Acute TrkB inhibition rescues phenobarbital-resistant seizures in a mouse model of neonatal ischemia

S. K. Kang, Michael V Johnston, S. D. Kadam

Research output: Contribution to journalArticle

Abstract

Neonatal seizures are commonly associated with hypoxic-ischemic encephalopathy. Phenobarbital (PB) resistance is common and poses a serious challenge in clinical management. Using a newly characterized neonatal mouse model of ischemic seizures, this study investigated a novel strategy for rescuing PB resistance. A small-molecule TrkB antagonist, ANA12, used to selectively and transiently block post-ischemic BDNF-TrkB signaling in vivo, determined whether rescuing TrkB-mediated post-ischemic degradation of the K+-Cl- co-transporter (KCC2) rescued PB-resistant seizures. The anti-seizure efficacy of ANA12 + PB was quantified by (i) electrographic seizure burden using acute continuous video-electroencephalograms and (ii) post-treatment expression levels of KCC2 and NKCC1 using Western blot analysis in postnatal day (P)7 and P10 CD1 pups with unilateral carotid ligation. ANA12 significantly rescued PB-resistant seizures at P7 and improved PB efficacy at P10. A single dose of ANA12 + PB prevented the post-ischemic degradation of KCC2 for up to 24 h. As anticipated, ANA12 by itself had no anti-seizure properties and was unable to prevent KCC2 degradation at 24 h without follow-on PB. This indicates that unsubdued seizures can independently lead to KCC2 degradation via non-TrkB-dependent pathways. This study, for the first time as a proof-of-concept, reports the potential therapeutic value of KCC2 modulation for the management of PB-resistant seizures in neonates. Future investigations are required to establish the mechanistic link between ANA12 and the prevention of KCC2 degradation.

Original languageEnglish (US)
Pages (from-to)2792-2804
Number of pages13
JournalEuropean Journal of Neuroscience
Volume42
Issue number10
DOIs
Publication statusPublished - Nov 1 2015

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Keywords

  • Bumetanide
  • Hypoxic-ischemic encephalopathy
  • KCC2
  • Neonatal seizure
  • PB resistance

ASJC Scopus subject areas

  • Neuroscience(all)

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