Bumetanide reduces seizure progression and the development of pharmacoresistant status epilepticus

Objective: Status epilepticus (SE) is a medical emergency defined as unrelenting seizures that last longer than 5 minutes and can be associated with mortality. The first line of treatment is benzodiazepines (e.g. diazepam) but these drugs stop working in more than half of the individuals with SE as seizures progress. Drugs like diazepam act on the inhibitory neurotransmitter gamma amino butyric acid (GABA). GABAergic neurotransmission is controlled by the level of chloride (Cl−) ions inside vs. outside neurons (the Cl− gradient) which is maintained by ion channels. Given the specific expression of ion channels in the immature brain, experiments have shown that a drug called bumetanide is effective in reducing seizures in neonates. In the current study, the authors wanted to know whether there is a breakdown of the GABAergic system during SE in the adult brain and whether bumetanide would allow diazepam to retain its function even as seizures progress. Mice were used for these experiments, and both in vitro (brain slices) and in vivo (in the intact animal) experiments were done.

Results: Bumetanide reduced seizure-like events in the brain slice and seizures in the intact mice.
As seen in people with SE, in mice too, the efficacy of diazepam decreased as the seizures progressed, and bumetanide was able to restore this imbalance.

Interpretation: Previous studies have suggested that bumetanide can be useful in neonates because of its action on the immature GABAergic system. This study shows that dysfunction of Cl- homeostasis and GABEergic neurotransmission can take place in SE as well, and that bumetanide can decrease seizures in SE by potentially restoring this imbalance.

Summary for specialists