Interleukin-1 receptor in seizure susceptibility after traumatic injury to the pediatric brain

Bridgette D. Semple, Terence J. O’Brien, Kayleen Gimlin, David K. Wright, Shi Eun Kim, Pablo M. Casillas-Espinosa, Kyria M. Webster, Steven Petrou, Linda J. Noble-Haeusslein

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44 Citations (Scopus)

Abstract

Epilepsy after pediatric traumatic brain injury (TBI) is associated with poor quality of life. This study aimed to characterize posttraumatic epilepsy in a mouse model of pediatric brain injury, and to evaluate the role of interleukin-1 (IL-1) signaling as a target for pharmacological intervention. Male mice received a controlled cortical impact or sham surgery at postnatal day 21, approximating a toddler-aged child. Mice were treated acutely with an IL-1 receptor antagonist (IL-1Ra; 100 mg/kg, s.c.) or vehicle. Spontaneous and evoked seizures were evaluated from video-EEG recordings. Behavioral assays tested for functional outcomes, postmortem analyses assessed neuropathology, and brain atrophy was detected by ex vivo magnetic resonance imaging. At 2 weeks and 3 months post-injury, TBI mice showed an elevated seizure response to the convulsant pentylenetetrazol compared with sham mice, associated with abnormal hippocampal mossy fiber sprouting. A robust increase in IL-1β and IL-1 receptor were detected after TBI. IL-1Ra treatment reduced seizure susceptibility 2 weeks after TBI compared with vehicle, and a reduction in hippocampal astrogliosis. In a chronic study, IL-1Ra- TBI mice showed improved spatial memory at 4 months post-injury. At 5 months, most TBI mice exhibited spontaneous seizures during a 7 d video-EEG recording period. At 6 months, IL-1Ra-TBI mice had fewer evoked seizures compared with vehicle controls, coinciding with greater preservation of cortical tissue. Findings demonstrate this model’s utility to delineate mechanisms underlying epileptogenesis after pediatric brain injury, and provide evidence of IL-1 signaling as a mediator of post-traumatic astrogliosis and seizure susceptibility.

Original languageEnglish
Pages (from-to)7864-7877
Number of pages14
JournalJournal of Neuroscience
Volume37
Issue number33
DOIs
Publication statusPublished - 16 Aug 2017
Externally publishedYes

Keywords

  • Cytokine
  • Interleukin
  • Neurotrauma
  • Pediatric
  • Seizure
  • Traumatic brain injury

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