Additional increased effects of mannitol-temozolomide combined treatment on blood-brain barrier permeability
Additional increased effects of mannitol-temozolomide combined treatment on blood-brain barrier permeability
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DOI：
10.1016/j.bbrc.2018.02.149
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发表时间：
2018-03-04
影响因子：
3.1
通讯作者：
Kim, Ok Joon
中科院分区：
文献类型：
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作者：
Choi, Chunggab;Kim, Hye Min;Kim, Ok Joon
血脑屏障(BBB)是慢性卒中药物或干细胞治疗的主要障碍。我们推测，在替莫唑胺(TMZ)中加入甘露醇是解决静脉注射甘露醇疗效低的一种实用方法。在这项研究中，我们研究了这种联合治疗是否可以增加血脑屏障的通透性。首先，我们建立了慢性缺血性卒中大鼠模型，并检测了这种联合治疗对病变部位伊文思蓝染料渗漏和紧密连接蛋白(TJPs)表达的影响。此外，在使用跨孔的体外血脑屏障模型中，我们分析了荧光示踪剂扩散和TJPs表达的变化。甘露醇-TMZ联合治疗不仅增加了卒中损伤部位伊文思蓝染色的数量，而且减少了大鼠脑微血管中阻滞素的表达。体外研究还表明，联合处理增加了两种不同大小荧光示踪剂的通透性，尤其是大尺寸荧光示踪剂，并降低了TJPs的表达，如occludin和ZO-1。与单一处理相比，复合处理对血脑屏障通透性的提高效果更为显著。甘露醇-TMZ联合治疗后，TJP降低，血脑屏障通透性增加。这种联合治疗在临床上是有用的，并可能提供新的治疗选择，使各种药物能够在脑内有效地输送，而这些药物由于无法穿透血脑屏障而无法用于治疗许多中枢神经系统疾病。(C)2018 Elsevier Inc.保留所有权利。
The blood-brain barrier (BBB) is major obstacle in drug or stem cell treatment in chronic stroke. We hypothesized that adding mannitol to temozolomide (TMZ) is a practically applicable method for resolving the low efficacy of intravenous mannitol therapy. In this study, we investigated whether BBB permeability could be increased by this combined treatment. First, we established a chronic ischemic stroke rat model and examined changes in leakage of Evans blue dye within a lesion site, and in expression of tight junction proteins (TJPs), by this combined treatment. Additionally, in an in vitro BBB model using trans-wells, we analyzed changes in diffusion of a fluorescent tracer and in expression of TJPs. Mannitol-TMZ combined treatment not only increased the amount of Evans blue dye within the stroke lesion site, but also reduced occludin expression in rat brain microvessels. The in vitro study also showed that combined treatment increased the permeability for two different-sized fluorescent tracers, especially large size, and decreased expression of TJPs, such as occludin and ZO-1. Increased BBB permeability effects were more prominent with combined than with single treatments. Mannitol-TMZ combined treatment induced a decrease of TJPs with a consequent increase in BBB permeability. This combined treatment is clinically useful and might provide new therapeutic options by enabling efficient intracerebral delivery of various drugs that could not otherwise be used to treat many CNS diseases due to their inability to penetrate the BBB. (C) 2018 Elsevier Inc. All rights reserved.