Molecular and Integrative Biosciences and Neuroscience Center, University of Helsinki, Helsinki, Finland.
Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Hannover, Germany.
Epilepsia. 2022 Jul;63(7):1868-1873. doi: 10.1111/epi.17279. Epub 2022 May 26.
In his editorial, Kevin Staley criticizes our recent work demonstrating the lack of effect of bumetanide in a novel model of neonatal seizures. The main points in our response are that (1) our work is on an asphyxia model, not one on "hypercarbia only"; (2) clinically relevant parenteral doses of bumetanide applied in vivo lead to concentrations in the brain parenchyma that are at least an order of magnitude lower than what would be sufficient to exert any direct effect-even a transient one-on neuronal functions, including neonatal seizures; and (3) moreover, bumetanide's molecular target in the brain is the Na-K-2Cl cotransporter NKCC1, which has vital functions in neurons, astrocytes, and oligodendrocytes as well as microglia. This would make it impossible even for highly brain-permeant NKCC1 blockers to specifically target depolarizing and excitatory actions of γ-aminobutyric acid in principal neurons of the brain, which is postulated as the rationale of clinical trials on neonatal seizures.
在他的社论中，Kevin Staley 批评了我们最近的研究工作，该工作表明布美他尼在一种新的新生儿癫痫模型中没有效果。我们回应的要点是：(1) 我们的工作是在窒息模型上进行的，而不是在“仅仅高碳酸血症”模型上进行的；(2) 临床上相关的布美他尼的静脉内剂量在体内应用会导致脑实质中的浓度至少低一个数量级，远低于足以发挥任何直接作用的浓度，即使是短暂的作用于神经元功能，包括新生儿癫痫；(3) 此外，布美他尼在脑中的分子靶标是 Na-K-2Cl 共转运蛋白 NKCC1，它在神经元、星形胶质细胞、少突胶质细胞和小胶质细胞中具有重要功能。即使是高度穿透血脑屏障的 NKCC1 阻滞剂也不可能专门针对大脑主要神经元中γ-氨基丁酸的去极化和兴奋作用，这被认为是新生儿癫痫临床试验的理论基础。
