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The Journal of Neuroscience, December 7, 2005, 25(49):11256-11268; doi:10.1523/JNEUROSCI.3271-05.2005

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Neurobiology of Disease
Decreased Neuronal Death in Na⁺/H⁺ Exchanger Isoform 1-Null Mice after In Vitro and In Vivo Ischemia

Jing Luo,^1,2 Hai Chen,^2,3 Douglas B. Kintner,² Gary E. Shull,⁴ and Dandan Sun^1,2

Departments of ¹Physiology and ²Neurosurgery and ³Neuroscience Training Program, University of Wisconsin Medical School, Madison, Wisconsin 53792, and ⁴Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, Cincinnati, Ohio 45267

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⁺_i rise but reduced the second phase of Na⁺_i rise by 40–50%. In addition, 60 min REOX evoked a 1.5-fold increase in [Ca²⁺]_i in 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 cytochrome c release were attenuated by inhibition of NHE1 activity. In an in vivo focal ischemic model, 2 h of left middle cerebral artery occlusion followed by 24 h of reperfusion induced 84.8 ± 8.0 mm³ infarction 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.

Key words: oxygen and glucose deprivation; HOE 642; Na⁺ and Ca²⁺ accumulation; Na⁺/Ca²⁺ exchange; cytochrome c; focal ischemia

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Received April 27, 2005; revised October 18, 2005; accepted October 20, 2005.

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