Downregulation of CD151 restricts VCAM-1 mediated leukocyte infiltration to reduce neurobiological injuries after experimental stroke.

BACKGROUND: Translational failures in anti-adhesion molecule therapies after stroke reveal the necessity of developing new strategies that not only interrupt leukocyte recruitment but also consider the inhibition of endothelial cell inflammation, verification of therapeutic time window, and normal function maintenance of circulating leukocytes. Our study focused on the potential therapeutic value of CD151 downregulation in improving current anti-adhesion molecule therapies. METHODS: Lentivirus intracerebroventricular administration was conducted to inhibit the CD151 expression and observe its functional influence on neurological injuries and outcomes. Then, immunohistochemistry and myeloperoxidase activity assessment were performed to explore the effects of CD151 expression on neutrophil and monocyte recruitment after rat cerebral ischemia. Primary rat brain microvascular endothelial cells were subjected to oxygen glucose deprivation and reoxygenation to elucidate the underlying working mechanisms between CD151 and VCAM-1. RESULTS: The CD151 downregulation remarkably reduced neurological injuries and improved neurological outcomes, which were accompanied with reduced neutrophil and monocyte infiltration after the CD151 downregulation. The VCAM-1 expression was remarkably decreased among the adhesion molecules on the endothelial cell responsible for neutrophil and monocyte infiltration. The activation of p38 MAPK and NF-κB pathways was restricted after the CD151 downregulation. p38 MAPK and NF-κB inhibitors decreased the VCAM-1 expression, and p38 acted as an upstream regulator of NF-κB. However, CD151 downregulation did not directly influence the neutrophil and monocyte activation. CONCLUSIONS: Overall, CD151 regulated the expression of adhesion molecules. It also played a critical role in suppressing VCAM-1-mediated neutrophil and monocyte infiltration via the p38/NF-κB pathway. This study possibly provided a new basis for improving current anti-adhesion molecule therapies.

CD151 Alleviates Early Blood-Brain Barrier Dysfunction After Experimental Focal Brain Ischemia in Rats.

Preservation of the blood-brain barrier (BBB) function is a potential protective strategy against cerebral ischemic injuries. CD151 has a beneficial effect in maintaining vascular stability and plays a role in pro-angiogenesis. Both vascular stability and angiogenesis can affect BBB function. Therefore, we aimed to examine the action of CD151 in regulating BBB permeability after cerebral ischemic injury in the present study. Using a transient focal cerebral ischemia (tFCI) rat model, we established that CD151 overexpression in the brain mitigated the leakage of endogenous IgG at 6-24 h after tFCI in vivo. Moreover, we found that CD151 can decrease the diffusion of macromolecules through monolayer brain microvessel endothelial cells (BMVECs) after glucose and oxygen deprivation (OGD)-reoxygenation in vitro. Furthermore, overexpression of CD151 in BMVECs suppressed OGD-reoxygenation-induced F-actin formation and RhoA activity. However, while preserving BBB integrity after tFCI, CD151 overexpression did not affect the post-stroke outcomes. Taken together, the present study demonstrated that CD151 overexpression in the brain protects BBB permeability at early phase after tFCI. CD151 may be a potential target for early BBB protection in ischemic stroke.

Incremental value of plaque enhancement in predicting stroke recurrence in symptomatic intracranial atherosclerosis.

PURPOSE: To investigate the association between plaque enhancement and stroke recurrence in subjects with intracranial atherosclerosis. METHODS: Ischemic stroke patients with symptomatic intracranial atherosclerosis were prospectively included and followed in a comprehensive stroke center. Pre- and post-contrast vessel wall images were used to evaluate plaque enhancement. Other established suggestive imaging markers were also acquired simultaneously. Univariate- and multivariate-adjusted Cox proportional hazard regression models were used to determine the association between plaque enhancement and stroke recurrence. Finally, receiver operating characteristic (ROC) curves were used to demonstrate the predictive value of different imaging markers. RESULTS: Of the 60 subjects included, 12 (20.0%) patients presented with ipsilateral stroke recurrence during the median 12-month follow-up. Cox proportional hazard regression models indicated that plaque enhancement was an independent risk factor associated with stroke recurrence after adjusted covariates, with a hazard ratio (HR) of 14.24 and 95% confidence interval (95% CI) (1.21, 168.11), p = 0.04. In addition, border zone infarction was also statistically significant in predicting stroke recurrence in multi-variable regression (HR = 3.80; 95% CI = 1.04, 13.80; p = 0.04). Collateral status was in marginal significance (HR = 0.25; 95% CI = 0.06, 1.08; p = 0.06). ROC analysis indicated that the area under the curve and 95% CI to identify stroke recurrence are 0.67 (0.51, 0.82) for plaque enhancement and 0.71 (0.54, 0.88) for infarction pattern and collateral status and may increase to 0.82 (0.70, 0.93) by combining the three markers above. CONCLUSION: Plaque enhancement is independently associated with stroke recurrence in subjects with intracranial atherosclerosis and has added value to hemodynamic indicators in predicting stroke recurrence.

Associations between systemic blood pressure parameters and intraplaque hemorrhage in symptomatic intracranial atherosclerosis: a high-resolution MRI-based study.

The associations between blood pressure parameters and intracranial vulnerable plaques have not been fully elucidated. The purpose of this study was to investigate the associations between systemic blood pressure parameters, as well as their variability, and intraplaque hemorrhage (IPH) in stroke patients with intracranial atherosclerosis. We retrospectively analyzed the high-resolution MRI data set of intracranial atherosclerosis from a comprehensive stroke center. The atherosclerotic plaque burden and presence of IPH in each vessel were obtained from vessel wall imaging. Blood pressure parameters in the first week of admission were used. The systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), and their variability (standard deviation [SD] and coefficient of variation [CV]) were compared between the IPH (+) and IPH (-) groups. Logistic regression analysis was used to demonstrate the correlations between different blood pressure parameters and IPH. The results indicated that SBP and PP were associated with multiple plaques and severe luminal stenosis after adjusting for confounders, with OR = 1.071, 95% CI: (1.044-1.098) and OR = 1.039, 95% CI: (1.019-1.060) for SBP and OR = 1.058, 95% CI: (1.027-1.089) and OR = 1.044, 95% CI: (1.019-1.070) for PP, respectively. SBP was associated with IPH after adjusting for cardiovascular risk factors, with OR = 1.021, 95% CI: (1.003-1.038), but not after correcting for plaque burden, with OR = 1.014, 95% CI: (0.996-1.032). No associations between blood pressure variability and atherosclerotic plaque burden or IPH were detected in this study. In conclusion, SBP is associated with IPH after adjusting for cardiovascular risk factors but not after further correction for atherosclerotic plaque burden. The association between blood pressure variability and intracranial atherosclerosis requires further study.

Generalization of the right acute stroke promotive strategies in reducing delays of intravenous thrombolysis for acute ischemic stroke: A meta-analysis.

The generalization of successful efforts for reducing time delays in intravenous thrombolysis (IVT) could help facilitate its utility and benefits in acute ischemic stroke (AIS) patients.We searched the PubMed and Embase databases for articles reporting interventions to reduce time delays in IVT, published between January 1995 and September 2017. The IVT rate was chosen as the primary outcome, while the compliance rates of onset-to-door time (prehospital delay) and door-to-needle time (in-hospital delay) within the targeted time frame were the secondary outcomes. Interventions designed to reduce prehospital, in-hospital, or total time delays were quantitatively described in meta-analyses. The efficacy of postintervention improvement was illustrated as odds ratios (ORs) and 95% confidence intervals (95% CIs).In total, 86 papers (17 on prehospital, 56 on in-hospital, and 13 on total delay) encompassing 17,665 IVT cases were enrolled, including 28 American, 23 Asian, 30 European, and 5 Australian studies. The meta-analysis revealed statistically significant improvement in promoting IVT delivery after prehospital improvement interventions with an OR of 1.45 (95% CI, 1.23-1.71) for the new transportation protocol, 1.38 (95% CI, 1.11-1.73) for educational and training programs, and 1.83 (95% CI, 1.44-2.32) for comprehensive prehospital stroke code. The benefits of reducing in-hospital delay were much greater in developed western countries than in Asian countries, with ORs of 2.90 (95% CI, 2.51-3.34), 2.17 (95% CI, 1.95-2.41), and 1.89 (95% CI, 1.74-2.04) in American, European, and Asian countries, respectively. And telemedicine (OR, 2.26; 95% CI, 2.08-2.46) seemed to work better than pre-notification alone (OR, 1.94; 95% CI, 1.74-2.17) and in-hospital organizational improvement programs (OR, 2.10; 95% CI, 1.97-2.23). Mobile stroke treatment unit and use of a comprehensive stroke pathway in the pre- and in-hospital settings significantly increased IVT rates by reducing total time delay, with ORs of 2.01 (95% CI, 1.60-2.51) and 1.77 (95% CI, 1.55-2.03), respectively.Optimization of the work flow with organizational improvement or novel technology could dramatically reduce pre- and in-hospital time delays of IVT in AIS. This study provided detailed information on the net and quantitative benefits of various programs for reducing time delays to facilitate the generalization of appropriate AIS management.