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

作者：Dzhala Volodymyr; Staley Kevin J^*

来源：CNS Neuroscience & Therapeutics, 2015, 21(2): 173-180.

DOI：10.1111/cns.12369

• Bumetanide
• NKCC1
• phenobarbital
• posttraumatic seizures
• Trauma

BackgroundSeizures 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 GABAergic anticonvulsants. The Na+-K+-2Cl(-) (NKCC1) 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.
MethodsAcute hippocampal slices were used as a model of severe traumatic brain injury and posttraumatic epileptogenesis. Hippocampal slices were then incubated for 3weeks. 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.
ResultsBumetanide reduced the frequency and power of early posttraumatic ictal-like discharges in vitro and enhanced the anticonvulsant efficacy of phenobarbital. Continuous 2-3weeks administration of bumetanide as well as phenobarbital in combination with bumetanide failed to prevent posttraumatic ictal-like discharges and epileptogenesis.
ConclusionsOur data demonstrate a persistent contribution of NKCC1 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.

• 出版日期2015-2