Effects of Dabigatran in Mouse Models of Aging and Cerebral Amyloid Angiopathy

Authors

Neethu Michael, University of California, Irvine
Mher Mahoney Grigoryan, University of California, Irvine
Kelley Kilday, University of California, Irvine
Rachita K. Sumbria, Chapman UniversityFollow
Vitaly Vasilevko, University of California, Irvine
Joanne van Ryn, Boehringer Ingelheim
David H. Cribbs, University of California, Irvine
Annlia Paganini-Hill, University of California, Irvine
Mark J. Fisher, University of California, IrvineFollow

Document Type

Article

Publication Date

9-27-2019

Abstract

Oral anticoagulants are a critical component of stroke prevention, but carry a risk of brain hemorrhage. These hemorrhagic complications tend to occur in elderly individuals, especially those with predisposing conditions such as cerebral amyloid angiopathy (CAA). Clinical evidence suggests that non-vitamin K antagonist oral anticoagulants are safer than traditional oral anticoagulants. We analyzed whether the anticoagulant dabigatran produces cerebral microhemorrhage (the pathological substrate of MRI-demonstrable cerebral microbleeds) or intracerebral hemorrhage in aged mice with and without hemorrhage-predisposing angiopathy. We studied aged (22 months old) Tg2576 (a model of CAA) and wild-type (WT) littermate mice. Mice received either dabigatran etexilate (DE) (Tg N = 7; WT N = 10) or vehicle (Tg N = 9; WT N = 7) by gavage for 4 weeks. Anticoagulation effects of DE were confirmed using thrombin time assay. No mice experienced intracerebral hemorrhage. Cerebral microhemorrhage analysis, performed using Prussian-blue and H&E staining, showed no significant change in either number or size of cerebral microhemorrhage in DE-treated animals. Analysis of biochemical parameters for endothelial activation (ICAM-1), blood-brain barrier disruption (IgG, claudin-5, fibrinogen), microglial activation (Iba-1), or astrocyte activation (GFAP) showed neither exacerbation nor protective effects of DE in either Tg2576 or WT mice. Our study provides histological and biochemical evidence that aged mice, with or without predisposing factors for brain hemorrhage, tolerate anticoagulation with dabigatran. The absence of dabigatran-induced intracerebral hemorrhage or increased frequency of acute microhemorrhage may provide some reassurance for its use in high-risk patient populations.

Comments

This article was originally published in Frontiers in Neurology, volume 10, in 2019. https://doi.org/10.3389/fneur.2019.00966

Recommended Citation

Michael N, Grigoryan MM, Kilday K, et al. Effects of dabigatran in mouse models of aging and cerebral amyloid angiopathy. Front Neurol. 2019;10:966. https://doi.org/10.3389/fneur.2019.00966

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This work is licensed under a Creative Commons Attribution 4.0 License.