results. For example, a study on MMP-9–deficient mice showed that collagenase injection into the striatum of the mutant mice resulted in enhanced bleeding, increased mortality, and exacerbated neurological deficits. These changes may be attributable to heightened expression

pathway could be a promising therapeutic target for ICH treatment.

*5.3.5. Matrix metalloproteinases(MMPs) [1-2, 4]*

the degradation of c-fibronectin.

#### *5.3.2. Nuclear factor kappa-B (NF-κB) [1-3]*

The apoptotic pathway in ICH may involve nuclear factor-kappa B (NF-κB), which is a ubiquitous transcription factor that, when activated, translocates to the nucleus and binds to DNA. NF-κB is associated with apoptotic cell death and has been reported in the role of cell death after experimental ICH in rats .

The inflammatory signaling involves a coordinated effort of different molecules and cell types and is largely coordinated by a ubiquitous transcription factor, NF-κB, a transcription factor involved in inflammatory responses, is a key regulator of many proinflammatory cytokines, such as TNF-α , IL-1β and MMP-9 are involved in various pathological conditions, including ICH-mediated brain injury. Activation of NF-κB occurs within minutes and lasts for at least 1 week after the onset of ICH. The activity of NF-κB correlates with perilesional cell death after ICH in rats and is positively associated with the progression of apoptotic cell death in patients with ICH. Several lines of evidence have shown that NF-κB is activated by RBCs and plasma via signaling pathways involving free radicals, cytokines and glutamate receptors. Cellular necrosis likely occurs at the core of the hemorrhage; however, apoptosis has been observed in the perihematomal region.

#### *5.3.3. CD36 [1, 3]*

Microglia and macrophages express various cell surface receptors, including scavenger receptors (eg, CD36) that assist in phagocytosis / endocytosis - mediated removal of cellular debris after tissue injury, including brain injury after ICH. One specific study evaluated CD36, a class II scavenger receptor that is transcriptionally regulated by peroxisome proliferatoractivated receptors (PPARs). This study used in vitro and in vivo models and demonstrated that: (1) microglia/macrophages utilize CD36 to promote phagocytosis of red blood cell; and (2) treating animals with PPAR agonists (eg, rosiglitazone, pioglitazone, or 15D-PGJ2), which increased CD36 expression, results in faster hematoma resolution and improved functional recovery after ICH.

#### *5.3.4. Toll-like receptors (TLRs) [3]*

Toll-like receptors (TLRs) is expressed in microglia, the resident macrophages of the brain, belong to a large family of pattern recognition receptors that play a key role in innate immunity and inflammatory responses. It has been reported that TLR4 is upregulated in a rat model of ICH and that its signaling pathway contributes to poor outcome after ICH. TLR4 is activated by many endogenous ligands, such as heme and fibrinogen, which are produced in the brain after ICH. Our recent *in vivo* study shows that activation of TLR4 by heme causes ICH-induced inflammatory injury via the MyD88/TRIF signaling pathway and that effective blockade of TLR4 by its antibody suppresses ICH-induced inflammation. Thus, the TLR4 signaling pathway could be a promising therapeutic target for ICH treatment.

#### *5.3.5. Matrix metalloproteinases(MMPs) [1-2, 4]*

proposition that TNF-α contributes to ICH-induced brain injury. Plasma TNF-α has been shown to correlate with the magnitude of the perihematomal brain edema in patients with ICH. Single-nucleotide polymorphisms in the TNF-α gene promoter are associated with spontaneous deep ICH. Similarly, IL-1β has been found to be upregulated after ICH in an animal model and to produce detrimental effects, including brain edema and blood–brain

The apoptotic pathway in ICH may involve nuclear factor-kappa B (NF-κB), which is a ubiquitous transcription factor that, when activated, translocates to the nucleus and binds to DNA. NF-κB is associated with apoptotic cell death and has been reported in the role of cell

The inflammatory signaling involves a coordinated effort of different molecules and cell types and is largely coordinated by a ubiquitous transcription factor, NF-κB, a transcription factor involved in inflammatory responses, is a key regulator of many proinflammatory cytokines, such as TNF-α , IL-1β and MMP-9 are involved in various pathological conditions, including ICH-mediated brain injury. Activation of NF-κB occurs within minutes and lasts for at least 1 week after the onset of ICH. The activity of NF-κB correlates with perilesional cell death after ICH in rats and is positively associated with the progression of apoptotic cell death in patients with ICH. Several lines of evidence have shown that NF-κB is activated by RBCs and plasma via signaling pathways involving free radicals, cytokines and glutamate receptors. Cellular necrosis likely occurs at the core of the hemorrhage; however, apoptosis has been observed in

Microglia and macrophages express various cell surface receptors, including scavenger receptors (eg, CD36) that assist in phagocytosis / endocytosis - mediated removal of cellular debris after tissue injury, including brain injury after ICH. One specific study evaluated CD36, a class II scavenger receptor that is transcriptionally regulated by peroxisome proliferatoractivated receptors (PPARs). This study used in vitro and in vivo models and demonstrated that: (1) microglia/macrophages utilize CD36 to promote phagocytosis of red blood cell; and (2) treating animals with PPAR agonists (eg, rosiglitazone, pioglitazone, or 15D-PGJ2), which increased CD36 expression, results in faster hematoma resolution and improved functional

Toll-like receptors (TLRs) is expressed in microglia, the resident macrophages of the brain, belong to a large family of pattern recognition receptors that play a key role in innate immunity and inflammatory responses. It has been reported that TLR4 is upregulated in a rat model of ICH and that its signaling pathway contributes to poor outcome after ICH. TLR4 is activated by many endogenous ligands, such as heme and fibrinogen, which are produced in the brain

barrier disruption.

36 Intracerebral Hemorrhage

*5.3.2. Nuclear factor kappa-B (NF-κB) [1-3]*

death after experimental ICH in rats .

the perihematomal region.

*5.3.3. CD36 [1, 3]*

recovery after ICH.

*5.3.4. Toll-like receptors (TLRs) [3]*

The hemorrhage itself also induces the overexpression of matrix metalloproteinases(MMPs). Matrix metalloproteinases also promote BBB disruption and have been associated with increased edema volume via extracellular matrix proteolysis, basal lamina destruction, and the degradation of c-fibronectin.

Matrix metalloproteinases (MMPs) are a large family of calcium-dependent zinc-containing endopeptidases, which are responsible for the tissue remodeling and degradation of the extracellular matrix (ECM), including collagens, elastins, gelatin, matrix glycoproteins, and proteoglycan. Matrix metalloproteinases are excreted by a variety of connective tissue and proinflammatory cells including fibroblasts, osteoblasts, endothelial cells, macrophages, neutro‐ phils, and lymphocytes. These enzymes are expressed as zymogens, which are subsequently processed by other proteolytic enzymes (such as serine proteases, furin, plasmin, and others) to generate the active forms. After hemorrhagic events in the brain, several members of the MMP family are recruited and involved in pathogenic processes. An early study on collagenase injection model reported that the MMP inhibitor BB-1101 could reduce brain edema when administered 6h after induction of ICH. In human ICH patients, expression of MMP-9 and MMP-3 increases after the incident. MMP-9 expression is induced in astrocytes and neurons in the perihematomal area, possibly by an action of hemoglobin. Increased MMP-9 is associated with the extent of perihematomal edema, whereas increased MMP-3 is associated with high mortality. Experiments using MMP-9–deficient mice demonstrated that MMP-9 derived from both blood and brain parenchyma contributes to edema formation after autologous blood injection. In addition, MMP-9–deficient mice displayed lower levels of neurodegeneration, neutrophil infiltration, and microglia/macrophage reactions than wild-type mice. In the collagenase injection model, MMP-9 expression was found mainly in neurons and vascular endothelial cells, and administration of the MMP inhibitor GM6001, beginning 2 h after induction of ICH, attenuated neutrophil infiltration, oxidative stress, brain edema, neurode‐ generation, and neurological impairment. With regard to MMP-3, early induction of this enzyme may contribute to brain damage in combination with other proteases such as MMP-9 and thrombin. Other lines of evidence indicate that MMP-12 may play a key role in the pathogenesis of ICH. That is, MMP-12 was induced most prominently among MMP isozymes in the collagenase-injection model in rats and mice, and MMP-12 deficient mice showed better functional recovery after ICH as well as reduced levels of recruitment of microglia/macro‐ phages in the perihematomal region.It should be noted that several studies reported conflicting results. For example, a study on MMP-9–deficient mice showed that collagenase injection into the striatum of the mutant mice resulted in enhanced bleeding, increased mortality, and exacerbated neurological deficits. These changes may be attributable to heightened expression of MMP-2 and MMP-3 in response to ICH, together with lowered levels of collagen in the brain of MMP-9–deficient mice . In addition, systemic administration of BB-94, a broad spectrum MMP inhibitor, from 30 min before collagenase injection increased hemorrhagic volume and the number of cells exhibiting DNA fragmentation.

CNS disorders, since over-activation of ionotropic glutamate receptors causes neuronal damage via processes called excitotoxicity. Several lines of evidence suggest that glutamate is involved in the pathogensis of ICH. Transient elevation of the extracellular concentration of glutamate in the perihematomal region was demonstrated in rabbits following injection of autologous blood into the gray matter of the cerebrum. Subsequently, the effect of memantine, a low-affinity blocker of the N-methyl-D-aspartate subtype of glutamate receptor–associated channels, was investigated in the collagenase-injection model in rats. Daily intraperitoneal administration of memantine, starting from 30 min after induction of ICH, reduced hemor‐ rhage volume, apoptotic cell death, neutrophil infiltration, and the number of microglia/

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Based on the recent publications, several potential factors of secondary ischemic injury after ICH have been consistently associated with acute ischemic lesions around hematoma. Although there is restricted diffusion within the hematoma during the first 2 weeks, an effect of increased viscosity and suspectibility effects from blood breakdown products, much more

In conclusion, blood constituents, including hemoglobin-derived products as well as proteases such as thrombin and Haptoglobin, play important roles in the pathogenic events. Inflamma‐ tory reactions involving activated microglia, neutrophils, and production of proinflammatory cytokines also constitute a critical aspect of pathology leading to neurodegeneration and tissue damage. The mechanisms of secondary cerebral injury after ICH are complex and multidisci‐ plinary. From a protective response into the later damaged process, they are interacting and overlapping, so we have to weigh the benefits (positive effects) and risks (adverse effects)

Department of Neurology, The Second Hospital, Shanxi Medical University, Shan Xi, China

attention has been paid to the potential for ischemia in the surrounding tissue.

macrophages in the periphery of hematoma.

**8. Ischemia [8, 4]**

**9. Conclusion**

**Author details**

Gaiqing Wang\*

carefully when we intervene in ICH.

Address all correspondence to: wanggq08@126.com
