Decreased Seizure Activity in a Human Neonate Treated With Bumetanide, an Inhibitor of the Na⁺-K⁺-2Cl^- Cotransporter NKCC1

Abstract

Neonatal seizures have devastating consequences for brain development and are inadequately treated by available antiepileptics. In neonates, gamma-aminobutyric acid (GABA) is an excitatory neurotransmitter due to elevated levels of intraneuronal chloride achieved by robust activity of the Na(+)-K(+)-2Cl( -) cotransporter (NKCC1). This depolarizing action of GABA likely contributes to the lowered seizure threshold, increased seizure propensity, and poor efficacy of GABAergic anticonvulsants among infants. The diuretic bumetanide inhibits NKCC1 and silences seizure activity in rodent models of neonatal seizures, but its effect on seizures in human neonates is unknown. Continuous electroencephalography (EEG) monitoring was used to quantify the number, duration, and frequency of seizures 2 hours before and after the administration of bumetanide in a neonate with intractable multifocal seizures. Significant reductions in mean seizure duration and frequency were noted following treatment, with no associated clinical side effects or metabolic imbalances. These results suggest bumetanide may exert antiepileptic effects in human neonates.

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

“…In line with this view, it has been reported that antiepileptic drugs such as topiramate inhibit the cytosolic carbonic anhydrase (Dodgson et al, 2000) thus decreasing or abolishing GABA A receptor-mediated depolarizing responses (Herrero et al, 2002). In addition, it has been proposed that inhibiting NKCC1 with bumetanide can reduce and even abolish seizures in rodent models of neonatal seizures (Dzhala et al, 2005(Dzhala et al, , 2010Nardou et al, 2009) and in human neonates (Kahle et al, 2009). NKCC1, which increases intracellular Cl − , is elevated in neonates where GABA A receptor-mediated conductances are mainly excitatory.…”

Cl − and K + channels and their role in primary brain tumour biology

“…One example of this is targeting NKCC1, which accumulates Cl 2 in glioma cells and is important for migration [11]. Its inhibitor, bumetanide, is already approved by the FDA as a loop diuretic and is currently also being tested to treat neonatal seizures [63].…”

Drug Resistance and Resistance Mechanisms in Epilepsy

“…[11] Bu durum, bu AEİ'lerin et- Hedef değişiklikleri metanidin insanlarda da antiepileptik etki gösterebileceğini düşündürmektedir. [23] Barbitürat ve benzodiazepin benzeri GABA agonistleri, olgunlaşmış nöronlarda, GABA reseptör ilişkili klorid kanallarının açılma süresini ve/veya sıklığını artırarak hücre içi klor düzeyinin artmasına neden olurlar. Dolayısıyla GABA elektrokimyasal gradyantle uyumlu olarak klorun pasif içe akımını, membran hiperpolarizasyonunu ve potansiyel nö-ronal inhibisyonu tetikleyerek nöbet aktivitesini düşürür.…”

“…[24] Eş taşıyıcının fonksiyonunu inhibe eden ilaçlar ile GABA'nın hiperpolarizasyon görevini yapmasını veya yeniden yapılanmasını sağlayabilecek klinik çalışmalar öngörülebilir. [23] Diğer hedefler, vigabatrin tarafından inhibe edilen GABA transaminaz, asetazolamid tarafından inhibe edilen karbonik anhidraz enzimleri ve levetirasetam bağlanma bölgesi olan sinaptik vezikül protein SV2A'dır. SE sonrası sıçanlarda ve hipokampal sklerozlu hasta dokularında levetirasetamın bağlandığı bölge olan SV2A'da belirgin değişiklikler göste-rilmiştir.…”