Bumetanide potentiates the anti-seizure and disease-modifying effects of midazolam in a noninvasive rat model of term birth asphyxia.

Birth asphyxia and the resulting hypoxic-ischemic encephalopathy (HIE) are highly associated with perinatal and neonatal death, neonatal seizures, and an adverse later-life outcome. Currently used drugs, including phenobarbital and midazolam, have limited efficacy to suppress neonatal seizures. There is a medical need to develop new therapies that not only suppress neonatal seizures but also prevent later-life consequences. We have previously shown that the loop diuretic bumetanide does not potentiate the effects of phenobarbital in a rat model of birth asphyxia. Here we compared the effects of bumetanide (0.3 or 10 mg/kg i.p.), midazolam (1 mg/kg i.p.), and a combination of bumetanide and midazolam on neonatal seizures and later-life outcomes in this model. While bumetanide at either dose was ineffective when administered alone, the higher dose of bumetanide markedly potentiated midazolam's effect on neonatal seizures. Median bumetanide brain levels (0.47-0.53 µM) obtained with the higher dose were in the range known to inhibit the Na-K-Cl-cotransporter NKCC1 but it remains to be determined whether brain NKCC1 inhibition was underlying the potentiation of midazolam. When behavioral and cognitive alterations were examined over three months after asphyxia, treatment with the bumetanide/midazolam combination, but not with bumetanide or midazolam alone, prevented impairment of learning and memory. Furthermore, the combination prevented the loss of neurons in the dentate hilus and aberrant mossy fiber sprouting in the CA3a area of the hippocampus. The molecular mechanisms that explain that bumetanide potentiates midazolam but not phenobarbital in the rat model of birth asphyxia remain to be determined.

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Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.