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.
|Number of pages||10|
|Journal||Journal of Neuroimmunology|
|State||Published - Aug 15 2016|
Bibliographical noteFunding Information:
Support : This work was supported in part by a grant from Boehringer Ingelheim ( 43048192 ), and a Research Career Scientist award from the Department of Veterans Affairs (DLF) . Author contributions: MNM contributed to design, performance, and analysis of all experiments. AS carried out mRNA analyses. DB, PEP, and SK carried out animal studies. ALM and MIG carried out sulfatide analysis. DLF and MNM designed studies and wrote the manuscript. All authors read and approved final manuscript.
- Vitamin K
ASJC Scopus subject areas
- Immunology and Allergy
- Clinical Neurology