Methamphetamine transiently increases the blood-brain barrier permeability in the hippocampus: Role of tight junction proteins and matrix metalloproteinase-9
Methamphetamine transiently increases the blood-brain barrier permeability in the hippocampus: Role of tight junction proteins and matrix metalloproteinase-9
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DOI：
10.1016/j.brainres.2011.07.013
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发表时间：
2011-09-09
期刊：
影响因子：
2.9
通讯作者：
Silva, Ana P.
中科院分区：
文献类型：
--
作者：
Martins, Tania;Baptista, Sofia;Silva, Ana P.
甲基苯丙胺（Methamphetamine，简称冰毒）是一种强效兴奋剂，在全球范围内逐渐流行起来。众所周知，冰毒具有高度神经毒性，会对脑细胞造成不可逆转的损害，导致神经和精神异常。最近的研究表明，甲基苯丙胺诱导的神经毒性也可能源于其损害血脑屏障（BBB）功能的能力。由于血脑屏障在维持大脑稳态和抵御有毒分子和致病生物方面的关键作用，其功能障碍可能会导致严重后果。在这项研究中，我们研究了急性高剂量冰毒（30mg /kg）在不同时间点和不同脑区对血脑屏障通透性的影响。为此，在给药后1小时、24小时或72小时处死年轻成年小鼠。甲基苯丙胺增加血脑屏障的通透性，但这种作用仅在给药后24小时检测到，因此是一种短暂的作用。有趣的是，我们还发现，与额叶皮质和纹状体相比，海马体是最易受冰毒影响的大脑区域。此外，为了确定甲基乙醚诱导血脑屏障功能障碍的关键因素，我们进一步研究了紧密连接蛋白（TJ）和基质金属蛋白酶-9 （MMP-9）的潜在改变。注射后24 h，甲基安非他明可降低海马组织中ZO -1、claudin-5和occludin蛋白水平，提高MMP-9的活性和免疫反应性。基质金属蛋白酶抑制剂BB-94 （30 mg/kg）预处理可阻止甲基醚诱导的海马MMP-9免疫反应性升高。总的来说，目前的数据表明，甲基安非他明会短暂地增加海马血脑屏障的通透性，这可以通过TJ蛋白和MMP-9的改变来解释。(C) 2011 Elsevier B.V.版权所有
Methamphetamine (METH) is a powerful stimulant drug of abuse that has steadily gained popularity worldwide. It is known that METH is highly neurotoxic and causes irreversible damage of brain cells leading to neurological and psychiatric abnormalities. Recent studies suggested that METH-induced neurotoxicity might also result from its ability to compromise blood-brain barrier (BBB) function. Due to the crucial role of BBB in the maintenance of brain homeostasis and protection against toxic molecules and pathogenic organisms, its dysfunction could have severe consequences. In this study, we investigated the effect of an acute high dose of METH (30 mg/kg) on BBB permeability after different time points and in different brain regions. For that, young adult mice were sacrificed 1 h, 24 h or 72 h post-METH administration. METH increased BBB permeability, but this effect was detected only at 24 h after administration, being therefore a transitory effect. Interestingly, we also found that the hippocampus was the most susceptible brain region to METH, comparing to frontal cortex and striatum. Moreover, in an attempt to identify the key players in METH-induced BBB dysfunction we further investigated potential alterations in tight junction (TJ) proteins and matrix metalloproteinase-9 (MMP-9). METH was able to decrease the protein levels of zonula occludens (ZO)-1, claudin-5 and occludin in the hippocampus 24 h post-injection, and increased the activity and immunoreactivity of MMP-9. The pre-treatment with BB-94 (30 mg/kg), a matrix metalloproteinase inhibitor, prevented the METH-induced increase in MMP-9 immunoreactivity in the hippocampus. Overall, the present data demonstrate that METH transiently increases the BBB permeability in the hippocampus, which can be explained by alterations on TJ proteins and MMP-9. (C) 2011 Elsevier B.V. All rights reserved.