title: Bumetanide augments the neuroprotective efficacy of phenobarbital plus hypothermia in a neonatal hypoxia-ischemia model.
abstract: BACKGROUND
  The NaKCl cotransporter NKCC1 facilitates intraneuronal chloride accumulation in the developing brain. Bumetanide (BUM), a clinically available diuretic, inhibits this chloride transporter and augments the antiepileptic effects of phenobarbital (PB) in neonatal rodents. In a neonatal cerebral hypoxia-ischemia (HI) model, elicited by right carotid ligation, followed by 90 min 8% O(2) exposure in 7-d-old (P7) rats, PB increases the neuroprotective efficacy of hypothermia (HT). We evaluated whether BUM influenced the neuroprotective efficacy of combination treatment with PB and HT.
  
  
  METHODS
  P7 rats underwent HI lesioning; 15 min later, all received PB (30 mg/kg), and 10 min later, half received BUM (10 mg/kg, PB-HT+BUM) and half received saline (PB-HT+SAL). One hour after HI, all were cooled (30 °C, 3 h). Contralateral forepaw sensorimotor function and brain damage were evaluated 1-4 wk later.
  
  
  RESULTS
  Forepaw functional measures were close to normal in the PB-HT+BUM group, whereas deficits persisted in PB-HT+SAL controls; there were corresponding reductions in right cerebral hemisphere damage (at P35, % damage: PB-HT+BUM, 21 ± 16 vs. 38 ± 20 in controls).
  
  
  CONCLUSIONS
  These results provide evidence that NKCC1 inhibition amplifies PB bioactivity in the immature brain and suggest that coadministration of PB and BUM may represent a clinically feasible therapy to augment the neuroprotective efficacy of therapeutic HT in asphyxiated neonates.
authors.affiliation: Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Yiqing
authors.initials: Y
authors.lastname: Liu
authors.forename: Yu
authors.initials: Y
authors.lastname: Shangguan
authors.forename: John D E
authors.initials: JD
authors.lastname: Barks
authors.forename: Faye S
authors.initials: FS
authors.lastname: Silverstein
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002034:Bumetanide / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004357:Drug Synergism; D007036:Hypothermia, Induced; D020925:Hypoxia-Ischemia, Brain / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D010634:Phenobarbital / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D018696:Neuroprotective Agents; D002034:Bumetanide; D010634:Phenobarbital