Tranexamic acid in a mouse model of cerebral amyloid angiopathy: setting the stage for a novel stroke treatment approach
Research and Practice in Thrombosis and Haemostasis, 2023
Liu Z., McCutcheon F., Ho H., Chia J., Xiao Y., Tippett I., Keragala C., Cloud G., Medcalf R.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
CVD Neurology | Pathophysiology | Plasma |  Olink Target 96 |
Abstract
Background
Symptomatic intracerebral haemorrhage (sICH) commonly occurs in patients with cerebral amyloid angiopathy (CAA). Amyloid also initiates plasminogen activation and might promote sICH. As amyloid-driven plasmin formation can be blocked by tranexamic acid (TXA), we evaluated the biodistribution and long-term consequences of TXA on brain amyloid-beta (Aβ) levels, inflammation and neurological function in APP/PS1 mice.
Methods
APP/PS1 mice overexpressing the mutant human amyloid precursor protein and wild-type littermates, were randomised to TXA (20 mg/mL) or placebo in the drinking water for 6-months. TXA in plasma and in various organs was determined by Liquid Chromatography-Mass Spectrometry. Plasmin activity assays were performed to evaluate changes in fibrinolytic activity. Neurological function was evaluated by Y-maze and Parallel Rod Floor testing. Proximity ligation-based immunoassays were used to quantitate changes of 92 biomarkers of inflammation. Brain Aβ levels were assessed by immunohistochemistry.
Results
Long-term oral TXA administration inhibited fibrinolysis. TXA accumulated in the kidney (19.4
11.2 μg/g) with 2-5-fold lower levels seen in the lung, spleen and liver. TXA levels were lowest in the brain (0.28
0.01 μg/g). Over 6-months, TXA had no discernible effect on motor coordination, novelty preference or on brain Aβ levels. TXA reduced plasma levels of EpCAM and increased CCL20.
Conclusion
Long-term TXA treatment does not alter brain Aβ levels or impact neurological behaviour in mice predisposed to amyloid deposition and had minor effects on levels of inflammatory mediators. This finding supports the safety of TXA and lays the foundation for TXA as a novel treatment to reduce sICH in patients with CAA.