Highlights
- •Birth asphyxia often causes hypoxic-ischemic encephalopathy, and neonatal seizures, and later-life adverse outcome.
- •In most cases, current therapies cannot prevent this outcome.
- •A rat model of birth asphyxia, neonatal seizures, and later-life adverse outcomes can be used to explore novel therapies.
- •The loop diuretic bumetanide enhances the anti-seizure and disease-modifying effects of midazolam in this model.
- •The mechanisms to explain that bumetanide potentiates midazolam but not phenobarbital remain to be determined.
Abstract
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.
Keywords
Abbreviations:
CAI (carbonic anhydrase inhibitor), HIE (hypoxic-ischemic encephalopathy), NKCC (Na-K-Cl-cotransporter), P11 (postnatal day 11), RAWM (radial-arm water maze)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: April 08, 2023
Accepted:
March 16,
2023
Received in revised form:
March 15,
2023
Received:
January 19,
2023
Identification
Copyright
© 2023 Elsevier Inc. All rights reserved.
