title: Differential effects on glial activation by a direct versus an indirect thrombin inhibitor.
abstract: Thrombin is a potent regulator of brain function in health and disease, modulating glial activation and brain inflammation. Thrombin inhibitors, several of which are in clinical use as anti-coagulants, can reduce thrombin-dependent neuroinflammation in pathological conditions. However, their effects in a healthy CNS are largely unknown. In adult healthy mice, we compared the effects of treatment by the direct thrombin inhibitor dabigatran etexilate (DE), to those of warfarin, which acts by preventing vitamin K recycling essential for coagulation. After 4weeks, warfarin increased both astrocyte GFAP and microglia Iba-1 staining throughout the CNS; whereas DE reduced expression of both markers. Warfarin, but not DE, reduced sulfatide levels; and warfarin showed longer lasting changes in cerebellar gene expression. DE also reduced glial activation in a mouse model of Alzheimer's disease, although no changes in amyloid plaque burden were observed. These results suggest that treatment with direct thrombin inhibitors may be preferable to those agents which reduce vitamin K levels and have the potential to increase glial activation.
authors.affiliation: Department of Anesthesiology, University of Illinois at Chicago, Chicago, IL 60612, United States.
authors.forename: M Natalia
authors.initials: MN
authors.lastname: Marangoni
authors.affiliation: Department of Anesthesiology, University of Illinois at Chicago, Chicago, IL 60612, United States.
authors.forename: David
authors.initials: D
authors.lastname: Braun
authors.affiliation: Department of Anesthesiology, University of Illinois at Chicago, Chicago, IL 60612, United States.
authors.forename: Annie
authors.initials: A
authors.lastname: Situ
authors.affiliation: Department of Anatomy and Cell Biology, University of Illinois, Chicago, IL 60612, United States.
authors.forename: Ana L
authors.initials: AL
authors.lastname: Moyano
authors.affiliation: Department of Anesthesiology, University of Illinois at Chicago, Chicago, IL 60612, United States.
authors.forename: Sergey
authors.initials: S
authors.lastname: Kalinin
authors.affiliation: Department of Anesthesiology, University of Illinois at Chicago, Chicago, IL 60612, United States.
authors.forename: Paul
authors.initials: P
authors.lastname: Polak
authors.affiliation: Department of Anatomy and Cell Biology, University of Illinois, Chicago, IL 60612, United States.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Givogri
authors.affiliation: Department of Anesthesiology, University of Illinois at Chicago, Chicago, IL 60612, United States; Department of Veterans Affairs, Jesse Brown VA Medical Center, Chicago, IL 60612, United States. Electronic address: dlfeins@uic.edu.
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Feinstein
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use*; D001921:Brain / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000069604:Dabigatran / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics; D014859:Warfarin / Q000627:therapeutic use*
chemical_list: C491049:Aif1 protein, mouse; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000925:Anticoagulants; D002135:Calcium-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C075222:amyloid beta-protein (1-42); D014859:Warfarin; D000069604:Dabigatran
keywords: Astrocyte; Dabigatran; Microglia; Sulfatides; Vitamin K; Warfarin