title: Pharmacotherapeutic targeting of cation-chloride cotransporters in neonatal seizures.
abstract: 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 (CCCs) NKCC1 and KCC2, probably contribute to the poor efficacy of standard antiepileptic drugs used in the treatment of neonatal seizures. Although CCCs 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 NKCC1 inhibitors with increased central nervous system penetration, and direct and indirect strategies to enhance KCC2-mediated neuronal chloride extrusion, might allow therapeutic modulation of the GABAergic system for neonatal seizure treatment. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
authors.affiliation: Department of Biosciences and Neuroscience Center, University of Helsinki, Helsinki, Finland.
authors.forename: Martin
authors.initials: M
authors.lastname: Puskarjov
authors.forename: Kristopher T
authors.initials: KT
authors.lastname: Kahle
authors.forename: Eva
authors.initials: E
authors.lastname: Ruusuvuori
authors.forename: Kai
authors.initials: K
authors.lastname: Kaila
mesh_terms: D000927:Anticonvulsants / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects; D002034:Bumetanide / Q000627:therapeutic use; D006801:Humans; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000188:drug therapy*; D012640:Seizures / Q000188:drug therapy*; D028021:Sodium-Potassium-Chloride Symporters / Q000187:drug effects*; D064506:Solute Carrier Family 12, Member 2 / Q000187:drug effects; D027981:Symporters / Q000187:drug effects; D000096922:K Cl- Cotransporters
chemical_list: D000927:Anticonvulsants; D002034:Bumetanide; D028021:Sodium-Potassium-Chloride Symporters; D064506:Solute Carrier Family 12, Member 2; D027981:Symporters; D000096922:K Cl- Cotransporters; C415467:SLC12A9 protein, human
keywords: Bumetanide; Cation-chloride cotransporters; KCC2; NKCC1; Neonate