Sex-dependent effects of tranexamic acid on blood-brain barrier permeability and the immune response following traumatic brain injury in mice.
2020
BACKGROUND Tranexamic acid (TXA) is an anti-fibrinolytic agent used to reduce bleeding in various conditions including traumatic brain injury (TBI). As the fibrinolytic system also influences the central nervous system and the immune response, TXA may also modulate these parameters following TBI. OBJECTIVES To determine the effect of TXA on blood-brain barrier (BBB) integrity and changes in immune and motor function in male and female mice subjected to TBI. METHODS Wild-type and plasminogen deficient (plg-/-) mice were subjected to TBI then administered either TXA/vehicle. The degree of BBB breakdown, intracerebral haemorrhage (ICH), motor dysfunction, and changes in inflammatory subsets in blood and brain were determined. RESULTS AND CONCLUSIONS TXA significantly reduced BBB breakdown, and increased blood neutrophils in male mice 3h-post TBI. In contrast, TXA treatment of female mice increased BBB permeability and ICH but had no effect on blood neutrophils at the same time-point. TXA improved motor function in male mice but still increased BBB breakdown in female mice 24h post-TBI. Brain u-PA antigen and activity levels were significantly higher in injured females compared to males. Since TXA can promote a pro-fibrinolytic effect via u-PA, these sex-differences may be related to brain u-PA levels. TXA also increased monocyte subsets and dendritic cells in the injured brain of wild-type male mice 1-week post-TBI. Plg-/- mice of both sexes had reduced BBB damage and were protected from TBI irrespective of treatment indicating that TXA modulation of the BBB is plasmin-dependent. In conclusion, TXA is protective post-TBI but only in male mice.
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