Institut National de la Santé Et de la Recherche Médicale (INSERM) U919 Serine Protease and Pathophysiology of the Neurovascular Unit, University Caen Basse-Normandie, GIP Cyceron, Bd Becquerel, BP5229, Caen, France.
Stroke. 2013 Jul;44(7):1988-96. doi: 10.1161/STROKEAHA.111.000544. Epub 2013 Jun 6.
Our aim was to assess the spatiotemporal evolution of the cerebrovascular inflammation occurring after ischemic and hemorrhagic strokes using a recently developed, fast, and ultra-sensitive molecular MRI method.
We first assessed longitudinally the cerebrovascular inflammation triggered by collagenase-induced hemorrhage and by permanent/transient middle cerebral artery occlusion in mice, using MRI after injection of microparticles of iron oxide targeted to vascular cell adhesion molecule-1 (MPIOs-αVCAM-1). Thereafter, we used this method to study the anti-inflammatory effects of celecoxib, atorvastatin, and dipyridamole after stroke.
Using multiparametric MRI, we demonstrated that the level and the kinetics of cerebrovascular VCAM-1 expression depend on several parameters, including stroke pathogenesis, the natural history of the disease, and the administration of inflammation-modulating drugs. Interestingly, in transient middle cerebral artery occlusion and intracranial hemorrhage models, VCAM-1 expression was maximal at 24 hours and almost returned to baseline 5 days after stroke onset. In contrast, after permanent middle cerebral artery occlusion, VCAM-1 overexpression was sustained between 24 hours and 5 days, and was particularly significant in the peri-infarct areas. Our results suggest that these perilesional areas expressing VCAM-1 constitute an inflammatory penumbra that is recruited by the ischemic core during the subacute phase. Using MPIOs-αVCAM-1-enhanced imaging, we also provided evidence that celecoxib and atorvastatin (but not dipyridamole) alleviate VCAM-1 overexpression after stroke and prevent formation of the inflammatory penumbra.
MPIOs-αVCAM-1-enhanced imaging seems to be promising in the detection of individuals presenting with severe cerebrovascular responses after stroke, which could therefore benefit from anti-inflammatory treatments.
本研究旨在应用一种新研发的快速、超高敏的分子 MRI 方法，评估缺血性和出血性卒中后发生的脑血管炎症的时空演变。
我们首先采用靶向血管细胞黏附分子-1（VCAM-1）的超顺磁性氧化铁微颗粒（MPIOs-αVCAM-1），通过胶原酶诱导的脑出血和永久性/短暂性大脑中动脉闭塞，对小鼠进行纵向评估，从而检测脑血管炎症。此后，我们采用这种方法研究塞来昔布、阿托伐他汀和双嘧达莫治疗卒中后的抗炎作用。
采用多参数 MRI，我们证实 VCAM-1 表达的水平和动力学依赖于多种参数，包括卒中发病机制、疾病的自然史和炎症调节药物的应用。有趣的是，在短暂性大脑中动脉闭塞和颅内出血模型中，VCAM-1 表达在卒中发病后 24 小时达到高峰，5 天后几乎恢复基线水平。相比之下，在永久性大脑中动脉闭塞中，VCAM-1 过表达持续 24 小时至 5 天，在梗死周边区尤为显著。我们的结果提示，这些表达 VCAM-1 的病变周围区构成了亚急性期内缺血核心募集的炎症半影区。通过 MPIOs-αVCAM-1 增强成像，我们还提供了证据，表明塞来昔布和阿托伐他汀（而非双嘧达莫）减轻卒中后 VCAM-1 过表达并防止炎症半影区的形成。
MPIOs-αVCAM-1 增强成像似乎有望用于检测卒中后表现出严重脑血管反应的个体，这些个体可能受益于抗炎治疗。
