Chronic relapsing experimental allergic encephalomyelitis (CREAE) in plasminogen activator inhibitor-1 knockout mice: the effect of fibrinolysis during neuroinflammation

East, E.;Gveric, D.;Baker, D.;Pryce, G.;Cuzner, M. L.;et.al.
(2008) Neuropathology and Applied Neurobiology — Vol. 34, n° 2, p. 216-230 (2008)

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  • East, E.UCLouvain
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  • Gveric, D.UCLouvain
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  • Baker, D.UCLouvain
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  • Pryce, G.UCLouvain
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  • Lijnen, H. R.UCLouvain
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  • Cuzner, M. L.UCLouvain
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Abstract
During neuroinflammation in multiple sclerosis (MS) fibrinogen, not normally present in the brain or spinal cord, enters the central nervous system through a compromised blood-brain barrier. Fibrin deposited on axons is ineffectively removed by tissue plasminogen activator (tPA), a key contributory factor being the upregulation of plasminogen activator inhibitor-1 (PAI-1). Aims: This study investigated the role of PAI-1 during experimental neuroinflammatory disease. Methods: Chronic relapsing experimental allergic encephalomyelitis (CREAE), a model of MS, was induced with spinal cord homogenate in PAI-1 knockout (PAI-1(-/-)) and wild type (WT) mice, backcrossed onto the Biozzi background. Results: Disease incidence and clinical severity were reduced in PAI-1(-/-) mice, with animals developing clinical signs significantly later than WTs. Clinical relapses were absent in PAI-1(-/-) mice and the subsequent reduction in neuroinflammation was coupled with a higher capacity for fibrinolysis in spinal cord samples from PAI-1(-/-) mice, in association with increased tPA activity. Axonal damage was less apparent in PAI-1(-/-) mice than in WTs, implicating fibrin in both inflammatory and degenerative events during CREAE. Conclusions: PAI-1 is a potential target for therapy in neuroinflammatory degenerative diseases, allowing effective fibrin removal and potentially reducing relapse rate and axonal damage.
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East, E., Gveric, D., Baker, D., Pryce, G., Lijnen, H. R., & Cuzner, M. L. (2008). Chronic relapsing experimental allergic encephalomyelitis (CREAE) in plasminogen activator inhibitor-1 knockout mice: the effect of fibrinolysis during neuroinflammation. Neuropathology and Applied Neurobiology, 34(2), 216-230. https://doi.org/10.1111/j.1365-2990.2007.00889.x (Original work published 2008)