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Pharmacotherapeutic targeting of cation‐chloride cotransporters in neonatal seizures
Author(s) -
Puskarjov Martin,
Kahle Kristopher T.,
Ruusuvuori Eva,
Kaila Kai
Publication year - 2014
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.12620
Subject(s) - bumetanide , medicine , epilepsy , neuroscience , anticonvulsant , cotransporter , pharmacology , tiagabine , central nervous system , bioinformatics , biology , chemistry , organic chemistry , sodium
Summary Seizures are a common manifestation of acute neurologic insults in neonates and are often resistant to the standard antiepileptic drugs that are efficacious in children and adults. The paucity of evidence‐based treatment guidelines, coupled with a rudimentary understanding of disease pathogenesis, has made the current treatment of neonatal seizures empiric and often ineffective, highlighting the need for novel therapies. Key developmental differences in γ‐aminobutyric acid ( GABA) ergic neurotransmission between the immature and mature brain, and trauma‐induced alterations in the function of the cation‐chloride cotransporters ( CCC s) NKCC 1 and KCC 2, probably contribute to the poor efficacy of standard antiepileptic drugs used in the treatment of neonatal seizures. Although CCC s are attractive drug targets, bumetanide and other existing CCC inhibitors are suboptimal because of pharmacokinetic constraints and lack of target specificity. Newer approaches including isoform‐specific NKCC 1 inhibitors with increased central nervous system penetration, and direct and indirect strategies to enhance KCC 2‐mediated neuronal chloride extrusion, might allow therapeutic modulation of the GABA ergic system for neonatal seizure treatment. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here .