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  • Title: Bumetanide augments the neuroprotective efficacy of phenobarbital plus hypothermia in a neonatal hypoxia-ischemia model.
    Author: Liu Y, Shangguan Y, Barks JD, Silverstein FS.
    Journal: Pediatr Res; 2012 May; 71(5):559-65. PubMed ID: 22398701.
    Abstract:
    INTRODUCTION: 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). DISCUSSION: 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.
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