title: In vivo effects of bumetanide at brain concentrations incompatible with NKCC1 inhibition on newborn DGC structure and spontaneous EEG seizures following hypoxia-induced neonatal seizures.
abstract: Neonatal seizures caused by perinatal asphyxia and hypoxic-ischemic encephalopathy can be refractory to conventional anticonvulsants. This may be due to the depolarizing effects of gamma-aminobutyric acid (GABA) achieved by the activity of the Na(+)-K(+)-2Cl(-) cotransporter (NKCC1). The aim of this study is to evaluate the long-term effects of bumetanide, a NKCC1 inhibitor, on hippocampal neurogenesis and seizure susceptibility in hypoxia-induced neonatal seizure model. Wistar rats were subjected to hypoxia-induced neonatal seizures at postnatal day 10 (P10). Following acute seizures, the rats were treated with intraperitoneal injection (i.p.) of bumetanide at a dose of 0.5mg/kg for 3 weeks. In later adulthood, hypoxia-induced seizures increased the number of newborn dentate gyrus cells (DGCs), promoted mossy fiber sprouting (MFS) and reduced the apical dendritic complexity of newborn DGCs 1 month after the insults. In addition, these seizures resulted in long-lasting consequences, such as spontaneous electroencephalography (EEG) seizures, though spatial learning impairments were not seen. Bumetanide treatments significantly enhanced cell proliferation and dendritic development of newborn DGCs after neonatal seizures, accompanied by the decreased seizure activity. However, systemic administration of bumetanide resulted in much lower brain concentrations, and was incompatible with NKCC1 inhibition in blood-brain barrier (BBB)-protected brain tissue. Our results suggested that bumetanide might have long-term effects in suppressing seizure activity, and altering the neurogenesis after neonatal seizures. These effects of bumetanide may be mediated by the targets outside the BBB-protected central nerve system (CNS) or CNS-located target(s) other than NKCC1.
authors.affiliation: Department of Neurology, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning, PR China.
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Neurology, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning, PR China.
authors.forename: X Q
authors.initials: XQ
authors.lastname: Zhang
authors.affiliation: Department of Neurology, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning, PR China.
authors.forename: C G
authors.initials: CG
authors.lastname: Song
authors.affiliation: Department of Dermatology, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning, PR China; Key Laboratory of Immunodermatology, Ministry of Health, Ministry of Education, Shenyang, Liaoning, PR China.
authors.forename: T
authors.initials: T
authors.lastname: Xiao
authors.affiliation: Department of Cardiology, The Shengjing Affiliated Hospital, China Medical University, Shenyang, Liaoning, PR China.
authors.forename: M
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Psychiatry, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning, PR China.
authors.forename: G
authors.initials: G
authors.lastname: Zhu
authors.affiliation: Department of Neurology, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning, PR China. Electronic address: cszhao@mail.cmu.edu.cn.
authors.forename: C S
authors.initials: CS
authors.lastname: Zhao
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D001923:Brain Chemistry; D002034:Bumetanide / Q000008:administration & dosage* / Q000032:analysis / Q000493:pharmacokinetics; D049109:Cell Proliferation / Q000187:drug effects; D018891:Dentate Gyrus / Q000187:drug effects* / Q000503:physiopathology*; D004569:Electroencephalography; D000860:Hypoxia / Q000150:complications*; D055495:Neurogenesis / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000209:etiology / Q000517:prevention & control*; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000008:administration & dosage* / Q000032:analysis / Q000493:pharmacokinetics; D064506:Solute Carrier Family 12, Member 2; D065853:Spatial Learning / Q000187:drug effects
chemical_list: C578879:Slc12a2 protein, rat; D049994:Sodium Potassium Chloride Symporter Inhibitors; D064506:Solute Carrier Family 12, Member 2; D002034:Bumetanide
keywords: NKCC1; epilepsy; hypoxia; neurogenesis; neuronal plasticity