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How does tranexamic acid induce seizures? Impaired inhibitory but unaffected excitatory synaptic transmission in the mouse amygdala as potential mechanism

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Kratzer, S.; Irl, H.; Kochs, E.; Rammes, G.; Haseneder, R.

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European Journal of Anaesthesiology (EJA): June 2013 - Volume 30 - Issue - p 4-4
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Background and Goal of Study: Tranexamic acid (TXA) is commonly used to reduce blood loss in cardiac surgery and in trauma patients1. High-dose application of TXA turned out to be a risk factor of postoperative seizures2. The neuronal mechanisms of TXA's proconvuslant action are unclear. We investigated the effects of TXA on synaptic transmission in the basolateral amygdala.

Materials and Methods: Coronar brain slices (350 μm) were obtained from male mice (BI6; d 28-35). Neurones in the amygdala were identified by infrared videomicroscopy. The effect of TXA on passive electrical membrane properties was investigated in patch clamp experiments. In a next step, compound currents, and AMPA and NMDA receptor-mediated currents were recorded upon electrical stimulation applied to the external capsule. GABAA receptor mediated currents were either evoked by electrical stimulation (GABAA-elPSCs) or by photolytic UV-laser-induced uncaging of caged-GABA (GABAA-pCs). Under control conditions, the slices were kept in carbogenated artificial cerebro-spinal fluid. After stable baseline recordings, TXA was added with a final concentration of 1 mM.

Results: In the presence of TXA (1 mM), resting membrane potential and input resistance remained unchanged. Action potentials (AP) were evoked by injection of a depolarizing current. TXA did neither affect AP frequency nor AP amplitude. Amplitudes of compound currents reflecting basal synaptic transmission remained unaffected (91.5 ± 7.2 % of control; n=6; p=0.481) but charge transfer was increased (118.7 ± 5.3 %; n=6; p=0.023) by a TXA-mediated prolongation of current deactivation kinetics. TXA did not impact excitatory AMPA (96.5 ± 4.9 %; n=5; p=0.511) or NMDA (102.5 ± 9.3 %I; n=5; p=0.706) receptor-mediated synaptic transmission. In contrast, TXA reduced GABAA-elPSCs (35.9 ± 3.2 % n=9; p< 0.001) and GABAA-pCs (40.7 ± 5.4 %; n=5; p< 0.001) to the same extent.

Conclusions: We could demonstrate that TXA reduces GABAA receptor-mediated inhibitory synaptic transmission via postsynaptic mechanisms. Highdose administration TXA leads to concentrations of 0.64-1.27 mM in the cerebrospinal fluid2. Thus the observed inhibition of GABAergic inhibitory synaptic transmission was produced by TXA at a clinically relevant concentration and might explain how TXA promotes epileptiform activity in the CNS.

References:

1. Roberts I, et al. Cochrane Database Syst Rev. 2011 (1):CD004896.
    2. Murkin JM, et al. Anesth Analg. 2010 Feb 1;110(2):350-3.
    © 2013 European Society of Anaesthesiology