title: Increased thrombin inhibition in experimental autoimmune encephalomyelitis.
abstract: 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.
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Orit
authors.initials: O
authors.lastname: Beilin
authors.forename: Dimitrios M
authors.initials: DM
authors.lastname: Karussis
authors.forename: Amos D
authors.initials: AD
authors.lastname: Korczyn
authors.forename: David
authors.initials: D
authors.lastname: Gurwitz
authors.forename: Ramona
authors.initials: R
authors.lastname: Aronovich
authors.forename: Daniel
authors.initials: D
authors.lastname: Hantai
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Grigoriadis
authors.forename: Rachel
authors.initials: R
authors.lastname: Mizrachi-Kol
authors.forename: Joab
authors.initials: J
authors.lastname: Chapman
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D000990:Antithrombin III / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism* / Q000473:pathology; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D005260:Female; D007150:Immunohistochemistry; D051379:Mice; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D058255:Protease Nexins; D011956:Receptors, Cell Surface / Q000378:metabolism; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation / Q000502:physiology
chemical_list: D016564:Amyloid beta-Protein Precursor; D058255:Protease Nexins; D011956:Receptors, Cell Surface; D000990:Antithrombin III; D013917:Thrombin