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Eur J Neurosci. 2015 Nov;42(10):2792-804. doi: 10.1111/ejn.13094.

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

Author information

1
Neuroscience Laboratory, Hugo Moser Research Institute at Kennedy Krieger, 716 North Broadway, Baltimore, MD, 21205, USA.
2
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
3
Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

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.

KEYWORDS:

Bumetanide; KCC2; PB resistance; hypoxic-ischemic encephalopathy; neonatal seizure

PMID:
26452067
PMCID:
PMC4715496
DOI:
10.1111/ejn.13094
[Indexed for MEDLINE]
Free PMC Article

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