Open AccessNa+-Dependent Chloride Transporter (NKCC1)-Null Mice Exhibit Less Gray and White Matter Damage after Focal Cerebral Ischemia
Author(s) -
Hai Chen,
Jing Luo,
Douglas B. Kintner,
Gary E. Shull,
Dandan Sun
Publication year - 2005
Publication title -
journal of cerebral blood flow and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.167
H-Index - 193
eISSN - 1559-7016
pISSN - 0271-678X
DOI - 10.1038/sj.jcbfm.9600006
Subject(s) - neuroprotection , ischemia , reperfusion injury , medicine , in vivo , white matter , cotransporter , pharmacology , edema , chemistry , endocrinology , anesthesia , biology , sodium , magnetic resonance imaging , microbiology and biotechnology , radiology , organic chemistry
We previously demonstrated that pharmacological inhibition of Na + −K + −Cl − cotransporter isoform 1 (NKCC1) is neuroprotective in in vivo and in vitro ischemic models. In this study, we investigated whether genetic ablation of NKCC1 provides neuroprotection after ischemia. Focal ischemia was induced by 2 hours occlusion of the left middle cerebral artery (MCAO) followed by 10 or 24 hours reperfusion. Two hours MCAO and ten or twenty-four hours reperfusion caused infarction (˜85 mm 3 ) in NKCC1 wild-type (NKCC1 +/+ ) mice. Infarction volume in NKCC1 −/− mice was reduced by ˜30% to 46%. Heterozygous mutant (NKCC1 +/– ) mice showed ˜28% reduction in infarction ( P>0.05). Two hours MCAO and twenty-four hours reperfusion led to a significant increase in brain edema in NKCC1 +/+ mice. In contrast, NKCC1 +/– and NKCC1 −/− mice exhibited ˜50% less edema ( P<0.05). Moreover, white matter damage was assessed by immunostaining of amyloid precursor protein (APP). An increase in APP was detected in NKCC1 +/+ mice after 2 hours MCAO and 10 hours reperfusion. However, NKCC1 −/− mice exhibited significantly less APP accumulation ( P<0.05). Oxygen-glucose deprivation (OGD) induced ˜67% cell death and a fourfold increase in Na + accumulation in cultured NKCC1 +/+ cortical neurons. OGD-mediated cell death and Na + influx were significantly reduced in NKCC1 −/− neurons ( P<0.05). In addition, inhibition of NKCC1 by bumetanide resulted in similar protection in NKCC1 +/+ neurons and astrocytes ( P<0.05). These results imply that stimulation of NKCC1 activity is important in ischemic neuronal damage.