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首页> 外文期刊>Neurological Research: An Interdisciplinary Quarterly Journal >THR-18, a 18-mer peptide derived from PAI-1, is neuroprotective and improves thrombolysis by tPA in rat stroke models.
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THR-18, a 18-mer peptide derived from PAI-1, is neuroprotective and improves thrombolysis by tPA in rat stroke models.

机译：THR-18是一种源自PAI-1的18-mer肽，具有神经保护作用，可改善tPA在大鼠中风模型中的溶栓作用。

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OBJECTIVE: The thrombolytic treatment of stroke is limited by a narrow therapeutic time window and is associated with significant adverse side effects. To improve this situation, the modulation of tissue-type plasminogen activator (tPA) activity by a synthetic plasminogen activator inhibitor-1-derived 18-mer peptide (THR-18) was examined in two models of stroke in rats. METHODS: In the first model (thromboembolic), stroke was induced by intra-carotid injection of micro-clots to rats, and tPA (6 mg/kg) was intravenously infused for 30 minutes with or without THR-18 (1 mg/kg) at 4 hours post-induction. In the second model [transient middle cerebral artery occlusion (tMCAO)], stroke was induced for 2 hours by a transient mechanical occlusion. tPA and/or THR-18 (0.02, 0.1, and 1 mg/kg) were intravenously infused for 60 minutes at the time of reperfusion. RESULTS: In the thromboembolic model, cerebral blood flow, measured before and up to 5.5 hours post-induction, revealed that tPA administration caused reperfusion of flow at 30 minutes post-infusion. Later on, an additional increase in reperfusion was seen in the tPA+THR-18 group, and not with tPA alone. In both models, the frequency of intracranial hemorrhage in the tPA-treated group was found to be significantly higher than the control, and this tPA effect was attenuated by THR-18. In the thromboembolic study, infarct size and brain edema were similar in the control and tPA-treated rats. However, the combination of tPA and THR-18 caused a statistically significant reduction in both parameters (infarct size 17.8 versus 25.0%, brain edema 5 versus 8%, tPA+THR-18 versus control, respectively). In the tMCAO mechanical model, infarct size and brain edema were both increased by tPA treatment as compared to the control group, and this increase was markedly diminished by THR-18 co-administration. Neurobehavioral assessment of the tMCAO animals performed at 72 hours post-stroke induction revealed significant improvements (P<0.05-0.01) in neuroscores in all groups of animals treated with peptide-tPA, as compared to the tPA monotherapy group. A significant (P<0.05) improvement in the neurological outcome was also seen in the THR-18 monoterapy group, as compared to the control animals, thus demonstrating a clear neuroprotective effect by the peptide on its own. DISCUSSION: The results support the use of THR-18 together with tPA in the thrombolytic therapy of stroke, in order to achieve better patency, less tPA-induced damage, and possibly a widening of tPA therapeutic time window.
机译：目的：中风的溶栓治疗受到狭窄的治疗时间窗口的限制，并伴有严重的不良副作用。为了改善这种情况，在大鼠的两种中风模型中检查了合成纤溶酶原激活物抑制剂-1衍生的18-mer肽（THR-18）对组织型纤溶酶原激活物（tPA）活性的调节。方法：在第一个模型（血栓栓塞性）中，通过向大鼠颈动脉内注射微凝块诱发中风，并在有或没有THR-18（1 mg / kg）的情况下静脉内注射tPA（6 mg / kg）30分钟）在诱导后4小时。在第二个模型中[短暂性大脑中动脉闭塞（tMCAO）]，通过短暂的机械性闭塞诱发中风2小时。在再灌注时，将tPA和/或THR-18（0.02、0.1和1 mg / kg）静脉输注60分钟。结果：在血栓栓塞模型中，在诱导前和诱导后5.5小时测量的脑血流量显示，tPA给药会在输注后30分钟引起血流再灌注。后来，在tPA + THR-18组中发现了再灌注的进一步增加，而不是单独使用tPA。在这两个模型中，发现tPA治疗组的颅内出血频率明显高于对照组，并且tHR-18减弱了这种tPA作用。在血栓栓塞研究中，对照组和tPA处理的大鼠的梗塞面积和脑水肿相似。然而，tPA和THR-18的组合导致两个参数的统计学显着降低（梗死面积分别为17.8对25.0％，脑水肿5对8％，tPA + THR-18对对照）。在tMCAO力学模型中，与对照组相比，tPA治疗可增加梗死面积和脑水肿，而THR-18并用可明显减少这种增加。在中风诱导后72小时对tMCAO动物进行的神经行为评估显示，与tPA单药治疗组相比，所有接受tp-tPA治疗的动物组的神经评分都有显着改善（P <0.05-0.01）。与对照动物相比，在THR-18单萜类药物治疗组中，神经系统预后也得到了显着改善（P <0.05），从而证明了该肽本身具有明显的神经保护作用。讨论：结果支持THR-18与tPA一起用于中风的溶栓治疗，以实现更好的通畅性，更少的tPA诱导的损害，并可能扩大tPA的治疗时间范围。

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