Early beneficial effect of matrix metalloproteinase inhibition on blood-brain barrier permeability as measured by magnetic resonance imaging countered by impaired long-term recovery after stroke in rat brain
Early beneficial effect of matrix metalloproteinase inhibition on blood-brain barrier permeability as measured by magnetic resonance imaging countered by impaired long-term recovery after stroke in rat brain
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DOI：
10.1038/sj.jcbfm.9600534
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发表时间：
2008-02-01
影响因子：
6.3
通讯作者：
Rosenberg, Gary A.
中科院分区：
文献类型：
--
作者：
Sood, Rohit R.;Taheri, Saeid;Rosenberg, Gary A.
在脑卒中后再灌注损伤中，由于基质金属蛋白酶（MMPs）导致细胞外基质的蛋白水解破坏，血脑屏障（BBB）开放。基质金属蛋白酶抑制剂阻断BBB的早期破坏，但短期MMP抑制剂的长期后果尚不清楚。最近，描述了一种通过图形方法来量化BBB渗透性的方法，其提供了一种在同一动物中研究BBB的早期破坏和对恢复的长期影响的方法。我们使用了一种广谱MMP抑制剂BB 1101，以确定磁共振成像（MRI）方法用于治疗研究的有用性和对恢复的长期影响。在专用4.7-T MRI扫描仪上对对照组（N = 6）和药物治疗组（N = 8）进行磁共振成像研究。成人Wistar-Kyoto进行了2小时的大脑中动脉闭塞，然后在3小时的再灌注后进行MRI研究，其中包括T2加权和弥散加权技术。此外，还实施了快速T1标测方案，以采集一个前钆-二亚乙基三胺五乙酸基线数据集，然后以3分钟间隔采集注射后数据集，持续45分钟。在48 h时再次对同一动物进行成像，以估计病变大小。对数据进行逐像素后处理，以生成表观扩散系数和渗透系数图。用BB 1101治疗在3 h时显著降低BBB渗透性，但在48 h时未能减小病变大小。行为研究表明，治疗大鼠的恢复受损。磁共振成像允许监测同一动物的多个参数。我们的研究表明，BB-1101是一个很好的BBB损伤抑制剂。然而，结果表明BB-1101可能是治疗动物神经系统状态显著恶化的原因。虽然这些初步结果表明，BB-1101是有用的，在减少早期血脑屏障泄漏，由于再灌注损伤中风，将需要进一步的研究，以确定是否可以消除后期的不利影响，通过较短的时间过程中的药物输送。
Proteolytic disruption of the extracellular matrix with opening of the blood-brain barrier (BBB) because of matrix metalloproteinases (MMPs) occurs in reperfusion injury after stroke. Matrix metalloproteinase inhibition blocks the early disruption of the BBB, but the long-term consequences of short-term MMP inhibition are not known. Recently, a method to quantify BBB permeability by graphical methods was described, which provides a way to study both early disruption of the BBB and long-term effects on recovery in the same animal. We used a broad-spectrum MMP inhibitor, BB1101, to determine both the usefulness of the Magnetic resonance imaging (MRI) method for treatment studies and the long-term effects on recovery. Magnetic resonance imaging studies were performed in control (N = 6) and drug-treated (N = 8) groups on a dedicated 4.7-T MRI scanner. Adult Wistar-Kyoto underwent a 2-h middle cerebral artery occlusion followed by an MRI study after 3 h of reperfusion, which consisted of T2- and diffusion-weighted techniques. Additionally, a rapid T1 mapping protocol was also implemented to acquire one pre-gadolinium-diethylenetriaminepentaacetic acid baseline data set followed by postinjection data sets at 3-min intervals for 45 mins. The same animal was imaged again at 48 h for lesion size estimation. Data was postprocessed pixel-wise to generate apparent diffusion coefficient and permeability coefficient maps. Treatment with BB1101 significantly reduced BBB permeability at 3 h, but failed to reduce lesion size at 48 h. Behavioral studies showed impairment in recovery in treated rats. Magnetic resonance imaging allowed for the monitoring of multiple parameters in the same animal. Our studies showed that BB-1101 was an excellent inhibitor of the BBB damage. However, results show that BB-1101 may be responsible for significant deterioration in neurologic status of treated animals. Although these preliminary results suggest that BB-1101 is useful in reducing early BBB leakage owing to reperfusion injury in stroke, further studies will be needed to determine whether the later detrimental effects can be eliminated by shorter time course of drug delivery.