Abstract

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.

Highlights

  • Multiple sclerosis (MS), a chronic, inflammatory, demyelinating disease of the central nervous system (CNS), is a leading cause of disability in young, mainly female, adults [1]

  • TM5484 is a plasminogen activator inhibitor 1 (PAI-1) inhibitory compound highly penetrating into CNS

  • Based upon the relation between PAI-1 and MS progression, we investigated the effects of a low molecular PAI-1 inhibitor, TM5484, and found that significantly attenuated neurological dysfunction in a mice model of MS as measured by the paralysis score

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Summary

Introduction

Multiple sclerosis (MS), a chronic, inflammatory, demyelinating disease of the central nervous system (CNS), is a leading cause of disability in young, mainly female, adults [1]. We developed a series of orally active, low molecular PAI-1 inhibitors, relying on virtual screening and the 3-dimentional structure of the complex of PAI-1 with its inhibitory peptide [7]. In addition to their predictable anti-thrombotic effects, these compounds have demonstrated to be valuable in numerous preclinical models, including pulmonary fibrosis, macrophage infiltration, bone marrow regeneration, and arteriosclerosis [7,8,9,10]. We optimized the existing candidates in order to obtain a drug with CNS-penetrant properties

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