Neurotoxic effects of exogenous recombinant tissue-type plasminogen activator on the normal rat brain
Neurotoxic effects of exogenous recombinant tissue-type plasminogen activator on the normal rat brain
复制标题
DOI：
10.1089/neu.2006.0183
复制
发表时间：
2007-04-01
影响因子：
4.2
通讯作者：
Suzuki, Michiyasu
中科院分区：
文献类型：
--
作者：
Goto, Hisaharu;Fujisawa, Hirosuke;Suzuki, Michiyasu
静脉和动脉内重组组织型纤溶酶原激活剂（rtPA）的溶栓治疗已被确立用于治疗急性缺血性卒中。然而，tPA也被认为具有神经毒性作用。本研究的目的是检查rtPA在体内的直接神经毒性。动物（Wistar大鼠）分为以下三组：低剂量（15 μ mol/L）rtPA组（n = 6）、高剂量（30 μ mol/L）rtPA组（n = 6）和对照（生理盐水）组（n = 6）。通过微透析探针将rtPA溶液灌注到皮质中。通过病变的图像分析对病变的体积进行组织学定量。通过静脉注射伊文思蓝评价血脑屏障（BBB）破坏，并使用抗层粘连蛋白抗体通过免疫组织化学评价基底层的损伤。在rtPA灌注的动物中，探针周围产生苍白的病变，显微镜下，神经元显示坏死变化。随着rtPA灌注浓度的增加，病灶体积显著增加。观察到明显的伊文思蓝外渗，rtPA诱导的病变中血管的层粘连蛋白免疫反应性丧失。这些结果表明，rtPA促进急性直接神经毒性，并参与破坏微血管基底膜，导致血脑屏障破坏，从而增加水肿形成。
Thrombolytic therapy with intravenous and intra-arterial recombinant tissue-type plasminogen activator (rtPA) has been established for the treatment of acute ischemic stroke. However, tPA has also been suggested to have neurotoxic effects. The purpose of this study was to examine direct neurotoxicity of rtPA in vivo. The animals (Wistar rats) were divided to the following three groups: low-dose (15 mu mol/L) rtPA group (n = 6); high-dose (30 mu mol/L) rtPA group (n = 6); and control (physiological saline) group (n = 6). The rtPA solution was perfused into the cortex via a microdialysis probe. The volume of the lesion was quantified histologically by image analysis of the lesions. Blood-brain barrier (BBB) disruption was evaluated by intravenous injection of Evans blue, and injury to the basal lamina was evaluated by immunohistochemistry using an anti-laminin antibody. In the rtPA-perfused animals, a pale lesion was produced around the probe, and microscopically, neurons showed necrotic changes. The volume of the lesions increased significantly as the concentration of perfused rtPA was increased. Marked extravasation of Evans blue was observed, and laminin immunoreactivity of blood vessels in the rtPA-induced lesions was lost. These results suggest that rtPA promotes acute direct neurotoxicity and participates in disruption of the microvascular basal lamina to cause BBB disruption, thereby increasing edema formation.