박현경
2016-11-03T05:32:19Z
2016-11-03T05:32:19Z
2015-04
PEDIATRIC RESEARCH, v. 77, NO 4, Page. 554-562
0031-3998
1530-0447
http://www.nature.com/pr/journal/v77/n4/full/pr20159a.html
http://hdl.handle.net/20.500.11754/24132
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.
This work was supported by the US National Institute of Neurological Disorders and Stroke at the National Institutes of Health (NS031718 and DP1 OD003347 from the Office of the Director to F.E.J.), the Heart and Stroke Foundation of Canada (to L.L.J), the William Randolph Hearst Foundation at Harvard Medical School (to L.L.J), the University of New Mexico Department of Pediatrics (to L.L.J), and Alberta Innovates Health Solutions Canada (to L.L.J).
en
NATURE PUBLISHING GROUP
NEONATAL HYPOXIA-ISCHEMIA
FOCAL CEREBRAL-ISCHEMIA
K+-CL-COTRANSPORTER
BRAIN-INJURY
MEDIATED EXCITOTOXICITY
NA+/CA2+ EXCHANGER
INFANTS
DAMAGE
OLIGODENDROCYTES
DISEASE
Chloride cotransporter NKCC1 inhibitor bumetanide protects against white matter injury in a rodent model of periventricular leukomalacia
Article
4
77
10.1038/pr.2015.9
554-562
PEDIATRIC RESEARCH
Jantzie, Lauren L.
Hu, Melody Y.
Park, Hyun-Kyung
Jackson, Michele C.
Yu, Jenny
Maxwell, Jessie R.
Jensen, Frances E.
2015002409
S
COLLEGE OF MEDICINE[S]
DEPARTMENT OF MEDICINE
neopark