Pyruvate protects against experimental stroke via an anti-inflammatory mechanism

Pyruvate, a key intermediate in glucose metabolism, was explored as a potential treatment in models of experimental stroke and inflammation. Pyruvate was administered to rodents after the onset of middle cerebral artery occlusion (MCAO). Since the extent of inflammation is often proportional to the size of the infarct, we also studied a group of animals given lipopolysaccharide (LPS) to cause brain inflammation without cell death. Following MCAO, pyruvate did not affect physiological parameters but significantly reduced infarct volume, improved behavioral tests and reduced numbers of neutrophils, microglial and NFκB activation. Animals given LPS showed increased microglial and NFκB activation which was almost completely abolished by pyruvate. Lactate, a major metabolite of pyruvate, was increased after pyruvate administration. However, administration of lactate itself did not have any anti-inflammatory effects. Pyruvate protects against ischemia possibly by blocking inflammation, but lactate itself does not appear to explain pyruvate's anti-inflammatory properties.     

Sleep deprivation attenuates experimental stroke severity in rats

Indirect epidemiological and experimental evidence suggest that the severity of injury during stroke is influenced by prior sleep history. The aim of our study was to test the effect of acute sleep deprivation on early outcome following experimental stroke. Young male Sprague-Dawley rats (n = 20) were subjected to focal cerebral ischemia by reversible right middle cerebral artery occlusion (MCAO) for 90 min. In 10 rats, MCAO was performed just after 6-h of total sleep deprivation (TSD) by “gentle handling”, whereas the other rats served as controls. Neurological function during the first week after stroke was monitored using a battery of behavioral tests investigating the asymmetry of sensorimotor deficit (tape removal test and cylinder test), bilateral sensorimotor coordination (rotor-rod and Inclined plane) and memory (T-maze and radial maze). Following MCAO, control rats had impaired behavioral performance in all tests. The largest impairment was noted in the tape test where the tape removal time from the left forelimb (contralateral to MCAO) was increased by ∼ 10 fold (p < 0.01). In contrast, rats subjected to TSD had complete recovery of sensorimotor performance consistent with a 2.5 fold smaller infarct volume and reduced morphological signs of neuronal injury at day 7 after MCAO. Our data suggest that brief TSD induces a neuroprotective response that limits the severity of a subsequent stroke, similar to rapid ischemic preconditioning.     

Olanzapine attenuates brain damage after focal cerebral ischemia in vivo

Atypical antipsychotic drugs are widely used in the treatment of schizophrenia. These agents are discovered to have some additional beneficial effects beyond their effectiveness as antipsychotic drugs. Among these initially unexpected effects are their potential effects as mood stabilizers in bipolar disorder and their efficacy in improving long-term outcome in schizophrenia. These effects recently raised the question whether these drugs may also have some neuroprotective effect in the brain. To examine this matter, in this study we evaluated the neuroprotective effect of olanzapine after permanent focal cerebral ischemia. Anaesthetized male C57BL/6j mice were submitted to permanent thread occlusion of the middle cerebral artery (MCA). Olanzapine (0.1 and 1 mg/kg) or vehicle was applied intraperitoneally just after permanent ischemia. Twenty-four hours after permanent ischemia, brain injury was evaluated by triphenyltetrazolium chloride staining (TTC). Olanzapine (0.1 and 1 mg/kg) showed significant neuroprotection after permanent focal cerebral ischemia.     

Risperidone attenuates brain damage after focal cerebral ischemia in vivo

Since their introduction, atypical neuroleptic agents have been discovered to have some beneficial effects beyond their effectiveness as neuroleptic drugs. Among these initially unexpected effects are their potential effects as mood stabilizers in bipolar disorder and their efficacy in improving long-term outcome in schizophrenia. These effects recently raised the question whether these drugs may also have some neuroprotective effect in the brain. To examine this matter, in this study we evaluated the neuroprotective effect of risperidone after permanent focal cerebral ischemia. Anaesthetized male C57BL/6j mice were submitted to permanent thread occlusion of the middle cerebral artery (MCA). Risperidone (0.1, 1 or 10 mg/kg) or vehicle was applied intraperitoneally just after permanent ischemia. Twenty-four hours after permanent ischemia, brain injury was evaluated by triphenyltetrazolium chloride staining (TTC). Risperidone (0.1, 1 and 10 mg/kg) showed significant neuroprotection after permanent focal cerebral ischemia.     

The expression and role of Fas ligand in intestinal inflammation

Fas ligand (FasL) is involved in the pathogenesis of inflammatory diseases and immune privilege. We examined the expression of FasL in the enteric nervous system (ENS) in murine colitis and guinea-pig ileitis. We studied FasL immunoreactivity, functional integrity of the ENS, severity of colitis, and distribution of neutrophils in wild type and B6/gld mice that lack functional FasL. In ileitis, the distribution of FasL, CD4+ and CD8+ T cells was examined. FasL expression was increased in the ENS of wild type mice with colitis, but decreased labelling of nerve fibres was noted in B6/gld mice. Neutrophils were more abundant and widely distributed in B6/gld mice. Colitis was more severe and persistent in B6/gld mice 7 days after induction. Functional parameters of intestinal secretion and motility in B6/gld mice were the same as controls. In ileitis, FasL expression was increased in the guinea-pig ENS and returned to control levels following the resolution of inflammation. While T cells were not present in the ENS of controls, they were observed during inflammation, but were excluded from ganglia. The number of enteric neurons was unchanged over the course of inflammation. The expression of FasL is altered in intestinal inflammation and contributes to its resolution in experimental colitis.     

Fas ligand/Fas system in the brain: regulator of immune and apoptotic responses

Apoptosis, also known as programmed cell death, is the major type of cell death involved in normal development, regeneration, proliferation and pathologic degeneration in the central nervous system (CNS). The apoptotic process can be divided further into two pathways depending on the involvement of mitochondria and related biochemical cascades. The internal pathway of apoptosis is initiated by a variety of cytotoxic stimuli and mediated by the release of cytochrome c and subsequent activation of downstream caspases. The external pathway is mainly triggered by ligation of death receptors such as Fas, tumor necrosis factor (TNF)-related apoptosis inducing ligand-R1 (TRAIL-R1), TRAIL-R2 and TNFRp55, and mediated by direct activation of upstream caspases. The Fas–FasL system has been known as a prototypic inducer of extrinsic cell death responsible for cell-mediated cytotoxicity, peripheral immune regulation, immune privilege and “counterattack” of malignant tumor cells against the host immune system. Fas and FasL are expressed in the normal CNS, and expression increases in inflamed and degenerated brains. Like other specialized tissues such as the eye and testis, the Fas–FasL system is thought to be involved in immune suppressed status in the CNS. Expression of Fas and FasL is significantly elevated in a variety of the neurologic disorders, suggesting the possibility that this system may play roles in degenerative and inflammatory responses in the CNS. Therefore, the FasL–Fas system should be considered as a double-edged sword in the CNS: maintaining the immune suppressed status in normal brain and inducing neuronal cell death and inflammation in a variety of neurologic disorders.     

Salvianolic acid B attenuates brain damage and inflammation after traumatic brain injury in mice

Salvianolic acid B (SalB), a bioactive compound isolated from the Chinese medicinal herb Danshen, has been shown to exert various anti-oxidative and anti-inflammatory activities in in vitro and in vivo studies. Here, we investigated the protective effects of SalB on traumatic brain injury (TBI) in mice. When administered within 2 h after TBI onset, SalB (25 mg/kg) reduced brain edema, lesion volume and motor functional deficits, and improved spatial learning and memory abilities. Moreover, SalB treatment inhibited the neutrophil infiltration and microglial activation at 48 h after TBI. Enzyme-linked immunosorbent assay (ELISA) for brain tissue homogenates was performed at 24 h after TBI to evaluate the expression of inflammation-related cytokines. The results showed that SalB suppressed the expression of pro-inflammatory cytokines TNF-α and IL-1β, whereas enhanced the expression of anti-inflammatory cytokines IL-10 and TGF-β1. All of these findings extended the protective role of SalB in the model of TBI and suggested that these protective effects might be associated with its anti-inflammatory activities. Thus SalB may have therapeutic potential for patients with TBI and perhaps other forms of acute brain injury.     

Association between inflammation and hemostatic markers in atherothrombotic stroke

INTRODUCTION: It has been reported that the influence of fibrinogen on the incidence of ischemic events is related to inflammation processes and reflects an association with advance atherosclerosis. The aim of this study was to evaluate the association of thrombogenic and inflammatory profiles in patients who have suffered a stroke. MATERIALS AND METHODS: The study involved 17 patients with atherothrombotic stroke and 34 healthy subjects as control group. The patients were examined 48 h, 3 and 6 months after the stroke occurred. To determine the inflammatory and thrombogenic profiles, plasma levels of fibrinogen, total sialic acid (TSA), C-reactive protein (CRP), tissue factor (TF) and fibrin D-dimer (D-dimer) were measured. RESULTS: The study showed that at 48 h and 3 months the levels of fibrinogen, TF, D-dimer, TSA and CRP were significantly higher than control group. TF, D-dimer and TSA remains significantly elevated throughout the entire study period. TF and D-dimer decreased over time without reaching the normal values. The multiple regression analysis showed that, at 48 h, 68% of the variance of fibrinogen and 22% of the variance of TF could be explained by the influence of CRP. At 3 and 6 months, 78% of the variance of fibrinogen could be explained by the influence of TSA. CONCLUSIONS: The results suggest a relation among inflammation markers, fibrinogen and TF in the acute phase of stroke. As TF and D-dimer are still elevated at 6 months, an increased thrombogenicity for a longer period following the acute event is present.     

APOE epsilon3 gene transfer attenuates brain damage after experimental stroke.

Apolipoprotein E (apoE, protein; APOE, gene) is the major lipid-transport protein in the brain and plays an important role in modulating the outcome and regenerative processes after acute brain injury. The aim of the present study was to determine if gene transfer of the epsilon3 form of APOE improves outcome in a murine model of transient focal cerebral ischaemia. Mice received an intrastriatal injection of vehicle, a second-generation adenoviral vector containing the green fluorescent protein gene (Ad-GFP) or a vector containing the APOE epsilon3 gene (Ad-APOE) 3 days before 60 mins focal ischaemia. Green fluorescent protein expression was observed in cells throughout the striatum and subcortical white matter indicating successful gene transfer and expression. ApoE levels in the brain were significantly increased after Ad-APOE compared with Ad-GFP or vehicle treatment. Ad-APOE treatment reduced the volume of ischaemic damage by 50% compared with Ad-GFP or vehicle treatment (13+/-3 versus 29+/-4 versus 27+/-5 mm(3)). The extent of postischaemic apoE immunoreactivity was enhanced in Ad-APOE compared with Ad-GFP or vehicle treated mice. These results show the ability of APOE gene transfer to markedly improve outcome after cerebral ischaemia and suggest that modulating apoE levels may be a potential strategy in human stroke therapy.     

Expression of Fas and Fas ligand after experimental traumatic brain injury in the rat.

Apoptotic cell death plays an important role in the cascade of neuronal degeneration after traumatic brain injury (TBI), but the underlying mechanisms are not fully understood. However, increasing evidence suggests that expression of Fas and its ligand (FasL) could play a major role in mediating apoptotic cell death in acute and chronic neurologic disorders. To further investigate the temporal pattern of Fas and FasL expression after experimental TBI in the rat, male Sprague Dawley rats were subjected to unilateral cortical impact injury. The animals were killed and examined for Fas and FasL protein expression and for immunohistologic analysis at intervals from 15 minutes to 14 days after injury. Increased Fas and FasL immunoreactivity was seen in the cortex ipsilateral to the injury site from 15 minutes to 72 hours after the trauma, respectively. Immunohistologic investigation demonstrated a differential pattern of Fas and FasL expression in the cortex, respectively: increased Fas immunoreactivity was seen in cortical astrocytes and neurons from 15 minutes to 72 hours after the injury. In contrast, increased expression of FasL was seen in cortical neurons, astrocytes, and microglia from 15 minutes to 72 hours after impact injury. Concurrent double-labeling examinations using terminal deoxynucleotidyl transferase-mediated deoxyuridine-biotin nick end labeling identified Fas- and FasL-immunopositive cells with high frequency in the cortex ipsilateral to the injury site. In contrast, there was no evidence of Fas- and FasL-immunopositive cells in the hippocampus ipsilateral to the injury site up to 14 days after the trauma. Further, Fas and FasL immunoreactivity was absent in the contralateral cortex and hippocampus at all time points investigated. These results reveal induction of Fas and FasL expression in the cortex after TBI in the rat. Further, these data implicate an involvement of Fas and FasL in the pathophysiologic mechanism of apoptotic neurodegeneration after TBI. Last, these data suggest that strategies aimed to repress posttraumatic Fas- and FasL-induced apoptosis may open new perspectives for the treatment of TBI.     

Brain inflammation is induced by co-morbidities and risk factors for stroke

Chronic systemic inflammatory conditions, such as atherosclerosis, diabetes and obesity are associated with increased risk of stroke, which suggests that systemic inflammation may contribute to the development of stroke in humans. The hypothesis that systemic inflammation may induce brain pathology can be tested in animals, and this was the key objective of the present study. First, we assessed inflammatory changes in the brain in rodent models of chronic, systemic inflammation. PET imaging revealed increased microglia activation in the brain of JCR-LA (corpulent) rats, which develop atherosclerosis and obesity, compared to the control lean strain. Immunostaining against Iba1 confirmed reactive microgliosis in these animals. An atherogenic diet in apolipoprotein E knock-out (ApoE^−/−) mice induced microglial activation in the brain parenchyma within 8 weeks and increased expression of vascular adhesion molecules. Focal lipid deposition and neuroinflammation in periventricular and cortical areas and profound recruitment of activated myeloid phagocytes, T cells and granulocytes into the choroid plexus were also observed. In a small, preliminary study, patients at risk of stroke (multiple risk factors for stroke, with chronically elevated C-reactive protein, but negative MRI for brain pathology) exhibited increased inflammation in the brain, as indicated by PET imaging. These findings show that brain inflammation occurs in animals, and tentatively in humans, harbouring risk factors for stroke associated with elevated systemic inflammation. Thus a “primed” inflammatory environment in the brain may exist in individuals at risk of stroke and this can be adequately recapitulated in appropriate co-morbid animal models.     

亚低温对大鼠脑缺血再灌注后炎症反应的作用研究

目的探讨亚低温对大鼠脑缺血再灌注后炎症反应的保护作用。方法雄性SD大鼠，线栓法建立脑缺血再灌注模型，随机分组．选择性头颅降温。结果(1)TNF—α、IL-1β、ICAM-1：缺血2h表达量即有不同程度增多，6～12h达高峰，再灌注组较持续缺血组增多更明显．降温组则明显减少；(2)多形核白细胞：缺血2h缺血区血管周围即可见白细胞浸润，6～12h后数量明显增加．再灌注组较持续缺血组多，降温组则明显减少；(3)脑梗死体积：降温持续缺血组和降温再灌注组的梗死体积均较相应常温组小．其中降温再灌注组的梗死体积更小，尤以降温再灌注12h组的梗死体积最小。结论本实验证实了大鼠脑缺血-再灌注后急性炎症反应的存在，亚低温对这种炎症级联反应的抑制可能是其发挥脑保护作用的重要机制之一。     

Fas and Fas ligand are associated with neuritic degeneration in the AD brain and participate in beta-amyloid-induced neuronal death

It has recently been suggested that neuronal cell death in response to many brain insults may be mediated by the upregulation of tumor necrosis factor receptor (TNFR) family members and their ligands. In the present study, we investigated whether the expression of the TNFR family death domain receptor, Fas, and its ligand, FasL, is altered in association with neuropathology and activated caspase markers in Alzheimer disease (AD) brain, and Abeta-induced neuronal cell death in vitro. To evaluate this hypothesis, we examined Fas and FasL expression in AD and control brain, and Abeta-treated primary neurons, using immunocytochemistry and Western blots. Neurons in both AD brain and Abeta-treated cultures exhibited FasL upregulation and changes in immunoreactivity for Fas receptor. Further, FasL expression was remarkably elevated in senile plaques and neurofilament-positive dystrophic neurites, and in association with caspase activation and neuritic apoptosis in AD brain. Based on these and previous data regarding protection of primary neuronal cultures from Abeta(1-42)-induced apoptosis by blockade of Fas-associated death domain signaling, we also tested the hypothesis that dynamic regulation of Fas and FasL may contribute to Abeta-mediated neuronal cell death. Accordingly, neuronal cultures derived from mice carrying inactivating mutations in Fas (Faslpr) or FasL (Fasgld) exhibited protection from Abeta(1-42)-induced cell death. These findings suggest that Fas-FasL interactions may contribute to mechanisms of neuronal loss and neuritic degeneration in AD.     

Estrogen inhibits Fas-mediated apoptosis in experimental stroke

Estrogen is protective in experimental cerebral ischemia, yet the mechanism remains unclear. Fas-mediated apoptosis has been shown to be induced after cerebral ischemia and significantly contribute to ischemic brain damage. In this study, we tested if estrogen is protective against cerebral ischemia by suppressing Fas-mediated apoptosis. 17β-estradiol-treated and untreated ovariectomized (OVX) female mice were subjected to 2 h middle cerebral artery occlusion (MCAO). Expression of Fas and Fas-associated death domain (FADD) were measured at 3, 6 and 12 h of reperfusion by RT-PCR and Western blot, respectively. Post-ischemic activities of caspase-8 and -3 activities, the two downstream effectors of Fas-induced apoptosis, were also assayed at same time points by ELISA. Finally, Fas antibody-induced cell death in primary cortical neurons was assayed by fluorescence activated cell sorter (FACS) in the presence and absence of estradiol. Our data showed that estradiol-treated OVX female mice sustained smaller infarct compared to untreated OVX mice. Ischemia upregulated Fas and FADD expression, and increased caspase-8 and -3 activities in OVX female mouse cortex, which were significantly attenuated by estradiol. Estradiol also significantly inhibited Fas antibody-induced neuronal cell apoptosis. Our data suggests that inhibition of ischemia-induced Fas-mediated apoptosis is an important mechanism of neuroprotection by estrogen in cerebral ischemia.     

Oxygen therapy in permanent brain ischemia: potential and limitations

BACKGROUND: Both normobaric (NBO) and hyperbaric (HBO) oxygen therapy are protective in transient cerebral ischemia. In contrast, in permanent ischemia models, which reflect the majority of clinical strokes, the effectiveness of NBO is unknown, and the effectiveness of HBO is controversial. The goals of the present study were to compare both oxygen therapies in 2 models of permanent ischemia, to study the effect of time window, and to evaluate the combination of both oxygen therapies. METHODS: Distal or proximal permanent occlusion of middle cerebral artery (MCAO) was induced by coagulation or filament, respectively. Mice received air, NBO, a single or repeated HBO (3 ata) treatments. Infarct sizes were quantified at 7 days (coagulation) and 24 h (filament), respectively. RESULTS: Following MCA coagulation, infarct volume was 12.9+/-1.6 mm3 in mice breathing air. When started 45 min or 120 min after MCAO, NBO (10.8+/-2.2) and significantly more potently HBO (7.8+/-0.9) reduced infarct size. Repeated HBO treatments had no additional effect (8.3+/-2.3). HBO also significantly decreased TUNEL cell staining at 24 h. Combination of 60 min NBO plus 60 min HBO resulted in smaller cortical infarcts (8.7+/-1.5) than 120 min NBO alone (11.1+/-3.2). In contrast, infarct volumes in filament-induced permanent MCAO did not differ among rodents receiving air (50+/-24 mm3), NBO (48+/-16), or HBO (46+/-21). After filament-induced transient MCAO, however, HBO reduced infarct volume significantly. CONCLUSIONS: NBO and more effectively HBO protect the brain against permanent cortical ischemia. In extensive focal ischemia, however, oxygen therapy is only effective in case of early recanalization.     

Markers of inflammation in cerebral ischemia

Abstract. The study sought to determine whether cerebral ischemia is associated with inflammatory reactions indicated by an increase in levels of selected acute phase proteins (APP), C-reactive protein (CRP), fibrinogen, -1 antitrypsin (AAT) and acidic -1 glycoprotein (AGP). These proteins are thought to be markers of inflammatory reactions. We investigated 30 patients with acute cerebrovascular ischemia, 20 patients with transient ischemic attack, and 20 patients from a control group. Levels of CRP, AAT, AGP, and fibrinogen in blood sera were determined in all patients by kinetic turbidimetry. In the patients with cerebral infarct an increase was found in the levels of APP, which suggests that ischemic necrosis is associated with inflammatory reactions. All patients require active treatment of an inflammatory process that is associated with stroke.     

Reperfusion following focal stroke hastens inflammation and resolution of ischemic injured tissue

Previously, we described cellular changes following Permanent Middle Cerebral Artery Occlusion (PMCAO) in spontaneously hypertensive rats. Ischemic changes following PMCAO included a time-related focal pan necrosis, inflammatory cell infiltration, gliosis, and eventual loss of necrotic tissue postPMCAO. We have now characterized changes which occur after Temporary Middle Cerebral Artery Occlusion (TMCAO; 80 or 160 min) followed by reperfusion and compared these changes to those which occur following PMCAO. TMCAO with reperfusion results in cortical infarcts which vary in size in an occlusion-time-dependent manner. After 1 h of reperfusion, ischemic changes were observed histologically, including microhemorrhages and the beginning of a slight inflammatory infiltration in and around the meningeal vasculature. This infiltrate consisted primarily of neutrophils, which by 6 h of reperfusion was significant with infiltration from deep blood vessels into brain tissue, including the presence of some monocytes adhering within blood vessels. Neutrophil infiltration occurred sooner and to a greater extent in reperfused tissues than in permanently occluded tissues, where it only began at 12 h postPMCAO. As occurred following PMCAO, increased Glial Fibrillary Acidic Protein (GFAP) immunoreactivity indicating astrogliosis was first observed at 12 h postTMCAO. Over 1–3 days of reperfusion, a heavy macrophage infiltrate was observed in the reperfused tissues in addition to a continued influx of neutrophils. Following 5 days of reperfusion, the lesion was completely replaced with inflammatory cells, of which macrophages predominated. Unlike PMCAO, which resulted in focal spots of neutrophil accumulation, neutrophils were more distributed throughout the infarcted cortex following TMCAO. Another apparent difference was in the great number of fibroblast-like cells seen in the fibrous connective tissue, especially adjacent to the meninges, following TMCAO. Finally, by 15 days after TMCAO few scattered macrophages were present within a loose fibrous connective tissue matrix that was once the lesion. This matrix continued to contain an abundance of fibroblasts and astroglia. In contrast, at this time after PMCAO, macrophages were observed within a diminished infarct area. The data indicate that reperfusion following focal ischemia alters the timing and extent of the inflammatory response that leads to resolution of the necrotic tissue.     

Normobaric hyperoxia retards the evolution of ischemic brain tissue toward infarction in a rat model of transient focal cerebral ischemia

Objectives: Oxygen therapy has been long considered a logical therapy for ischemic stroke. Our previous studies showed that normobaric hyperoxia (normobaric hyperoxia (NBO), 95% O₂ with 5% CO₂) treatment during ischemia reduced ischemic neuronal death and cerebromicrovascular injury in animal stroke models. In this study, we studied the effects of NBO on the evolution of ischemic brain tissue to infarction in a rat model of transient focal cerebral ischemia.

Methods: Male Sprague-Dawley rats were given NBO (95% O₂) or normoxia (21% O₂) during 90-min filament occlusion of the middle cerebral artery (MCAO), followed by 3 or 22.5 h of reperfusion. 2,3,5-triphenyltetrazolium chloride (TTC) staining was used to evaluate the longitudinal evolution of tissue infarction.

Results： In normoxic rats, MCA-supplied cortical and striatal tissue was infarcted after 90-min MCAO with 22.5 h of reperfusion. NBO-treated rats showed a 61.4% reduction in infarct size and tissue infarction mainly occurred in the ischemic striatum. When infarction was assessed at an earlier time point, i.e. at 3 h of reperfusion, normoxic rats showed significantly smaller but mature infarction (no TTC staining, white color), with the infarction mainly occurring in the striatum. Unexpectedly, NBO-treated rats only showed immature lesion (partially stained by TTC, light white color) in the ischemic striatum, indicating that NBO treatment also retarded the process of neuronal death in the ischemic core. Of note, NBO-preserved striatal tissue underwent infarction after prolonged reperfusion.

Conclusions： Our results demonstrate that NBO treatment given during cerebral ischemia retards the evolution of ischemic brain tissue toward infarction and NBO-preserved cortical tissue survives better than NBO-preserved striatal tissue during the phase of reperfusion.     

The impact of inflammation on the pathogenesis and prognosis of ischemic stroke

The inflammation plays a critical role in the stroke onset and even in the worsening of the lesions. Therefore, the investigation of inflammatory response in the acute stage may contribute to improve the treatment of ischemic stroke. High-sensitive CRP (hsCRP), IL-6 and TNFalpha were measured as inflammatory markers on admission and in the 28th day after the onset. Oxidized LDL was measured simultaneously, since it can be a marker of reactive oxygen species which reflect the activity of inflammation. Ischemic stroke patients within 24 h after the onset (n=105) were included in this study. All patients were classified into cardioembolism, large-artery atherosclerosis, lacunar infarction, branch atheromatous disease and arterial dissection groups based on the findings of MRI and MRA and clinical records. Oxidized LDL was significantly increased in the acute phase of all cases. The amplified level of IL-6 was related to the worse outcome. The increase of TNFalpha in lacunar infarction was statistically correlated to the neurological severity on admission. In conclusion, IL-6 may predict not only the severity of the stroke lesions but also the outcome of patients. TNFalpha may suggest the small arterial lesions.     

Neuroprotective effect of high-dose albumin therapy against global ischemic brain injury in rats

The purpose of this study was to determine whether treatment with high-dose human serum albumin (HSA) would offer protection in a model of high-grade transient forebrain ischemia. Twenty-six fasted Wistar rats underwent bilateral common carotid artery occlusion and severe hypotension (50 mmHg) for 10 min. The agent (25% HSA) or vehicle (0.9% NaCl) was administered i.v. 5 min after termination of ischemia. HSA-treated rats showed significantly improved neurological deficits throughout a 7-day survival period. Histologically, HSA-treated rats showed 2.4- to 5.3-fold increases in numbers of surviving CA1 hippocampal pyramidal neurons compared to saline-treated animals. These results document that high-dose albumin therapy instituted 5 min after global ischemia significantly improves neurological score and reduces histological damage.