A New Mouse Model for Exploring Tranexamic Acid-Associated Seizures.

Abstract

Tranexamic acid (TXA) plays a central role in antifibrinolytic strategies, raising intense concerns regarding TXA-associated seizures. The aim of the study was to develop an in vivo TXA-induced seizure (TIS) model and identify its features on behavior, electroencephalograph (EEG), histology, and metabolomics. Adult healthy male C57BL/6J mice (n = 42) were randomized into 7 dosage groups to receive intracerebroventricular injection of TXA (vehicle, 1, 5, 7.5, 10, 25, 50 μg/μL, n = 6 each). The dose titration was based on behavioral observation according to the Racine scale. Further, continuous video-EEG was performed in another 8 TIS mice and 5 control mice with the stereotaxic implantation of electrodes and guide cannulas. Then hippocampus samples were obtained from an additional 10 TIS mice and 9 control mice for histological evaluation and metabolomic analysis. Behavioral observation revealed a dose-dependent relationship between the intensity of seizures and the intraventricular gradient of the agent. A dose of 2 μL 7.5 μg/μL TXA i.c.v. was confirmed as the target scheme to establish the model with intense behavioral seizures and typical spike epileptic EEG discharges. Histological exploration illustrated necrosis and loss of neurons as well as loss of Nissl granules in the CA3 area of the hippocampus. Additionally, metabolomic analysis revealed a variety of disturbed metabolic pathways related to seizures including amino acid, energy, antioxidant stress metabolism, and nerve signal regulation. The study provided an in vivo mouse TIS model with specific features on behavioral seizures, EEG discharges, histological findings, and metabolomic pathways.