246 Scientific Programme 22. European Stroke Conference © 2013 S. Karger AG, Basel 1 Experimental studies Endothelial NOX4 is a key mediator of oxidative stress and neurodegeneration after focal ce-rebral ischemia in mice E. Göb1, F. Langhauser2, K.A. Radermacher3, H. van Essen4, J. Debets5, P. Lijnen6, H.H.H.W. Schmidt7, C. Kleinschnitz8 University of Würzburg, Würzburg, GERMANY1, University of Würzburg, Würzburg, GERMA-NY2, Maastricht University, Maastricht, THE NETHERLANDS3, Maastricht University, Maastricht, THE NETHERLANDS4, Maastricht University, Maastricht, THE NETHERLANDS5, Maastricht University, Maastricht, THE NETHERLANDS6, Maastricht University, Maastricht, THE NETHER-LANDS7, University of Würzburg, Würzburg, GERMANY8 Background: Reactive oxygen species (ROS) critically contribute to neuronal cell damage after stroke but strategies to scavenge ROS in the ischemic brain have largely failed. The enzyme family of NADPH oxidases (NOX) is a major source of ROS in different tissues including the CNS. By using a constitutive knockout model we could recently show that inhibition of NOX4 prevents oxi-dative stress and neurodegeneration after middle cerebral artery occlusion (MCAO) in mice but the main cellular source of NOX4 remained unclear (Kleinschnitz et al., PLoS Biol, 2010). The present study aimed to uncover the functional impact of cell specific NOX4 ROS production in stroke by using NOX4 conditional knockout mice. Methods: Endothelium specific NOX4 deficient mice were generated by crossbreeding of mice con-taining a floxed NOX4 allel with Tie2-Cre transgenic mice. NOX4FF/Tie2-Cre mice and control littermates were subjected to transient or permanent MCAO. 24 or 72 hours afterwards neurological deficits were assed and infarct volumes were quantified. Oxidative stress was visualized using dihy-droethidium (DHE) and blood-brain-barrier (BBB) stability was analysed by Evans blue extravasa-tion and tight junction protein expression. Results: Endothelial NOX4 deficiency significantly reduced stroke size and improved neurological outcome on day 1 after transient and permanent MCAO. This protective effect was also preserved at later stages of infarct development (day 3). Mechanistically, NOX4FF/Tie2-Cre mice developed significantly less brain edema and the integrity of the BBB was maintained compared to control lit-termates. Markers of oxidative stress were significantly lower in the absence of endothelial NOX4. Conclusion: We here identify endothelial NOX4 as major source of oxidative stress in the ischemic brain. Specific inhibition of NOX4 rather than scavenging of ROS could become a novel strategy for stroke therapy. 15 Small vessel stroke and white matter disease White matter lesion burden in migraine with aura is associated with reduced cerebral blood flow B. Cucchiara1, Q. Zhang2, R. Datta3, S.E. Kasner4, G.K. Aguirre5, J.A. Detre6 University of Pennsylvania, Philadelphia, USA1, Tianjin Medical University, Tianjin, CHINA2, University of Pennsylvania, Philadelphia, USA3, University of Pennsylvania, Philadelphia, USA4, University of Pennsylvania, Philadelphia, USA5, University of Pennsylvania, Philadelphia, USA6 Background: Prior studies have suggested an increased prevalence of white matter hyperintensities (WMH) on MRI in subjects with migraine. The mechanisms underlying this finding remain uncer-tain. Methods: We performed the Anatomy and Cerebral Hemodynamic Evaluation of Migraine (ACHE-M) study, a prospective, case-control study. Migraine with aura (MWA), migraine with-out aura (MwoA), and control subjects between the age of 25-50 were enrolled in a 1:1:1 ratio. 3T MRI (FLAIR/T2/MPRAGE) was performed to examine brain parenchyma and arterial spin labeled perfusion MRI to measure CBF. To facilitate comparison with prior studies, analysis of WMH was performed using methods similar to those in the Cerebral Abnormalities in Migraine Epidemiologic Risk Analysis study. In addition, the association between WMH and CBF was analyzed. Results: 170 subjects were included (54 control, 56 MWA, 60 MwoA). There was a non-signifi-cantly higher prevalence of WMH and higher WMH load in migraine compared to control subjects (Table). In multivariate analysis, age was significantly associated with high WMH load (OR 1.08 per year, 95% CI 1.2-1.15, p=0.006) with a trend for current smoking (OR 2.62 compared to never/ former smoker, 95% CI 0.78-8.9, p=0.12). Global CBF was significantly lower in men (p<0.001), those with a history of hypertension (p=0.014), and those with higher systolic (p=0.004) and diastol-ic blood pressure (p=0.003). In the control and MwoA groups, there was no difference in CBF be-tween those with high WMH load and those with low/no WMH load. In the MWA group, subjects with high WMH load had significantly reduced global CBF (45.5±9.2 vs. 52.9±11.2 ml/100g/min, p=0.049). This remained significant after adjustment for age, sex, history of hypertension, SBP, DBP and smoking status (p=0.03). Conclusions: WMH were non-significantly more common in subjects with migraine, and were associated with age. In MWA subjects, high WMH load was associated with reduced CBF. Table: Con-trol (n=54) MWA (n=56) MwoA (n=60) Migraine com-bined (n=116) p value MWA vs. con-trol p value MwoA vs. con-trol p value Migraine vs. control Subjects with ≥1 WMH 22% 29% 35% 32% 0.44 0.13 0.19 High WMH load 16.7% 21.4% 25.0% 23.3% 0.53 0.28 0.33 E-Poster Terminal 4
Karger_ESC London_2013
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