Chloride cotransporter NKCC1 inhibitor bumetanide protects against white matter injury in a rodent model of periventricular leukomalacia
- Chloride cotransporter NKCC1 inhibitor bumetanide protects against white matter injury in a rodent model of periventricular leukomalacia
- NEONATAL HYPOXIA-ISCHEMIA; FOCAL CEREBRAL-ISCHEMIA; K+-CL-COTRANSPORTER; BRAIN-INJURY; MEDIATED EXCITOTOXICITY; NA+/CA2+ EXCHANGER; INFANTS; DAMAGE; OLIGODENDROCYTES; DISEASE
- Issue Date
- NATURE PUBLISHING GROUP
- PEDIATRIC RESEARCH, v. 77, NO 4, Page. 554-562
- 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 x 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.
CONCLUSION: 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.
- 0031-3998; 1530-0447
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