Differential effects on glial activation by a direct versus an indirect thrombin inhibitor

- Warfarin, but not dabigatran, increased glial activation throughout the CNS.
- Dabigatran reduced basal levels of glial cell activation.
- Warfarin, but not dabigatran, reduced brain sulfatide levels.
- In a mouse model of Alzheimer's disease, dabigatran reduced astrocyte activation but had little effect on amyloid burden.

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.

Representative images from mice treated for 4 weeks with nothing (vehicle), warfarin (Warf), or the direct thrombin inhibitor dabigatran etexilate (DE) stained for astrocyte marker GFAP (red) show an increase in the hippocampus due to warfarin treatment. In contrast, treatment with DE decreased overall GFAP staining.251