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

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.

Neonatal Hypoxia Ischaemia: Mechanisms, Models, and Therapeutic Challenges

“…Cultured rat subplate neurons were more vulnerable to OGD compared to mixed cortical neurons (Nguyen and McQuillen, 2010). In rats exposed to systemic HI at E18, a significant decrease in Nurr1-expressing subplate neurons was documented by P2 (Jantzie et al, 2014, 2015a,b,c) and similarly in fetal sheep (Dean et al, 2011). However, Nurr1-expressing Layer VI neurons were also decreased.…”

Brain-immune interactions in perinatal hypoxic-ischemic brain injury

“…The optimized hypoxia-ischemia Rice-Vannucci rodent models can mimic many aspects of brain white matter injury in the preterm newborn. PND3 and PND6 rat HI models have been used to resemble PVL in the immature brain (Jantzie et al, 2015; Zhu et al, 2017). In a PND5 mouse HI model, hypoxia-ischemia induces a pattern of diffuse white and focal gray matter injury similar to that in preterm infants with PVL (Albertsson et al, 2014).…”

Glial Na+‐dependent ion transporters in pathophysiological conditions

“…Oligodendrocyte in periventricular white matter and white matter tracts in spinal cord abundantly express NKCC1 (Jantzie et al, ; Plotkin et al, ). The resting [Na + ] i in oligodendrocytes is found to be ∼18.4 mM.…”

“…PVR is a gestation-dependent white matter lesion found in preterm infants and a major precursor of cognitive impairment and cerebral palsy (Volpe, 2003). A rodent model of PVR shows that NKCC1 is highly expressed in oligodendrocytes during early development and increases white matter's vulnerability to hypoxic ischemic injury (Jantzie et al, 2015). Inhibition of NKCC1 activity with bumetanide conferred significant protection against white matter injury (Jantzie et al, 2015).…”

“…A rodent model of PVR shows that NKCC1 is highly expressed in oligodendrocytes during early development and increases white matter's vulnerability to hypoxic ischemic injury (Jantzie et al, 2015). Inhibition of NKCC1 activity with bumetanide conferred significant protection against white matter injury (Jantzie et al, 2015). Taken together, these results suggest that like neurons oligodendrocytes are highly sensitive to ischemic damage and understanding the mechanisms of oligodendrocyte death may suggest new therapeutic strategies to preserve or restore white matter function and structure after ischemic insults.…”