α4整合素的抑制可保护正常血压和高血压大鼠免受短暂性局灶性脑缺血的影响。

Inhibition of alpha4 integrin protects against transient focal cerebral ischemia in normotensive and hypertensive rats.

作者信息

Relton J K, Sloan K E, Frew E M, Whalley E T, Adams S P, Lobb R R

机构信息

Biogen Inc, Cambridge, MA 02142, USA.

出版信息

Stroke. 2001 Jan;32(1):199-205. doi: 10.1161/01.str.32.1.199.

DOI:10.1161/01.str.32.1.199

PMID:11136937

Abstract

BACKGROUND AND PURPOSE

The present study was performed to determine the role of alpha4 (CD49d), a member of the integrin family of adhesion molecules, in ischemic brain pathology.

METHODS

Male spontaneously hypertensive rats (SHR) or Sprague-Dawley rats underwent 60-minute middle cerebral artery occlusion (MCAO) followed by 23-hour reperfusion. Animals were injected intravenously with 2.5 mg/kg anti-rat alpha4 antibody (TA-2) or isotype control antibody (anti-human LFA-3 IgG(1), 1E6) 24 hours before MCAO. Infarct volume was quantified by staining of fresh tissue with tetrazolium chloride and myeloperoxidase activity measured in SHR tissue homogenates 24 hours after MCAO. In SHR, mean arterial blood pressure was recorded before and after MCAO in animals treated with TA-2 and 1E6. Fluorescence-activated cell sorting analysis was performed on peripheral blood leukocytes before and after MCAO.

RESULTS

TA-2 treatment significantly reduced total infarct volume by 57.7% in normotensive rats (1E6, 84.2+/-11.5 mm(3), n=17; TA-2, 35.7+/-5.9 mm(3), n=16) and 35.5% in hypertensive rats (1E6, 146.6+/-15.5 mm(3), n=15; TA-2, 94.4+/-25.8 mm(3), n=11). In both strains, TA-2 treatment significantly reduced body weight loss and attenuated the hyperthermic response to MCAO. In SHR, treatment with TA-2 significantly reduced brain myeloperoxidase activity. Resting mean arterial blood pressure was unaffected by treatment. Leukocyte counts were elevated in TA-2-treated rats. Fluorescence-activated cell sorting analysis demonstrated the ability of TA-2 to bind to CD3+, CD4+, CD8+, and CD11b+ cells in both naive animals and after MCAO.

CONCLUSIONS

These data demonstrate that inhibition of alpha4 integrin can protect the brain against ischemic brain injury and implicate endogenous alpha4 integrin in the pathogenesis of acute brain injury. The mechanism by which alpha4 integrin inhibition offers cerebroprotection is independent of blood pressure modulation and is likely due to inhibition of leukocyte function.

摘要

背景与目的

本研究旨在确定整合素家族黏附分子成员α4（CD49d）在缺血性脑病理中的作用。

方法

雄性自发性高血压大鼠（SHR）或Sprague-Dawley大鼠接受60分钟大脑中动脉闭塞（MCAO），随后再灌注23小时。在MCAO前24小时，给动物静脉注射2.5mg/kg抗大鼠α4抗体（TA-2）或同型对照抗体（抗人LFA-3 IgG(1)，1E6）。通过用氯化三苯基四氮唑对新鲜组织染色来定量梗死体积，并在MCAO后24小时测量SHR组织匀浆中的髓过氧化物酶活性。在SHR中，记录用TA-2和1E6处理的动物在MCAO前后的平均动脉血压。对MCAO前后的外周血白细胞进行荧光激活细胞分选分析。

结果

TA-2处理使正常血压大鼠的总梗死体积显著减少57.7%（1E6组，84.2±11.5mm(3)，n = 17；TA-2组，35.7±5.�mm(3)，n = 16），使高血压大鼠的总梗死体积显著减少35.5%（1E6组，146.6±15.5mm(3)，n = 15；TA-2组，94.4±25.8mm(3)，n = 11）。在两种品系中，TA-2处理均显著减少体重减轻并减弱对MCAO的体温过高反应。在SHR中，TA-2处理显著降低脑髓过氧化物酶活性。静息平均动脉血压不受处理影响。TA-2处理的大鼠白细胞计数升高。荧光激活细胞分选分析表明，TA-2在未处理动物和MCAO后均能与CD3+、CD4+、CD8+和CD11b+细胞结合。