ArticlePloS one2015
Plasminogen Activator Inhibitor-1 Antagonist TM5484 Attenuates Demyelination and Axonal Degeneration in a Mice Model of Multiple Sclerosis.
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 47 citations in OpenAlex.
- Targeting PAI-1 with TM5441 Mitigates Chronic Social Stress-Induced Anxiety-Like Behavior and Stress-Induced Increases in Ethanol Intake and Preference.Neurochemical research · 2026Article
- The Antifibrotic Effects of Plasminogen Activator Inhibitor-1 Antagonists are Observed in Rats with Epidural Fibrosis.Sisli Etfal Hastanesi tip bulteni · 2025Article
- Proteomic analysis reveals candidate molecules to mediate cortical pathology and identify possible biomarkers in an animal model of multiple sclerosis.Frontiers in immunology · 2025Article
- The Hidden Hand in White Matter: Pericytes and the Puzzle of Demyelination.ACS pharmacology & translational science · 2024Review
- Chemical Adjustment of Fibrinolysis.Pharmaceuticals (Basel, Switzerland) · 2024Article
- Anti-inflammatory effects of CBD in human microglial cell line infected with HIV-1.Scientific reports · 2023Article
- Glucocorticoid-Responsive Tissue Plasminogen Activator (tPA) and Its Inhibitor Plasminogen Activator Inhibitor-1 (PAI-1): Relevance in Stress-Related Psychiatric Disorders.International journal of molecular sciences · 2023Review
- Inflammation in multiple sclerosis induces a specific reactive astrocyte state driving non-cell-autonomous neuronal damage.Clinical and translational medicine · 2022Article
- Neuroprotective Effect of Plasminogen Activator Inhibitor-1 Antagonist in the Rat Model of Mild Traumatic Brain Injury.Inflammation · 2021Article
- Structural Insight into the Two-Step Mechanism of PAI-1 Inhibition by Small Molecule TM5484.International journal of molecular sciences · 2021Article
- Targeting of plasminogen activator inhibitor-1 activity promotes elimination of chronic myeloid leukemia stem cells.Haematologica · 2021Article
- TGF-β1-Mediated Activation of SERPINE1 is Involved in Hemin-Induced Apoptotic and Inflammatory Injury in HT22 Cells.Neuropsychiatric disease and treatment · 2021Article
- Inhibition of Plasminogen Activator Inhibitor-1 Activation Suppresses High Fat Diet-Induced Weight GainFrontiers in pharmacology · 2020Article
- Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease.PLoS genetics · 2019Article
- Amyloid beta soluble forms and plasminogen activation system in Alzheimer's disease: Consequences on extracellular maturation of brain-derived neurotrophic factor and therapeutic implications.CNS neuroscience & therapeutics · 2019Review
- Coagulation Pathways in Neurological Diseases: Multiple Sclerosis.Frontiers in neurology · 2019Review
- Article
- No Sweetie Pie: Newly Uncovered Role for PAI (Plasminogen Activator Inhibitor)-1 in Inflammatory Responses to Ischemia/Reperfusion.Arteriosclerosis, thrombosis, and vascular biology · 2018Article
- A novel plasminogen activator inhibitor-1 inhibitor, TM5441, protects against high-fat diet-induced obesity and adipocyte injury in mice.British journal of pharmacology · 2016Article
- Novel Plasminogen Activator Inhibitor-1 Inhibitors Prevent Diabetic Kidney Injury in a Mouse Model.PloS one · 2016Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.