Visualizing the Distribution of Matrix Metalloproteinases in Ischemic Brain Using In Vivo 19F-Magnetic Resonance Spectroscopic Imaging
Visualizing the Distribution of Matrix Metalloproteinases in Ischemic Brain Using In Vivo 19F-Magnetic Resonance Spectroscopic Imaging
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DOI：
10.1155/2019/8908943
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发表时间：
2019-01-01
影响因子：
--
通讯作者：
Nakada, Tsutomu
中科院分区：
文献类型：
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作者：
Huber, Vincent J.;Igarashi, Hironaka;Nakada, Tsutomu
基质金属蛋白酶（MMPs）损伤神经血管单位，促进缺血性卒中后血脑屏障（BBB）的破坏，并在出血性转化（HT）中发挥重要作用，出血性转化是溶栓治疗最严重的副作用之一。然而，目前还没有鉴定出可用于追踪脑中MMP分布变化的生物标志物。在这里，我们开发了一种新的F-19-分子配体，TGF-019，用于使用F-19-磁共振光谱成像（F-19-MRSI）可视化MMPs在体内的分布。我们证明了TGF-019对缺血性中风期间引起HT的特异性MMP具有足够的敏感性，即，MMP 2、MMP 9和MMP 3。然后，我们利用它来评估这些MMP在实验性局灶性脑缺血后22至24小时的MMP 2-null小鼠，以及野生型小鼠与和没有重组组织纤溶酶原激活剂（rt-PA）的全身给药。TGN-019给药小鼠的F-19-MRSI显示缺血性病变内的高信号强度，其与总MMP 2和MMP 9活性相关，这通过缺血组织的酶谱分析得到证实。根据本研究的结果，TGN-019给药后的F-19-MRSI可用于评估缺血性卒中的潜在治疗策略。
Matrix metalloproteinases (MMPs) damage the neurovascular unit, promote the blood-brain barrier (BBB) disruption following ischemic stroke, and play essential roles in hemorrhagic transformation (HT), which is one of the most severe side effects of thrombolytic therapy. However, no biomarkers have presently been identified that can be used to track changes in the distribution of MMPs in the brain. Here, we developed a new F-19-molecular ligand, TGF-019, for visualizing the distribution of MMPs in vivo using F-19-magnetic resonance spectroscopic imaging (F-19-MRSI). We demonstrated TGF-019 has sufficient sensitivity for the specific MMPs suspected in evoking HT during ischemic stroke, i.e., MMP2, MMP9, and MMP3. We then utilized it to assess those MMPs at 22 to 24 hours after experimental focal cerebral ischemia on MMP2-null mice, as well as wild-type mice with and without the systemic administration of the recombinant tissue plasminogen activator (rt-PA). The F-19-MRSI of TGN-019-administered mice showed high signal intensity within ischemic lesions that correlated with total MMP2 and MMP9 activity, which was confirmed by zymographic analysis of ischemic tissues. Based on the results of this study, F-19-MRSI following TGN-019 administration can be used to assess potential therapeutic strategies for ischemic stroke.