Tranexamic Acid Modulation of Excitatory and Inhibitory Amino Acid Receptors: A Potential Mechanism for Postoperative Seizures
Tranexamic acid (TXA) is an antifibrinolytic drug that is used worldwide to reduce blood loss in a variety of hemorrhagic conditions. TXA causes seizures and myoclonic spasms, particularly during the postoperative period, and these seizures are associated with a higher incidence of neurological complications, longer recovery times, and higher mortality rates. The molecular mechanisms underlying TXA-associated seizures remain poorly understood and there are no effective treatment or prevention strategies. One potential mechanism by which TXA may give rise to seizures is by shifting the balance between excitatory and inhibitory neurotransmission. Specifically, TXA could promote hyperexcitability by enhancing the function of excitatory amino acid receptors (NMDA, AMPA, and kainate receptors). Alternatively, TXA could cause disinhibition by reducing the activity of inhibitory receptors (GABA and glycine receptors). The purpose of this thesis is to identify molecular targets that are sensitive to clinically relevant concentrations of TXA. TXA is a structural analogue of the amino acid glycine. Thus, we hypothesized that TXA acts as an agonist at the glycine binding site of the NMDA subtype of glutamate receptor. Alternatively, we postulated that TXA acts as a competitive antagonist of the glycine receptor. Further, we postulated that drugs that reverse TXA actions on excitatory or inhibitory receptors can be used to mitigate or prevent TXA-associated seizures. First, we determined the clinically relevant concentrations of TXA by measuring drug levels in the cerebrospinal fluid (CSF) of patients. We found that peak TXA concentration in the CSF of patients was 200 ÎźM. Next, we showed that TXA 200 ÎźM was sufficient to increase network excitability in cortical slices and reduce the resting membrane potential in mouse neurons. TXA had no effect on excitatory receptors at clinically relevant concentrations. Conversely, TXA competitively inhibited both GABAA and glycine receptors but the potency of TXA was highest for glycine receptors that generate a tonic inhibitory current. Finally, the general anesthetics isoflurane and propofol reversed TXA-mediated inhibition of glycine receptors and attenuated the effect of TXA on network excitability. Collectively, these results identify a potential mechanism for TXA-associated seizures and drugs that could be used to treat or prevent seizures.
Glycine, Ion channels, Seizures, Tonic current, Tranexamic acid
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