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首页> 外文期刊>Neuropathology: official journal of the Japanese Society of Neuropathology >Minocycline suppresses experimental autoimmune encephalomyelitis by increasing tissue inhibitors of metalloproteinases.
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Minocycline suppresses experimental autoimmune encephalomyelitis by increasing tissue inhibitors of metalloproteinases.

机译：米诺环素通过增加金属蛋白酶的组织抑制剂来抑制实验性自身免疫性脑脊髓炎。

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Matrix metalloproteinases (MMPs) that are secreted by activated T cells play a significant role in degradation of the extracellular matrix around the blood vessels and facilitate autoimmune neuroinflammation; however, it remains unclear how MMPs act in lesion formation and whether MMP-targeted therapies are effective in disease suppression. In the present study, we attempted to treat experimental autoimmune encephalomyelitis (EAE) by administration of small interfering RNAs (siRNAs) for MMP-2, MMP-9, and minocycline, all of which have MMP-inhibiting functions. Minocycline, but not siRNAs, significantly suppressed disease development. In situ zymography revealed that gelatinase activities were almost completely suppressed in the spinal cords of minocycline-treated animals, while significant gelatinase activities were measured in the EAE lesions of control animals. However, MMP-2 and MMP-9 mRNAs and proteins in the spinal cords of treated rats were unexpectedly upregulated. At the same time, mRNA for tissue inhibitors of MMPs (TIMP)-1 and -2 were also upregulated. The EnzChek Gelatinase/Collagenase assay using tissue containing native MMPs and TIMPs demonstrated that gelatinase activity levels in the spinal cords of treated rats were suppressed to the same level as those in normal spinal cord tissues. Finally, double immunofluorescent staining demonstrated that MMP-9 immunoreactivities of treated rats were almost the same as those of control rats and that MMP-9 and TIMP-1 immunoreactivities were colocalized in the spinal cord. These findings suggest that minocycline administration does not suppress MMPs at mRNA and protein levels but that it suppresses gelatinase activities by upregulating TIMPs. Thus, MMP-targeted therapies should be designed after the mechanisms of candidate drugs have been considered.
机译：活化的T细胞分泌的基质金属蛋白酶（MMP）在血管周围的细胞外基质降解中起重要作用，并促进自身免疫性神经炎症。然而，目前尚不清楚MMP在病变形成中的作用以及以MMP为靶标的疗法在抑制疾病方面是否有效。在本研究中，我们试图通过给予MMP-2，MMP-9和米诺环素小干扰RNA（siRNA）来治疗实验性自身免疫性脑脊髓炎（EAE），它们均具有MMP抑制功能。 Minocycline而非siRNA可以显着抑制疾病的发展。原位酶谱分析显示，在米诺环素处理的动物的脊髓中，明胶酶的活性几乎完全被抑制，而在对照动物的EAE病变中，明胶酶的活性却明显升高。然而，处理的大鼠脊髓中的MMP-2和MMP-9 mRNA和蛋白出乎意料地被上调。同时，MMPs组织抑制剂（TIMP）-1和-2的mRNA也上调。使用含有天然MMP和TIMP的组织进行的EnzChek明胶酶/胶原酶测定表明，治疗大鼠的脊髓中的明胶酶活性水平被抑制到与正常脊髓组织中的水平相同。最后，双重免疫荧光染色表明，治疗大鼠的MMP-9免疫反应性几乎与对照大鼠相同，并且MMP-9和TIMP-1免疫反应性在脊髓中共定位。这些发现表明，米诺环素给药不会在mRNA和蛋白质水平上抑制MMP，而是通过上调TIMPs抑制明胶酶活性。因此，应在考虑候选药物的机制后设计针对MMP的疗法。

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