Acute and Chronic Efficacy of Bumetanide in an in vitro Model of Posttraumatic Epileptogenesis

Summary Background Seizures triggered by acute injuries to the developing brain respond poorly to first‐line medications that target the inhibitory chloride‐permeable GABA A receptor. Neuronal injury is associated with profound increases in cytoplasmic chloride ([Cl − ] i ) resulting in depolarizing GABA signaling, higher seizure propensity and limited efficacy of GABA ergic anticonvulsants. The Na + ‐K + ‐2Cl − ( NKCC 1) cotransporter blocker bumetanide reduces [Cl − ] i and causes more negative GABA equilibrium potential in injured neurons. We therefore tested both the acute and chronic efficacy of bumetanide on early posttraumatic ictal‐like epileptiform discharges and epileptogenesis. Methods Acute hippocampal slices were used as a model of severe traumatic brain injury and posttraumatic epileptogenesis. Hippocampal slices were then incubated for 3 weeks. After a 1‐week latent period, slice cultures developed chronic spontaneous ictal‐like discharges. The anticonvulsant and anti‐epileptogenic efficacy of bumetanide, phenobarbital, and the combination of these drugs was studied. Results Bumetanide reduced the frequency and power of early posttraumatic ictal‐like discharges in vitro and enhanced the anticonvulsant efficacy of phenobarbital. Continuous 2–3 weeks administration of bumetanide as well as phenobarbital in combination with bumetanide failed to prevent posttraumatic ictal‐like discharges and epileptogenesis. Conclusions Our data demonstrate a persistent contribution of NKCC 1 cotransport in posttraumatic ictal‐like activity, presumably as a consequence of chronic alterations in neuronal chloride homeostasis and GABA ‐mediated inhibition. New strategies for more effective reduction in posttraumatic and seizure‐induced [Cl − ] i accumulation could provide the basis for effective treatments for posttraumatic epileptogenesis and the resultant seizures.