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Chronic relapsing experimental allergic encephalomyelitis (CREAE) in plasminogen activator inhibitor‐1 knockout mice: the effect of fibrinolysis during neuroinflammation
Author(s) -
East E.,
Gverić D.,
Baker D.,
Pryce G.,
Lijnen H. R.,
Cuzner M. L.
Publication year - 2008
Publication title -
neuropathology and applied neurobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.538
H-Index - 95
eISSN - 1365-2990
pISSN - 0305-1846
DOI - 10.1111/j.1365-2990.2007.00889.x
Subject(s) - neuroinflammation , medicine , fibrin , plasminogen activator , fibrinolysis , multiple sclerosis , immunology , spinal cord , encephalomyelitis , plasminogen activator inhibitor 1 , fibrinogen , pathology , inflammation , psychiatry
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.