Targeting leukocyte MMPs and transmigration - Minocycline as a potential therapy for multiple sclerosis
Targeting leukocyte MMPs and transmigration - Minocycline as a potential therapy for multiple sclerosis
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DOI：
10.1093/brain/awf133
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发表时间：
2002-06-01
期刊：
影响因子：
14.5
通讯作者：
Yong, VW
中科院分区：
文献类型：
--
作者：
Brundula, V;Rewcastle, NB;Yong, VW
多发性硬化的特征是白细胞浸润到CNS中。由于基质金属蛋白酶（MMPs）促进白细胞穿过基质屏障，我们测试了靶向MMPs可以减轻神经炎症的假设。我们报告，米诺环素，一种广泛使用的仿制药，具有良好的安全记录，抑制MMP活性，减少MMP-9的产生，并减少T淋巴细胞穿过纤连蛋白基质屏障的迁移。此外，米诺环素对小鼠（多发性硬化症的动物模型）的轻度和重度实验性自身免疫性脑脊髓炎（EAE）均有效。当产生严重的EAE时，米诺环素预处理延迟了疾病的进程：当在媒介物处理的EAE小鼠中发生最大疾病活动时，米诺环素动物相对正常，并且在CNS中具有最小的炎症和脱髓鞘迹象。当在患有轻度EAE的小鼠中进行测试时，米诺环素在整个治疗过程中减轻了疾病的临床严重程度。这些结果表明，米诺环素可能构成一个安全和廉价的治疗多发性硬化症。
Multiple sclerosis is characterized by the infiltration of leukocytes into the CNS. As matrix metalloproteinases (MMPs) facilitate the passage of leukocytes across matrix barriers, we tested the hypothesis that targeting MMPs could attenuate neuro-inflammation. We report that minocycline, a widely used generic drug with a good safety record, inhibited MMP activity, reduced production of MMP-9 and decreased the transmigration of T lymphocytes across a fibronectin matrix barrier. In addition, minocycline was efficacious against both mild and severe experimental autoimmune encephalomyelitis (EAE) in mice, an animal model of multiple sclerosis. When severe EAE was produced, minocycline pre-treatment delayed the course of the disease: when maximal disease activity occurred in vehicle-treated EAE mice, minocycline animals were relatively normal and had minimal signs of inflammation and demyelination in the CNS. When tested in mice afflicted with mild EAE, minocycline attenuated the clinical severity of disease throughout the course of treatment. These results indicate that minocycline may constitute a safe and inexpensive therapy for multiple sclerosis.