Plasminogen Activator Inhibitor-1 Antagonist TM5484 Attenuates Demyelination and Axonal Degeneration in a Mice Model of Multiple Sclerosis.
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.
Department of Molecular Medicine and Therapy, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
Nicolas
N
Pelisch
Department of Molecular Medicine and Therapy, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
Takashi
T
Dan
Department of Molecular Medicine and Therapy, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
Atsuhiko
A
Ichimura
Department of Molecular Medicine and Therapy, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
Hiroki
H
Sekiguchi
Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
Douglas E
DE
Vaughan
Service de Nephrologie, Cliniques Universitaires Saint Luc, Brussels, Belgium.
Charles
C
van Ypersele de Strihou
Department of Molecular Medicine and Therapy, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
Toshio
T
Miyata
D000818:Animals; D001369:Axons; D001682:Biological Availability; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D024141:Collagen Type IV / Q000378:metabolism; D003711:Demyelinating Diseases / Q000188:drug therapy / Q000473:pathology*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000473:pathology*; D009474:Neurons / Q000187:drug effects* / Q000473:pathology*; D010243:Paralysis / Q000188:drug therapy / Q000209:etiology; D010539:Permeability; D017395:Plasminogen Activator Inhibitor 1 / Q000494:pharmacology*; D011597:Psychomotor Performance / Q000187:drug effects
D019208:Brain-Derived Neurotrophic Factor; D024141:Collagen Type IV; D017395:Plasminogen Activator Inhibitor 1; D002795:Choline O-Acetyltransferase