title: Chloride cotransporter NKCC1 inhibitor bumetanide protects against white matter injury in a rodent model of periventricular leukomalacia.
abstract: BACKGROUND
  Periventricular leukomalacia (PVL) is a major form of preterm brain injury. Na(+)-K(+)-Cl(-) 1 cotransporter (NKCC1) expression on neurons and astrocytes is developmentally regulated and mediates Cl(-) reversal potential. We hypothesized that NKCC1 is highly expressed on oligodendrocytes (OLs) and increases vulnerability to hypoxia-ischemia (HI) mediated white matter injury, and that the NKCC1 inhibitor bumetanide would be protective in a rodent PVL model.
  
  
  METHODS
  Immunohistochemistry in Long-Evans rats and PLP-EGFP transgenic mice was used to establish cell-specific expression of NKCC1 in the immature rodent brain. HI was induced on postnatal day 6 (P6) in rats and the protective efficacy of bumetanide (0.3 mg/kg/i.p. q12h × 60 h) established.
  
  
  RESULTS
  NKCC1 was expressed on OLs and subplate neurons through the first 2 postnatal weeks, peaking in white matter and the subplate between P3-7. Following HI, NKCC1 is expressed on OLs and neurons. Bumetanide treatment significantly attenuates myelin basic protein loss and neuronal degeneration 7 d post-HI.
  
  
  CONCLUSIONS
  Presence and relative overexpression of NKCC1 in rodent cerebral cortex coincides with a period of developmental vulnerability to HI white matter injury in the immature prenatal brain. The protective efficacy of bumetanide in this model of preterm brain injury suggests that Cl(-) transport is a factor in PVL and that its inhibition may have clinical application in premature human infants.
authors.affiliation: 1] Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts [2] Department of Pediatrics, University of New Mexico, Albuquerque, New Mexico.
authors.forename: Lauren L
authors.initials: LL
authors.lastname: Jantzie
authors.affiliation: Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Melody Y
authors.initials: MY
authors.lastname: Hu
authors.affiliation: Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Hyun-Kyung
authors.initials: HK
authors.lastname: Park
authors.affiliation: Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Michele C
authors.initials: MC
authors.lastname: Jackson
authors.affiliation: Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Jenny
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Pediatrics, University of New Mexico, Albuquerque, New Mexico.
authors.forename: Jessie R
authors.initials: JR
authors.lastname: Maxwell
authors.affiliation: 1] Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts [2] Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Frances E
authors.initials: FE
authors.lastname: Jensen
mesh_terms: D000818:Animals; D002034:Bumetanide / Q000737:chemistry*; D002540:Cerebral Cortex / Q000254:growth & development* / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D000860:Hypoxia / Q000473:pathology; D007511:Ischemia / Q000473:pathology; D007969:Leukomalacia, Periventricular / Q000188:drug therapy* / Q000517:prevention & control; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000737:chemistry*; D064506:Solute Carrier Family 12, Member 2 / Q000378:metabolism*; D066127:White Matter / Q000187:drug effects*
chemical_list: C578878:Slc12a2 protein, mouse; C578879:Slc12a2 protein, rat; D049994:Sodium Potassium Chloride Symporter Inhibitors; D064506:Solute Carrier Family 12, Member 2; D002034:Bumetanide