The complement cascade is a central component of innate immunity which plays a critical role in brain inflammation. Complement C3a receptor (C3aR) is a key mediator of post-ischemic cerebral injury, and pharmacological antagonism of the C3a receptor is neuroprotective in stroke. Cerebral ischemia injures brain endothelial cells, causing blood brain barrier (BBB) disruption which further exacerbates ischemic neuronal injury. In this study, we used an in vitro model of ischemia (oxygen glucose deprivation; OGD) to investigate the protective effect of a C3aR antagonist (C3aRA, SB290157) on brain endothelial cells (bEnd.3). Following 24 hours of reperfusion, OGD-induced cell death was assessed by TUNEL and Caspase-3 staining. Western blot and immunocytochemistry were utilized to demonstrate that OGD upregulates inflammatory, oxidative stress and antioxidant markers (ICAM-1, Cox-2, Nox-2 and MnSOD) in endothelial cells and that C3aRA treatment significantly attenuate these markers. We also found that C3aRA administration restored the expression level of the tight junction protein occludin in endothelial cells following OGD. Interestingly, OGD/reperfusion injury increased the phosphorylation of ERK1/2 and C3aR inhibition significantly reduced the activation of ERK suggesting that endothelial C3aR may act via ERK signaling. Furthermore, exogenous C3a administration stimulates these same inflammatory mechanisms both with and without OGD, and C3aRA suppresses these C3a-mediated responses, supporting an antagonist role for C3aRA. Based on these results, we conclude that C3aRA administration attenuates inflammation, oxidative stress, ERK activation, and protects brain endothelial cells following experimental brain ischemia.
Blood-Brain Barrier ; Blotting, Western ; Brain Ischemia ; Brain ; Caspase 3 ; Cell Death ; Complement C3a ; Complement System Proteins ; Encephalitis ; Endothelial Cells ; Glucose ; Immunity, Innate ; Immunohistochemistry ; In Situ Nick-End Labeling ; In Vitro Techniques ; Inflammation ; Ischemia ; Neurons ; Occludin ; Oxidative Stress ; Phosphorylation ; Reperfusion ; Stroke ; Tight Junctions

OBJECTIVETo assess the association of a disintegrin and metallo-proteinase with thrombospondin type 1 motifs (ADAMTS-1) gene polymorphism and ischemic stroke caused by large artery atherosclerosis (LAA).

METHODSIn total 767 patients and 506 controls were recruited. Single nucleotide polymorphisms (SNPs) rs416905 (T/C) and rs402007 (G/C) of the ADAMTS-1 gene were genotyped by polymerase chain reaction and DNA sequencing.

RESULTSFrequencies of the rs402007 GC+CC genotype and the C allele were significantly different between the two groups (68.84% vs. 60.67%, χ2=9.012, P=0.003, OR=1.432; 45.24% vs. 38.54%, χ2=11.208, P=0.001, OR=1.318). Binary logistic regression has confirmed that the above difference was significant (P=0.001, OR=1.521, 95%CI: 1.183-1.955). The frequencies of TC+CC and GC+CC genotypes were similar between the two groups, and so was it with the C allele. The two SNPs had been in complete linkage disequilibrium (D'=1.0, r2=1.0).

CONCLUSIONThe rs416905 and rs402007 polymorphisms of the ADAMTS-1 gene may be associated with ischemic stroke caused by LAA. The C allele of the rs402007 locus may be a susceptibility factor for this subtype of stroke.

ADAM Proteins ; genetics ; ADAMTS1 Protein ; Aged ; Alleles ; Atherosclerosis ; complications ; Base Sequence ; Blood Glucose ; metabolism ; Brain Ischemia ; complications ; Fasting ; blood ; Female ; Gene Frequency ; Genetic Predisposition to Disease ; genetics ; Genotype ; Humans ; Logistic Models ; Male ; Middle Aged ; Polymerase Chain Reaction ; Polymorphism, Single Nucleotide ; Risk Factors ; Sequence Analysis, DNA ; Smoking ; Stroke ; blood ; etiology ; genetics

BACKGROUND AND PURPOSE: Hemorrhagic transformation (HT) of a large infarct is a relatively common occurrence. However, its prevalence, predictive factors, as well as its clinical significance outside of thrombolysis trials remains obscure, especially in our local setting. Early studies on hemorrhagic transformation occurring in situ were limited by sample size and various methodological flaws. The aim of this study is to determine the risk factors for early (within 3-7 days) hemorrhagic transformation among these subsets of patients.

METHODS: This is a prospective cohort study among adult patients admitted at a tertiary medical center with a diagnosis of medium to large acute ischemic stroke.

RESULTS: Among the 60 patients included in this study (mean age: 57.87 15.86; 53.3% males), 8 (13.3%; mean age: 55.5 +/16.02; 50% males) developed hemorrhagic transformation. All HTs were parenchymal hematomas. Five (62.5%) were PH-1, 3 (37.5%) were PH-2. Inability to speak on presentation (p=0.044), mainstem MCA infarction (p
Human ; Male ; Adult (a Person 19-44 Years Of Age) ; Stroke ; Risk Factors ; Infarction, Middle Cerebral Artery ; Logistic Models ; Prevalence ; Blood Glucose ; Brain Ischemia ; Sample Size ; Prospective Studies ; Hematoma ; Neuroimaging ; Hemorrhage ; Edema

BACKGROUND: The intravenous thrombolysis is a well established treatment of acute ischemic stroke. However, baseline prognostic factors were poorly identified by previous studies. METHODS: From January 2001 to May 2006, prospective data of 121 patients treated with intravenous tissue plasminogen activator (tPA) were collected. The clinical, radiologic, transcranial Dopper (TCD) and laboratory finding were evaluated. Clinical assessment was done by National Institutes of Health Stroke Scale (NIHSS) for one week, and by modified Rankin Scale (mRS) at baseline for three months. Early improvement was defined as the complete resolution of the neurological deficit or an improvement of > or =4 points by NIHSS within 24 hours, and good outcome as mRS score of < or =2 at three months. We assessed the possible relationship of the factors with early improvement and good outcome, and also analyzed the correlation of TCD grade with NIHSS score. RESULTS: On univariate analysis, younger age, absence of abnormal CT findings (hyperdense middle cerebral artery sign [HMCAS], focal hypodensity >33% of total MCA territory) were significantly associated with early improvement. Good outcome was associated with younger age, lower levels of baseline NIHSS score, mean blood pressure, fasting glucose, lipoprotein (a), and normal CT finding. Multivariate analysis revealed age <66 years and no HMCAS as independent predictors of early improvement. Thrombolysis in brain ischemia grade by TCD monitoring significantly correlated with NIHSS score for 24 hours. CONCLUSIONS: These results suggest that younger age and normal CT findings are important prognostic factors of acute thrombolytic therapy.
Blood Pressure ; Brain Ischemia ; Fasting ; Glucose ; Humans ; Lipoprotein(a) ; Middle Cerebral Artery ; Multivariate Analysis ; National Institutes of Health (U.S.) ; Prognosis ; Prospective Studies ; Stroke* ; Thrombolytic Therapy* ; Tissue Plasminogen Activator

A prospective study including 70 patients with acute cerebral infarction at Hospital 108 from July 2004 to Jun 2005. Results: Increasing blood glucose level is very common among acute stroke patients accounting for 54.3%. Blood glucose level due to response during acute stroke is commonly within the range of 7 – 10mmol/l (50%). There are reverse correlations between blood glucose and Glasgow, Herry and Barthel scores. HbA1c is essential to differentiate hyperglycemia due to diabetes or response
Stroke, Brain Ischemia, Blood Glucose