Plasminogen Activator Inhibitor-1 Antagonist TM5484 Attenuates Demyelination and Axonal Degeneration in a Mice Model of Multiple Sclerosis.
Plasminogen Activator Inhibitor-1 Antagonist TM5484 Attenuates Demyelination and Axonal Degeneration in a Mice Model of Multiple Sclerosis.
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DOI：
10.1371/journal.pone.0124510
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Miyata T
中科院分区：
文献类型：
--
作者：
Pelisch N;Dan T;Ichimura A;Sekiguchi H;Vaughan DE;van Ypersele de Strihou C;Miyata T
多发性硬化症（MS）的特点是炎症性脱髓鞘和纤维蛋白原沉积在中枢神经系统（CNS）。哺乳动物纤维蛋白溶栓系统的关键抑制剂，纤溶酶原激活物抑制剂1 （PAI-1）的水平升高已经在ms的人类和动物模型中得到证实。在类似神经炎症疾病的实验研究中，与野生型小鼠相比，PAI-1缺陷小鼠显示出保留的神经结构和功能。我们之前在PAI-1的三维结构和虚拟筛选的基础上确定了一系列PAI-1抑制剂。据报道，这些化合物在体外和体内具有许多益处，但由于它们穿透血脑屏障（BBB）的能力有限，因此没有一种化合物在中枢神经系统疾病模型中进行过测试。因此，现有的候选物被优化以获得cns渗透化合物。我们使用血脑屏障模型进行了体外筛选，并能够鉴定出一种新的低分子PAI-1抑制剂TM5484，在所有候选物中具有最高的穿透率。接下来，我们在实验性过敏性脑脊髓炎小鼠模型中测试了其对炎症和脱髓鞘的影响。结果与芬戈莫德或6α-甲基强的松龙进行比较。从症状开始口服TM5484，可改善小鼠的瘫痪，减轻脱髓鞘和脊髓轴突变性。此外，它还能调节脑源性神经营养因子和胆碱乙酰转移酶的表达。脑源性神经营养因子和胆碱乙酰转移酶在神经元免受各种病理损伤中起保护作用。综上所述，这些结果证明了一种新型PAI-1抑制剂TM5484在治疗多发性硬化症中的潜在益处。
Multiple sclerosis (MS) is characterized by inflammatory demyelination and deposition of fibrinogen in the central nervous system (CNS). Elevated levels of a critical inhibitor of the mammalian fibrinolitic system, plasminogen activator inhibitor 1 (PAI-1) have been demonstrated in human and animal models of MS. In experimental studies that resemble neuroinflammatory disease, PAI-1 deficient mice display preserved neurological structure and function compared to wild type mice, suggesting a link between the fibrinolytic pathway and MS. We previously identified a series of PAI-1 inhibitors on the basis of the 3-dimensional structure of PAI-1 and on virtual screening. These compounds have been reported to provide a number of in vitro and in vivo benefits but none was tested in CNS disease models because of their limited capacity to penetrate the blood-brain barrier (BBB). The existing candidates were therefore optimized to obtain CNS-penetrant compounds. We performed an in vitro screening using a model of BBB and were able to identify a novel, low molecular PAI-1 inhibitor, TM5484, with the highest penetration ratio among all other candidates. Next, we tested the effects on inflammation and demyelination in an experimental allergic encephalomyelitis mice model. Results were compared to either fingolimod or 6α-methylprednisolone. Oral administration of TM5484 from the onset of signs, ameliorates paralysis, attenuated demyelination, and axonal degeneration in the spinal cord of mice. Furthermore, it modulated the expression of brain-derived neurotrophic factor, which plays a protective role in neurons against various pathological insults, and choline acetyltransferase, a marker of neuronal density. Taken together, these results demonstrate the potential benefits of a novel PAI-1 inhibitor, TM5484, in the treatment of MS.
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