Reply to the commentary by Ben‐Ari and Delpire: Bumetanide and neonatal seizures: Fiction versus reality

Abstract

In this response to a commentary by Ben‐Ari and Delpire on our recent study on the pharmacology of neonatal seizures in a novel, physiologically validated rat model of birth asphyxia, we wish to rectify their inaccurate descriptions of our model and data. Furthermore, because Ben‐Ari and Delpire suggest that negative data on bumetanide from preclinical and clinical trials of neonatal seizures have few implications for (alleged) bumetanide actions on neurons in other brain disorders, we will discuss this topic as well. Based on the poor brain penetration of bumetanide, combined with the extremely wide cellular expression patterns of the target protein NKCC1, it is obvious that the numerous actions of systemically applied bumetanide described in the literature are not mediated by the drug's effects on central neurons.

Global transgenic upregulation of KCC2 confers enhanced diazepam efficacy in treating sustained seizures

“…Although KCC2 can import Cl − under some circumstances, 7 thus theoretically exacerbating impaired GABAergic inhibition, we observed no evidence for this. Notably, blocking Cl − import by targeting the Na + ‐K + ‐Cl − co‐transporter NKCC1, is an alternative, potentially synergistic, Cl − homeostasis‐based approach for treating seizures, with promising results in animal studies 9 but mixed results in human trials 18 . We note, however, that only increasing KCC2 function can actively drive [Cl − ] i below its passive equilibrium, thus restoring GABAergic hyperpolarization, and that KCC2 has better neuronal specificity as compared to the more ubiquitously expressed NKCC1 18 .…”

“…Notably, blocking Cl − import by targeting the Na + ‐K + ‐Cl − co‐transporter NKCC1, is an alternative, potentially synergistic, Cl − homeostasis‐based approach for treating seizures, with promising results in animal studies 9 but mixed results in human trials 18 . We note, however, that only increasing KCC2 function can actively drive [Cl − ] i below its passive equilibrium, thus restoring GABAergic hyperpolarization, and that KCC2 has better neuronal specificity as compared to the more ubiquitously expressed NKCC1 18 . Thus our results support the pursuit of drugs that enhance KCC2 expression 19 and a clinical scenario wherein KCC2 is prophylactically overexpressed in individuals with higher seizure‐risk profiles to further guarantee the efficacy of antiepileptic drugs such as diazepam, in effect extending their therapeutic widow.…”

Dysregulation of GABAergic Signaling in Neurodevelomental Disorders: Targeting Cation-Chloride Co-transporters to Re-establish a Proper E/I Balance

“…Overall, bumetanide has been shown to exert a symptomatic action mitigating, at least in a subpopulation of autistic children, the severity of symptoms, which reappear after interruption of the treatment. A limitation however in using bumetanide for treating Neurodevelopmental Disorders lies on the fact that this drug has poor pharmacokinetic properties and low capability to cross the blood brain barrier (BBB) to reach either neuronal or non-neuronal targets (Puskarjov et al, 2014a ; Virtanen et al, 2020 ; Löscher and Kaila, 2021 ; Tóth et al, 2021 ). Moreover, an active efflux of bumetanide from the brain to the blood, which involves several transporters expressed at the BBB, including organic anion ones, would contribute to maintain a very low concentration of the drug in the brain (Römermann et al, 2017 ).…”

The debate on the treatment of neonatal seizures: Introductory remarks

“…3 These data were challenged by Ben-Ari and Delpire, 4 who wrote a commentary regarding these data, to which Kaila and Löscher responded. 5 The present group of papers further discusses the treatment of neonatal seizures. The discussion begins with a commentary by Kevin Staley in which he reviews bumetanide's mechanism of action and discusses its lack of efficacy in animal models.…”

“…Bumetanide alone or in combination with phenobarbital was ineffective 3 4 who wrote a commentary regarding these data, to which Kaila and Löscher responded 5 …”