Complex spectrum of phenobarbital effects in a mouse model of neonatal hypoxia-induced seizures

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Date
2018
Authors
Quinlan, Sean M. M.
Rodriguez-Alvarez, Natalia
Molloy, Eleanor J.
Madden, Stephen F.
Boylan, Geraldine B.
Henshall, David C.
Jimenez-Mateos, Eva M.
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Nature Publishing Group
Published Version
10.1038/s41598-018-28044-2
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Abstract
Seizures in neonates, mainly caused by hypoxic-ischemic encephalopathy, are thought to be harmful to the brain. Phenobarbital remains the first line drug therapy for the treatment of suspected neonatal seizures but concerns remain with efficacy and safety. Here we explored the short- and long-term outcomes of phenobarbital treatment in a mouse model of hypoxia-induced neonatal seizures. Seizures were induced in P7 mice by exposure to 5% O-2 for 15 minutes. Immediately after hypoxia, pups received a single dose of phenobarbital (25 mg.kg(-1)) or saline. We observed that after administration of phenobarbital seizure burden and number of seizures were reduced compared to the hypoxic period; however, PhB did not suppress acute histopathology. Behavioural analysis of mice at 5 weeks of age previously subjected to hypoxia-seizures revealed an increase in anxiety-like behaviour and impaired memory function compared to control littermates, and these effects were not normalized by phenobarbital. In a seizure susceptibility test, pups previously exposed to hypoxia, with or without phenobarbital, developed longer and more severe seizures in response to kainic acid injection compared to control mice. Unexpectedly, mice treated with phenobarbital developed less hippocampal damage after kainic acid than untreated counterparts. The present study suggests phenobarbital treatment in immature mice does not improve the long lasting functional deficits induces by hypoxia-induced seizures but, unexpectedly, may reduce neuronal death caused by exposure to a second seizure event in later life.
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Keywords
Antiepileptic drugs , Febrile seizures , Neuronal injury , P2x7 receptor , Cell-death , Rat brain , Exposure , Mice , Susceptibility , Pathogenesis
Citation
Quinlan, S. M. M., Rodriguez-Alvarez, N., Molloy, E. J., Madden, S. F., Boylan, G. B., Henshall, D. C. and Jimenez-Mateos, E. M. (2018) 'Complex spectrum of phenobarbital effects in a mouse model of neonatal hypoxia-induced seizures', Scientific Reports, 8(1), 9986 (12pp). doi: 10.1038/s41598-018-28044-2
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https://www.nature.com/articles/s41598-018-28044-2
URI
https://hdl.handle.net/10468/6674
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Paediatrics and Child Health - Journal Articles
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© 2018, the Authors. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/