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


OBJECTIVE
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.
East
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E
Department of Neuroinflammation, Institute of Neurology, University College London, London, UK. E.East@ion.ucl.ac.uk
Gverić
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D
Baker
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D
Pryce
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Lijnen
H R
HR
Cuzner
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ML
D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D002908:Chronic Disease; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D005342:Fibrinolysis / Q000502:physiology*; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D013116:Spinal Cord / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010959:Tissue Plasminogen Activator / Q000378:metabolism
D017395:Plasminogen Activator Inhibitor 1; D010959:Tissue Plasminogen Activator