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Acute TrkB inhibition rescues phenobarbital‐resistant seizures in a mouse model of neonatal ischemia
Author(s) -
Kang S. K.,
Johnston M. V.,
Kadam S. D.
Publication year - 2015
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/ejn.13094
Subject(s) - phenobarbital , tropomyosin receptor kinase b , neonatal seizure , medicine , pharmacology , kindling , epilepsy , endocrinology , chemistry , receptor , neurotrophic factors , psychiatry
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, ANA 12, 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 ( KCC 2) rescued PB ‐resistant seizures. The anti‐seizure efficacy of ANA 12 + PB was quantified by (i) electrographic seizure burden using acute continuous video‐electroencephalograms and (ii) post‐treatment expression levels of KCC 2 and NKCC 1 using Western blot analysis in postnatal day (P)7 and P10 CD 1 pups with unilateral carotid ligation. ANA 12 significantly rescued PB ‐resistant seizures at P7 and improved PB efficacy at P10. A single dose of ANA 12 + PB prevented the post‐ischemic degradation of KCC 2 for up to 24 h. As anticipated, ANA 12 by itself had no anti‐seizure properties and was unable to prevent KCC 2 degradation at 24 h without follow‐on PB . This indicates that unsubdued seizures can independently lead to KCC 2 degradation via non‐TrkB‐dependent pathways. This study, for the first time as a proof‐of‐concept, reports the potential therapeutic value of KCC 2 modulation for the management of PB ‐resistant seizures in neonates. Future investigations are required to establish the mechanistic link between ANA 12 and the prevention of KCC 2 degradation.