Chloride cotransporter NKCC1 inhibitor bumetanide protects against white matter injury in a rodent model of periventricular leukomalacia

Lauren L. Jantzie, Melody Y. Hu, Hyun Kyung Park, Michele C. Jackson, Jenny Yu, Jessie R. Maxwell, Frances E. Jensen

Research output: Contribution to journalArticle

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.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.

Original languageEnglish (US)
Pages (from-to)554-562
Number of pages9
JournalPediatric research
Volume77
Issue number4
DOIs
StatePublished - Apr 19 2015
Externally publishedYes

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

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