title: Chronic relapsing experimental allergic encephalomyelitis (CREAE) in plasminogen activator inhibitor-1 knockout mice: the effect of fibrinolysis during neuroinflammation.
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).
  
  
  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.
authors.affiliation: Department of Neuroinflammation, Institute of Neurology, University College London, London, UK. E.East@ion.ucl.ac.uk
authors.forename: E
authors.initials: E
authors.lastname: East
authors.forename: D
authors.initials: D
authors.lastname: Gverić
authors.forename: D
authors.initials: D
authors.lastname: Baker
authors.forename: G
authors.initials: G
authors.lastname: Pryce
authors.forename: H R
authors.initials: HR
authors.lastname: Lijnen
authors.forename: M L
authors.initials: ML
authors.lastname: Cuzner
mesh_terms: 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
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D010959:Tissue Plasminogen Activator