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Increased thrombin inhibition in experimental autoimmune encephalomyelitis
Author(s) -
Beilin Orit,
Karussis Dimitrios M.,
Korczyn Amos D.,
Gurwitz David,
Aronovich Ramona,
Hantai Daniel,
Grigoriadis Nikolaos,
MizrachiKol Rachel,
Chapman Joab
Publication year - 2004
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.20270
Subject(s) - experimental autoimmune encephalomyelitis , thrombin , multiple sclerosis , medicine , central nervous system , antithrombin , encephalomyelitis , immunology , inflammation , coagulation , endocrinology , pharmacology , platelet , heparin
Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are inflammatory diseases of the central nervous system (CNS). Activated coagulation factors are associated with inflammation and are elevated in the plasma of animals with EAE. Thrombin is a key coagulation factor and its major endogenous inhibitors are antithrombin III (ATIII) in the plasma and protease nexin 1 (PN‐1) in the brain. We measured the capacity of brain homogenates to inhibit exogenous thrombin and the CNS levels of ATIII and PN‐1 during the course of EAE. Acute EAE was induced in SJL/J mice by immunization with mouse spinal cord homogenates. On Days 8, 13, and 22 post‐immunization, inhibition of exogenous thrombin activity was measured by a recently developed fluorimetric assay. PN‐1 and ATIII were assayed both by immunohistochemistry and by immunoblots in the brain and spinal cord. Total brain thrombin inhibitory activity increased (32%) in EAE mice at the peak of clinical disease (Day 13, P = 0.04 compared to controls). Brain ATIII also increased at the peak of disease (2.5‐fold higher than controls, P = 0.0001), and correlated significantly with clinical scores at all stages of disease ( r = 0.72, P = 0.0068). In contrast, PN‐1 elevations were more pronounced at the preclinical stage on Day 8 (3‐fold higher than controls, P = 0.01) than on Day 13 (1.4‐fold higher, P = 0.005). Increased brain thrombin inhibition at the clinical peak of EAE probably reflects increased influx of plasma thrombin inhibitors. Early PN‐1 changes represent a potential target for thrombin modulating drugs in EAE and MS. © 2004 Wiley‐Liss, Inc.