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The rapid loss of neurons is a major pathological outcome of intracerebral hemorrhage (ICH). Several mechanisms may produce the neurotoxicity observed in ICH, and these include proteolytic enzymes such as thrombin and matrix metalloproteinase-9 (MMP-9). We tested the hypothesis that thrombin and MMP-9 combine to injure neurons in culture and that they interact to promote the acute neurotoxicity that occurs in ICH in vivo. We report that human fetal neurons die when exposed to thrombin or MMP-9 in isolation and that a combination of these two enzymes increased neurotoxicity. The toxicity of thrombin involved protease-activated receptor-1 and the conversion of proMMP-9 to active MMP-9. In ICH, which was induced in mice by the intracerebral injection of autologous blood, significant areas of brain damage, neuronal death, microglia/macrophage activation, and neutrophil accumulation occurred by 24 h of injury. Importantly, these neuropathological features were reduced in MMP-9 null mice compared with wild-type controls, and the concordant antagonism of thrombin using hirudin also alleviated the injury found in MMP-9 null mice. Our collective results demonstrate that thrombin and MMP-9 collaborate to promote neuronal death in culture and in ICH. To improve the prognosis of ICH, the neurotoxic actions of thrombin and MMP-9 must be inhibited early and simultaneously after injury.

Background and Purpose-Tumor necrosis factor-␣ (TNF-␣) expression is increased in brain after cerebral ischemia, although little is known about its abundance and role in intracerebral hemorrhage (ICH). A TNF-␣-specific antisense oligodeoxynucleotide (ORF4-PE) was used to study the extent to which TNF-␣ expression influenced neurobehavioral outcomes and brain damage in a collagenase-induced ICH model in rat. Methods-Male Sprague-Dawley rats were anesthetized, and ICH was induced by intrastriatal administration of heparin and collagenase. Immediately before or 3 hours after ICH induction, ORF4-PE was administered directly into the site of ICH. TNF-␣ mRNA and protein levels were measured by reverse transcriptase-polymerase chain reaction and immunoblot analyses. Cell death was measured by terminal deoxynucleotidyl transferase-mediated uridine 5Јtriphosphate-biotin nick end labeling (TUNEL). Neurobehavioral deficits were measured for 4 weeks after ICH. Results-ICH induction (nϭ6) elevated TNF-␣ mRNA and protein levels (PϽ0.01) at 24 hours after the onset of injury compared with sham controls (nϭ6). Immunohistochemical labeling indicated that ICH was accompanied by elevated expression of TNF-␣ in neutrophils, macrophages, and microglia. Administration of ORF4-PE (2.0 nmol) directly into striatal parenchyma, 15 minutes before (nϭ4) or 3 hours after (nϭ6) ICH, decreased levels of TNF-␣ mRNA (PϽ0.001) and protein (PϽ0.01) in the brain tissue surrounding the hematoma compared with animals treated with saline alone (nϭ6). MeanϮSEM striatal cell death (cells per high-powered field) was also reduced in animals receiving ORF4-PE (34.1Ϯ5.0) compared with the saline-treated ICH group (80.3Ϯ7.50) (PϽ0.001). ORF4-PE treatment improved neurobehavioral deficits observed at 24 hours (PϽ0.001) after induction of ICH (nϭ6) compared with the untreated ICH group (nϭ6). This improvement was maintained at 28 days after hemorrhage induction (PϽ0.001). Conclusions-These

The prognosis of intracerebral haemorrhage continues to be devastating despite much research into this condition. A prominent feature of intracerebral haemorrhage is neuroinflammation, particularly the excessive representation of pro-inflammatory CNS-intrinsic microglia and monocyte-derived macrophages that infiltrate from the circulation. The pro-inflammatory microglia/macrophages produce injury-enhancing factors, including inflammatory cytokines, matrix metalloproteinases and reactive oxygen species. Conversely, the regulatory microglia/macrophages with potential reparative and anti-inflammatory roles are outcompeted in the early stages after intracerebral haemorrhage, and their beneficial roles appear to be overwhelmed by pro-inflammatory microglia/macrophages. In this review, we describe the activation of microglia/macrophages following intracerebral haemorrhage in animal models and clinical subjects, and consider their multiple mechanisms of cellular injury after haemorrhage. We review strategies and medications aimed at suppressing the pro-inflammatory activities of microglia/macrophages, and those directed at elevating the regulatory properties of these myeloid cells after intracerebral haemorrhage. We consider the translational potential of these medications from preclinical models to clinical use after intracerebral haemorrhage injury, and suggest that several approaches still lack the experimental support necessary for use in humans. Nonetheless, the preclinical data support the use of deactivator or inhibitor of pro-inflammatory microglia/macrophages, whilst enhancing the regulatory phenotype, as part of the therapeutic approach to improve the prognosis of intracerebral haemorrhage.

Background and Purpose-Extravasation of blood is associated with intracerebral hemorrhage and head trauma. The mechanism of brain cell injury associated with hemorrhage differs from that due to pure ischemia. The purpose of this study was to investigate the acute changes after intracerebral injections of proteins that are involved in blood clotting and clot lysis. Methods-Sixty-eight adult rats were subjected to stereotaxic intrastriatal injections of normal saline (5 L), low-(2.5 U/5 L) and high-dose (

Preoperative FPG levels and donor liver steatosis were independent risk factors for NODAT, whereas administration of an IL-2R antagonist reduced the risk of NODAT. Patients with NODAT had reduced survival and an increased incidence of sepsis and chronic renal insufficiency. Significant causes of death in the NODAT group were pulmonary infection and multisystem failure.

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