Translational Investigation | Published:

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

Pediatric Research volume 77, pages 554562 (2015) | Download Citation

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.

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Acknowledgements

The authors are particularly appreciative of Shenandoah Robinson for helpful discussions regarding the manuscript.

Author information

Affiliations

  1. Department of Neurology, Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts

    • Lauren L. Jantzie
    • , Melody Y. Hu
    • , Hyun-Kyung Park
    • , Michele C. Jackson
    • , Jenny Yu
    •  & Frances E. Jensen
  2. Department of Pediatrics, University of New Mexico, Albuquerque, New Mexico

    • Lauren L. Jantzie
    •  & Jessie R. Maxwell
  3. Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

    • Frances E. Jensen

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Correspondence to Frances E. Jensen.

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DOI

https://doi.org/10.1038/pr.2015.9

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