As ischemic stroke is associated with an excessive release of glutamate into the neuronal extracellular space, a decrease in blood glutamate levels could provide a mechanism to remove it from the brain tissue, by increasing the brain-blood gradient. In this regard, the ability of glutamate oxaloacetate transaminase (GOT) to metabolize glutamate in blood could represent a potential neuroprotective tool for ischemic stroke. This study aimed to determine the neuroprotective effects of GOT in an animal model of cerebral ischemia by means of a middle cerebral arterial occlusion (MCAO) following the Stroke Therapy Academic Industry Roundtable (STAIR) group guidelines. In this animal model, oxaloacetate-mediated GOT activation inhibited the increase of blood and cerebral glutamate after MCAO. This effect is reflected in a reduction of infarct size, smaller edema volume, and lower sensorimotor deficits with respect to controls. Magnetic resonance spectroscopy confirmed that the increase of glutamate levels in the brain parenchyma after MCAO is inhibited after oxaloacetate-mediated GOT activation. These findings show the capacity of the GOT to remove glutamate from the brain by means of blood glutamate degradation, and suggest the applicability of this enzyme as an efficient and novel neuroprotective tool against ischemic stroke.

In experimental models, growth factors (GFs) such as vascular endothelial growth factor (VEGF), Angiopoietin 1 (Ang-1), or granulocyte-colony stimulating factor (G-CSF) mediate brain recovery after intracerebral hemorrhage (ICH). Our aim was to study the association between serum levels of GF and clinical outcome in patients with ICH. A total of 95 patients with primary ICH (male, 66.3%; mean age, 67.8 ± 9.8 years) were prospectively included in the study within 12 h from symptoms onset. The main outcome variable was good functional outcome at 3 months (modified Rankin scale p2). Median serum levels of GF at 72 h from stroke onset were significantly higher in patients with good outcome (n = 39) compared with those with poor outcome (all P < 0.0001). Serum levels of VEGF X330 pg/mL, G-CSF X413 pg/mL, and Ang-1 X35 ng/mL at 72 h were independently associated with good functional outcome (odds ratio (OR), 11.2; 95% confidence interval (CI): 2.9 to 43.0; OR, 19.6; 95% CI: 3.9 to 97.9; and OR, 14.7; 95% CI: 3.6 to 60.0, respectively), neurologic improvement (all P < 0.0001) and reduced residual cavity at 3 months (all P < 0.01). These results illustrate that high serum levels of GF are associated with good functional outcome and reduced lesion volume in ICH.

Oxygen therapy is currently used as a supportive treatment in septic patients to improve tissue oxygenation. However, oxygen can exert deleterious effects on the inflammatory response triggered by infection. We postulated that the use of high oxygen concentrations may be partially responsible for the worsening of sepsis-induced multiple system organ dysfunction in an experimental clinically relevant model of sepsis. We used Sprague-Dawley rats. Sepsis was induced by cecal ligation and puncture. Sham-septic controls (n = 16) and septic animals (n = 32) were randomly assigned to four groups and placed in a sealed Plexiglas cage continuously flushed for 24 h with medical air (group 1), 40% oxygen (group 2), 60% oxygen (group 3), or 100% oxygen (group 4). We examined the effects of these oxygen concentrations on the spread of infection in blood, urine, peritoneal fluid, bronchoalveolar lavage, and meninges; serum levels of inflammatory biomarkers and reactive oxygen species production; and hematological parameters in all experimental groups. In cecal ligation and puncture animals, the use of higher oxygen concentrations was associated with a greater number of infected biological samples (P < 0.0001), higher serum levels of interleukin-6 (P < 0.0001), interleukin-10 (P = 0.033), and tumor necrosis factor-α (P = 0.034), a marked decrease in platelet counts (P < 0.001), and a marked elevation of reactive oxygen species serum levels (P = 0.0006) after 24 h of oxygen exposure. Oxygen therapy greatly influences the progression and clinical manifestation of multiple system organ dysfunction in experimental sepsis. If these results are extrapolated to humans, they suggest that oxygen therapy should be carefully managed in septic patients to minimize its deleterious effects.

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Background: Neuron-specific enolase (NSE) and S100 protein are implicated in several brain injuries, including stroke. Our objective was to analyze the temporal profile and the clinical significance of NSE and S-100 in acute ischemic (IS) and intracerebral hemorrhage (ICH). Methods: We studied 224 patients with IS and 44 patients with ICH. Computerized tomography (CT) scans were performed to assess infarct volume. Stroke severity was evaluated using the National Institute of Health Stroke Scale (NIHSS), and functional outcome at 3 months with the modified Rankin Scale (mRS). Serum NSE and S100 protein were measured using an electrochemiluminescenceimmunoassay. Results: Peak values were found at 72 h for NSE and at 24 h for S100 in IS. For ICH, peak values were found at 24 h for both NSE and S100. At these time intervals S100 and NSE correlated with the NIHSS score and were independently associated with poor outcome. Conclusions: High serum NSE and S100 are associated with poor outcome in IS, and high serum NSE is associated with poor outcome in ICH. These findings suggest the potential utility of NSE and S100 as prognostic markers for acute stroke. Clin Chem Lab Med 2009;47:1513-8.

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Background and Purpose-The underlying mechanisms of small vessel disease (SVD) subtypes are diffuse arteriopathy (diffuse-SVD) or microatheroma (focal-SVD). Endothelial dysfunction by ␤-amyloid peptide (A␤) deposition has been associated with lacunar infarcts and leukoaraiosis, but its specific relationship with SVD subtypes is unknown. We hypothesized that plasma A␤ levels can play a different role in SVD subtypes in patients with acute lacunar stroke. Methods-We studied 149 patients with acute ischemic stroke of SVD etiology according to Trial Of Org 10172 In Acute Stroke Treatment criteria and 25 age-matched control subjects. Patients were classified into focal-SVD: 39 patients with isolated lacunar infarct without leukoaraiosis and diffuse-SVD: 110 patients with an isolated lacunar infarct with leukoaraiosis or with multiple lacunar infarcts with or without leukoaraiosis. Baseline data included vascular risk factors and extensive laboratory tests, including plasma A␤ levels. Results-Median[quartiles] A␤ 1-40 levels (40.4 [35.1, 50.5] versus 55.1 [42.3, 69.6] pg/mL), but not A␤ 1-42 levels, were significantly higher in the diffuse-SVD group than in focal-SVD group (PϽ0.001) and control subjects (PϽ0.001). No differences in A␤ 1-40 levels were found between focal-SVD and control subjects. Logistic regression analysis showed that age (OR, 1.06; 95% CI, 1.01 to 1.12), history of hypertension (OR, 3.5; 95% CI, 1.3 to 9.2), and plasma ␤-amyloid 1-40 levels over the median value (OR, 17.3; 95% CI, 3.0 to 99 for the third quartile and OR, 6.0; 95% CI, 1.6 to 23 for the fourth quartile) were independently associated with the diffuse-SVD subtype. Key Words: acute stroke Ⅲ beta-amyloid protein Ⅲ leukoaraiosis Ⅲ small vessel disease T he pathogenesis of cerebral small vessel disease (SVD) is incompletely understood. Pathological studies have suggested that there may be 2 types of SVD that can be differentiated on brain imaging. 1 A diffuse arteriopathy of the perforating arteries with hyaline deposition: a pattern referred to as lipohyalinosis (diffuse-SVD) and localized small vessel microatheroma at the origin of the deep perforating arteries (focal-SVD). Diffuse-SVD is associated with multiple small lacunar infarcts with leukoaraiosis and focal-SVD with single large lacunar infarcts without leukoaraiosis. 2,3 Endothelial dysfunction may play an important role in the pathogenesis of the diffuse-SVD subtype. 4 -6 Plasma ␤-amyloid peptide (A␤) is a peptide consisting of either 42 (A␤ 1-42 ) or 40 (A␤ 1-40 ) amino acids derived from a proteolytic processing of the amyloid precursor protein. 7 Insoluble A␤ fibrils are the predominant constituents of senile plaques, one of the pathological hallmarks of Alzheimer disease, 8,9 and of cerebrovascular amyloid in the related condition of cerebral amyloid angiopathy. 10 Plaque amyloid is primarily comprised of A␤ 1-42 , whereas vascular amyloid is formed by the A␤ 1-40 species. Recent evidence suggests that amyloid precursor protein overexpression and A␤ accumulation impair cer...

BackgroundSevoflurane is an anesthetic agent which also participates in protective mechanisms in sepsis, likely due to anti-inflammatory properties. A key tissue in sepsis is the endothelium, which expresses TLR2 and TLR4 receptors, known regulators of inflammatory mechanisms and potential therapeutic targets for this pathology. In this context, we explored the effect of sevoflurane postconditioning in an in vitro sepsis model.MethodsPrimary cultures of human umbilical vein endothelial cells were used for two different experiments. In the first set, cultures were placed in an airtight incubation chamber and exposed to different concentrations of sevoflurane (0,1,3 or 7% vol,) for 1 hour. In the second set, lipopolysaccharide from Escherichia coli 0111:B4 (1 μg/mL) was added to culture medium for 3 hours and cells were subsequently exposed to sevoflurane (0,1,3 or 7% vol,) for 1 hour as explained before. In both cases, cell viability was measured by MTT and Trypan blue assays, TLR2 and TLR4 expression were analyzed by flow cytometry, and TNFα and IL-6 levels were quantified in cell culture media by an immunoassay immediately after exposure, at 6 and 24 hours.ResultsExposure to 3% sevoflurane decreased TLR2 at 24 hours and TLR4 at 6 and 24 hours (both p<0.05), whereas exposure to 7% decreased TLR4 expression at 6 hours (p<0.05). Both 3 and 7% sevoflurane decreased TNF-α and IL-6 levels at 24 hours (both p<0.05). In LPS-stimulated cultures, exposure to 3% sevoflurane was cytoprotective at 6 and 24 hours (p<0.05) compared with control, and decreased TLR2 and TLR4 expression at 24 hours (p<0.05); whereas 7% decreased TLR4 expression at 24 hours (p<0.05). Both 3% and 7% sevoflurane decreased TNF-α and IL-6 levels at 24 hours (both p<0.05).ConclusionsPostconditioning with the halogenated anesthetic agent sevoflurane after LPS stimulation shows a cytoprotective effect in an in vitro model, decreasing cell death and reducing TLR2 and TLR4 expression as well as levels of the inflammatory mediators TNF-α and IL-6 in human endothelial cells.