**6. Oxidative injury [1-2]**

Neurological deficits associated with ICH were also released from RBC lysis is a potent cytotoxic chemical that generates free radicals and oxidative damage, causing death of surrounding cells. ROS are produced after ICH and contribute to ICH pathogenesis. In addition, phagocytosis generates a large amount of ROS that can damage macrophages and neurons. Oxidative stress appears to play a prominent role in ICH pathogenesis. In addition to increased free radical generation, damage to brain tissue may result from the impairment of the endogenous antioxidative enzyme system in response to ICH. Direct evidence for the causal relationship between free radicals and ICH injury was by demonstrating the efficacy of antioxidants as therapeutic agents. Specifically, the free radical scavengers, such as dime‐ thylthiourea, α-phenyl-N-tert-butyl nitrone, NXY-059 (a sulfonyl derivative of α-phenyl-Ntert-butyl nitrone) or deferoxamine, a drug chelating pro-oxidative iron, significantly reduced brain injury in animal models of ICH. Mice with generically deleted NADPH oxidase, a key enzyme involved in generating ROS, showed reduced damage after ICH.

It reported a significant reduction in the levels of manganese superoxide dismutase and copper/zinc superoxide dismutase, the key enzymes of the antioxidant defense system in brains, after intracerebral injection of lysed erythrocytes.

Nrf2, a key player in antioxidative homeostasis. By binding to the antioxidant response element, Nrf2 regulates the expression of many detoxification and antioxidant enzymes, including superoxide dismutase, catalase, glutathione- Stransferase, glutathione peroxidase, HO-1, NAD(P)H quinine oxidoreductase -1, peroxiredoxin, or thioredoxin. To activate Nrf2 in animals after ICH, researchers utilized a naturally occurring organosulfur compound, sulforaphane. As expected, treatment with sulforaphane effectively increased the expression of Nrf2-regulated antioxidant genes, including catalase, superoxide dismutase, and gluta‐ thione-Stransferase, in brain tissue after ICH. Notably, this expression of antioxidants corre‐ sponded to reduced oxidative damage to proteins and lipids within the ICH-affected brain and importantly, with less severe neurological deficits. Nrf2 plays critical safeguard function in defending brain against oxidative stress associated with ICH pathogenesis.

### **7. Glutamate [2]**

Glutamate has long been recognized as the major excitatory neurotransmitter in the central nervous system (CNS). This amino acid is also well known as an important player in various

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/ macrophages in the periphery of hematoma.

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

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

Neurological deficits associated with ICH were also released from RBC lysis is a potent cytotoxic chemical that generates free radicals and oxidative damage, causing death of surrounding cells. ROS are produced after ICH and contribute to ICH pathogenesis. In addition, phagocytosis generates a large amount of ROS that can damage macrophages and neurons. Oxidative stress appears to play a prominent role in ICH pathogenesis. In addition to increased free radical generation, damage to brain tissue may result from the impairment of the endogenous antioxidative enzyme system in response to ICH. Direct evidence for the causal relationship between free radicals and ICH injury was by demonstrating the efficacy of antioxidants as therapeutic agents. Specifically, the free radical scavengers, such as dime‐ thylthiourea, α-phenyl-N-tert-butyl nitrone, NXY-059 (a sulfonyl derivative of α-phenyl-Ntert-butyl nitrone) or deferoxamine, a drug chelating pro-oxidative iron, significantly reduced brain injury in animal models of ICH. Mice with generically deleted NADPH oxidase, a key

It reported a significant reduction in the levels of manganese superoxide dismutase and copper/zinc superoxide dismutase, the key enzymes of the antioxidant defense system in

Nrf2, a key player in antioxidative homeostasis. By binding to the antioxidant response element, Nrf2 regulates the expression of many detoxification and antioxidant enzymes, including superoxide dismutase, catalase, glutathione- Stransferase, glutathione peroxidase, HO-1, NAD(P)H quinine oxidoreductase -1, peroxiredoxin, or thioredoxin. To activate Nrf2 in animals after ICH, researchers utilized a naturally occurring organosulfur compound, sulforaphane. As expected, treatment with sulforaphane effectively increased the expression of Nrf2-regulated antioxidant genes, including catalase, superoxide dismutase, and gluta‐ thione-Stransferase, in brain tissue after ICH. Notably, this expression of antioxidants corre‐ sponded to reduced oxidative damage to proteins and lipids within the ICH-affected brain and importantly, with less severe neurological deficits. Nrf2 plays critical safeguard function

Glutamate has long been recognized as the major excitatory neurotransmitter in the central nervous system (CNS). This amino acid is also well known as an important player in various

enzyme involved in generating ROS, showed reduced damage after ICH.

in defending brain against oxidative stress associated with ICH pathogenesis.

brains, after intracerebral injection of lysed erythrocytes.

the number of cells exhibiting DNA fragmentation.

**6. Oxidative injury [1-2]**

38 Intracerebral Hemorrhage

**7. Glutamate [2]**

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