Failure of the Nemo Trial: Bumetanide Is a Promising Agent to Treat Many Brain Disorders but Not Newborn Seizures

Abstract

The diuretic bumetanide failed to treat acute seizures due to hypoxic ischemic encephalopathy (HIE) in newborn babies and was associated with hearing loss (NEMO trial, Pressler et al., 2015). On the other hand, clinical and experimental observations suggest that the diuretic might provide novel therapy for many brain disorders including Autism Spectrum Disorders (ASD), schizophrenia, Rett syndrome, and Parkinson disease. Here, we discuss the differences between the pathophysiology of severe recurrent seizures in the neonates and neurological and psychiatric disorders stressing the uniqueness of severe seizures in newborn in comparison to other disorders.

Keywords: GABA; autism; bumetanide; clinical trials; epilepsy; parkinson disease.

Figure 1

(I) Phenobarbital (PB) attenuates early seizures but aggravates late ones. In a triple chamber with the 2 intact hippocampi interconnected by their commissural connections in vitro, kainate was applied to one hippocampus generating interictal and ictal discharges in the ipsi-lateral hippocampus (dark trace) that propagated to the contralateral hippocampus.PB application to the contralateral hippocampus (red trace) blocked the initial paroxysmal activity, (Ia) but aggravated them when first applied after 15 recurrent ictal and interictal discharges (Ib). Right side: time frequency power plots to illustrate the different effects after a single and any recurrent ictal and interictal discharges. Note the exclusively low frequency events recorded initially in the PB treated hippocampus and the enhanced high frequency events observed after 15 paroxysmal activities. In (IIa–c), spikes evoked in the contralateral hippocampus by focal applications of GABA in the presence of glutamate receptor antagonists. Intact hippocampus subjected to many recurrent IIds and IDs. PB (red) increased the number of spikes in comparison to control (IIa-dark) and wash out (IIc-blue). (IIIa,b) Superimposed perforated-patch recordings of the currents evoked by GABA before (IIa-black), during (IIb-red), and after PB wash out (IIc-blue) in the presence of antagonists of glutamate receptors. Note the enhanced GABA currents produced by PB (taken with permission from Nardou et al., 2011).