TY - JOUR
T1 - Differential effects on glial activation by a direct versus an indirect thrombin inhibitor
AU - Marangoni, M. Natalia
AU - Braun, David
AU - Situ, Annie
AU - Moyano, Ana L.
AU - Kalinin, Sergey
AU - Polak, Paul
AU - Givogri, Maria I.
AU - Feinstein, Douglas L.
N1 - Publisher Copyright:
© 2015.
PY - 2016/8/15
Y1 - 2016/8/15
N2 - 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 4 weeks, 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.
AB - 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 4 weeks, 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.
KW - Astrocyte
KW - Dabigatran
KW - Microglia
KW - Sulfatides
KW - Vitamin K
KW - Warfarin
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UR - http://www.scopus.com/inward/citedby.url?scp=84973454121&partnerID=8YFLogxK
U2 - 10.1016/j.jneuroim.2016.05.018
DO - 10.1016/j.jneuroim.2016.05.018
M3 - Article
C2 - 27397090
AN - SCOPUS:84973454121
SN - 0165-5728
VL - 297
SP - 159
EP - 168
JO - Journal of Neuroimmunology
JF - Journal of Neuroimmunology
ER -