Understanding the molecular mechanism of blood-brain barrier damage in an experimental model of Japanese encephalitis: Correlation with minocycline administration as a therapeutic agent
Understanding the molecular mechanism of blood-brain barrier damage in an experimental model of Japanese encephalitis: Correlation with minocycline administration as a therapeutic agent
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DOI：
10.1016/j.neuint.2009.07.006
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发表时间：
2009-12-01
影响因子：
4.2
通讯作者：
Basu, Anirban
中科院分区：
文献类型：
--
作者：
Mishra, Manoj Kumar;Dutta, Kallol;Basu, Anirban
血脑屏障（BBB）用于保护中枢神经系统（CNS）免受外源分子的损害。日本脑炎 (JE) 由嗜神经性黄病毒引起，会导致中枢神经系统炎症、神经元死亡，还会损害血脑屏障的结构和功能完整性。米诺环素是一种半合成四环素，已被发现对以炎症和细胞死亡为特征的神经疾病模型具有广泛的保护作用，目前正在临床试验中进行评估。在本研究中，我们提出米诺环素在乙脑实验模型中的神经保护作用也延伸到对血脑屏障的保护。日本脑炎病毒 (JEV) 感染后接受米诺环素治疗后，通过埃文蓝色染料排除试验评估 BBB 损伤。静脉注射 JEV 的小鼠体内发生了 131313 的分解。这导致与蛋白质结合的埃文蓝染料渗漏到脑组织中。半定量 RT-PCR 显示 JEV 感染后趋化因子受体和粘附分子的上调。免疫染色显示乙脑病毒感染后白细胞和中性粒细胞浸润。 JEV感染后24小时开始腹腔注射米诺环素，通过减少BBB损伤、降低iNOS、Cox-2、VEGF的表达以及降低脑中趋化因子受体和粘附分子转录物的升高水平来消除这种效应。已知基质金属蛋白酶 (MMP) 会破坏 BBB，而米诺环素可显着降低脑组织匀浆中 MMP-9 的活性。因此，在临床相关时间施用米诺环素似乎可以在乙脑病毒感染后维持血脑屏障的完整性。 (C) 2009 Elsevier Ltd. 保留所有权利。
The blood-brain barrier (BBB) serves to protect the central nervous system (CNS) from damage by exogenous molecules. Japanese encephalitis (JE), caused by a neurotropic flavivirus, leads to inflammation in the CNS, neuronal death and also compromises the structural and functional integrity of the BBB. Minocycline, a semisynthetic tetracycline, has been found to be broadly protective in neurological disease models featuring inflammation and cell death and at present, is being evaluated in clinical trials. In the present study, we propose that the neuroprotective role of minocycline in experimental models of JE extends also to the protection of the BBB. Damage to the BBB was assessed by Evan's blue dye exclusion test after minocycline treatment following Japanese encephalitis virus (JEV) infection. A breakdown of the 131313 occurred in mice inoculated intravenously with JEV. This resulted in leakage of protein-bound Evan's blue dye into the brain tissue. Semi-quantitative RT-PCR revealed an up-regulation of chemokine receptors and adhesion molecules following JEV infection. Immunostaining showed leukocyte and neutrophil infiltration following JEV infection. Intraperitoneal injection of minocycline, beginning 24 h post-JEV infection, abrogated the effects by reducing BBB damage, decreasing expression of iNOS, Cox-2, VEGF and also by reducing the elevated level of transcript of chemokine receptors and adhesion molecules in the brain. Matrix metalloproteinases (MMPs) are known to disrupt the BBB and minocycline was found to significantly decrease the activity of MMP-9 in brain tissue homogenates. Thus, minocycline, administered at a clinically relevant time, appears to maintain blood-brain barrier integrity following JEV infection. (C) 2009 Elsevier Ltd. All rights reserved.