Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province 325000, PR China.
Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province 325000, PR China; Department of Biology, South University of Science and Technology of China, 1088 Xueyuan Road, Nanshan District, Shenzhen, Guangdong Province 518055, PR China.
Eur J Pharmacol. 2014 Aug 5;736:70-6. doi: 10.1016/j.ejphar.2014.04.034. Epub 2014 May 2.
We have previously shown that Idazoxan (IDA), an imidazoline 2 receptor ligand, is neuroprotective against spinal cord injury caused by experimental autoimmune encephalomyelitis (EAE) in mouse, an animal modal of multiple sclerosis (MS). However, the protective mechanism remains unclear. Here, we provided evidence to show that IDA confers neuroprotection through reduction in blood-brain barrier (BBB) damage. EAE was induced by immunizing C57 BL/6 mice with myelin oligodendrocyte glycoprotein35-55 amino acid peptide (MOG35-55). IDA was administrated for 14 days after MOG immunization at 2 mg/kg (i.p., bid). Significant reduction in BBB damage occurred in the IDA-treated group of mice compared with the saline-treated group, as evidenced by the reduction in Evan׳s blue content in the brain tissue and the reduced BBB tight junction damage viewed under a transmission electron microscope. Moreover, EAE-induced reductions in tight junction proteins (JAM-1, Occludin, Claudin-5 and ZO-1) were also significantly ameliorated in IDA-treated mice, all of which supported the notion that IDA reduced BBB damage. Interestingly, the expression levels of extracellular matrix metalloproteinase-9 (MMP-9) and the ratio of MMP-9 against tissue inhibitor of metalloproteinase-1 (TIMP-1), which is known to be associated with MS-induced BBB damage, were significantly reduced in IDA-treated group, lending further support to the hypothesis that IDA confers brain protection through reducing BBB damage. This study raised a possibility that IDA is a promising pro-drug for development against MS.
我们之前已经表明，咪唑啉 2 受体配体伊达唑胺（IDA）可通过减少血脑屏障（BBB）损伤对实验性自身免疫性脑脊髓炎（EAE）引起的脊髓损伤具有神经保护作用，EAE 是多发性硬化症（MS）的动物模型。然而，保护机制尚不清楚。在这里，我们提供的证据表明，IDA 通过减少血脑屏障（BBB）损伤来发挥神经保护作用。通过用髓鞘少突胶质细胞糖蛋白 35-55 氨基酸肽（MOG35-55）免疫 C57BL/6 小鼠来诱导 EAE。在 MOG 免疫后，IDA 以 2mg/kg（腹腔内，每日两次）给药 14 天。与生理盐水处理组相比，IDA 处理组的小鼠的 BBB 损伤明显减少，这表现在脑组织中的 Evans 蓝含量减少，以及在透射电子显微镜下观察到的 BBB 紧密连接损伤减少。此外，IDA 处理的小鼠中 EAE 诱导的紧密连接蛋白（JAM-1、Occludin、Claudin-5 和 ZO-1）减少也明显改善，所有这些都支持 IDA 减少 BBB 损伤的观点。有趣的是，细胞外基质金属蛋白酶-9（MMP-9）的表达水平和 MMP-9 与组织抑制剂金属蛋白酶-1（TIMP-1）的比值（已知与 MS 引起的 BBB 损伤有关）在 IDA 处理组中也显著降低，这进一步支持了 IDA 通过减少 BBB 损伤来发挥脑保护作用的假说。这项研究提出了一个可能性，即 IDA 是一种有前途的开发多发性硬化症的前药。
