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<p>Tranexamic acid (TXA) has been associated with an increased risk of postoperative seizures. However, the neuronal mechanisms underlying its proconvulsant effects remain unclear. This study investigated the dose-dependent effects of TXA on neuronal excitability in a penicillin-induced epileptiform activity model and its interaction with GABA<sub>A</sub> and GABA<sub>B</sub> receptor pathways using electrophysiological techniques.&#xa0;Sixty-two male Sprague-Dawley rats were divided into nine experimental groups. Under urethane anesthesia (1.25&#xa0;g/kg), a craniotomy exposed the left cerebral cortex for stereotaxic implantation. Interictal epileptiform activity was induced via intracortical penicillin injection (500 IU) in all groups except the TXA-only control. Following stabilization of epileptiform activity, groups received intracerebroventricular (i.c.v.) injections of either saline (penicillin control), TXA (50, 100, or 200&#xa0;µg), or combinations of 200&#xa0;µg TXA with GABA<sub>A</sub> (ago: 10&#xa0;µg muscimol, ant: 10&#xa0;µg bicuculline) and GABA<sub>B</sub> (ago: 10&#xa0;µg baclofen, ant: 10&#xa0;µg phaclofen) receptor agonist or antagonist. Electrocorticogram (ECoG) recordings were acquired for at least 60&#xa0;min post-injection. Epileptiform activity latency, spike frequency, and amplitude were analyzed across groups.&#xa0;The 200&#xa0;µg TXA-only group exhibited epileptiform discharges with a significantly shorter onset latency (60 ± 28&#xa0;s) compared to the penicillin control (<i>p</i> &lt; 0.05). Co-administration of the GABA<sub>B</sub> agonist baclofen with TXA significantly reduced spike frequency (<i>p</i> &lt; 0.01), whereas the GABA<sub>B</sub> antagonist phaclofen increased it (<i>p</i> &lt; 0.01). In contrast, neither the GABA<sub>A</sub> agonist muscimol nor the antagonist bicuculline altered spike frequency.&#xa0;In conclusion, 200&#xa0;µg of TXA administered intracortically to Sprague-Dawley rats alone caused epileptiform discharges. According to the findings obtained from the interaction studies within the scope of this study, TXA was evaluated to cause epileptiform activity by blocking the GABA<sub>A</sub> receptor. These findings are expected to contribute to the development of safer dosing strategies and potential preventive interventions for the clinical use of TXA.</p>

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Efficacy of Tranexamic Acid on GABAA Receptors in Penicillin-Induced Epileptiform Activity

  • 期刊论文

  • 发表日期：

    2025年10月30日

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  • Ferda Serdoğan,
  • Kemal Tolga Saraçoğlu,
  • Uğur Aykın,
  • Metehan Akça,
  • Cumaali Demirtaş,
  • Ayten Saraçoğlu,
  • Elif Akova Deniz,
  • Tamer Kuzucuoğlu,
  • Mehmet Yildirim

摘要

Tranexamic acid (TXA) has been associated with an increased risk of postoperative seizures. However, the neuronal mechanisms underlying its proconvulsant effects remain unclear. This study investigated the dose-dependent effects of TXA on neuronal excitability in a penicillin-induced epileptiform activity model and its interaction with GABAA and GABAB receptor pathways using electrophysiological techniques. Sixty-two male Sprague-Dawley rats were divided into nine experimental groups. Under urethane anesthesia (1.25 g/kg), a craniotomy exposed the left cerebral cortex for stereotaxic implantation. Interictal epileptiform activity was induced via intracortical penicillin injection (500 IU) in all groups except the TXA-only control. Following stabilization of epileptiform activity, groups received intracerebroventricular (i.c.v.) injections of either saline (penicillin control), TXA (50, 100, or 200 µg), or combinations of 200 µg TXA with GABAA (ago: 10 µg muscimol, ant: 10 µg bicuculline) and GABAB (ago: 10 µg baclofen, ant: 10 µg phaclofen) receptor agonist or antagonist. Electrocorticogram (ECoG) recordings were acquired for at least 60 min post-injection. Epileptiform activity latency, spike frequency, and amplitude were analyzed across groups. The 200 µg TXA-only group exhibited epileptiform discharges with a significantly shorter onset latency (60 ± 28 s) compared to the penicillin control (p < 0.05). Co-administration of the GABAB agonist baclofen with TXA significantly reduced spike frequency (p < 0.01), whereas the GABAB antagonist phaclofen increased it (p < 0.01). In contrast, neither the GABAA agonist muscimol nor the antagonist bicuculline altered spike frequency. In conclusion, 200 µg of TXA administered intracortically to Sprague-Dawley rats alone caused epileptiform discharges. According to the findings obtained from the interaction studies within the scope of this study, TXA was evaluated to cause epileptiform activity by blocking the GABAA receptor. These findings are expected to contribute to the development of safer dosing strategies and potential preventive interventions for the clinical use of TXA.