Decreased Neuronal Death in Na+/H+Exchanger Isoform 1-Null Mice afterIn VitroandIn VivoIschemia

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Abstract
Na+/H+exchanger isoform 1 (NHE1) is a major acid extrusion mechanism after intracellular acidosis. We hypothesized that stimulation of NHE1 after cerebral ischemia contributes to the disruption of Na+homeostasis and neuronal death. In the present study, expression of NHE1 was detected in cultured mouse cortical neurons. Three hours of oxygen and glucose deprivation (OGD) followed by 21 h of reoxygenation (REOX) led to 68 ± 10% cell death. Inhibition of NHE1 with the potent inhibitor cariporide (HOE 642) or genetic ablation of NHE1 reduced OGD-induced cell death by ∼40–50% (p< 0.05). In NHE1+/+neurons, OGD caused a twofold increase in [Na+]i, and 60 min REOX triggered a sevenfold increase. Genetic ablation of NHE1 or HOE 642 treatment had no effects on the OGD-mediated initial Na+irise but reduced the second phase of Na+irise by ∼40–50%. In addition, 60 min REOX evoked a 1.5-fold increase in [Ca2+]iin NHE1+/+neurons, which was abolished by inhibition of either NHE1 or reverse-mode operation of Na+/Ca2+exchange. OGD/REOX-mediated mitochondrial Ca2+accumulation and cytochromecrelease were attenuated by inhibition of NHE1 activity. In anin vivofocal ischemic model, 2 h of left middle cerebral artery occlusion followed by 24 h of reperfusion induced 84.8 ± 8.0 mm3infarction in NHE1+/+mice. NHE1+/+mice treated with HOE 642 or NHE1 heterozygous mice exhibited a ∼33% decrease in infarct size (p< 0.05). These results imply that NHE1 activity disrupts Na+and Ca2+homeostasis and contributes to ischemic neuronal damage.