| First Author | Luo J | Year | 2005 |
| Journal | J Neurosci | Volume | 25 |
| Issue | 49 | Pages | 11256-68 |
| PubMed ID | 16339021 | Mgi Jnum | J:123442 |
| Mgi Id | MGI:3718306 | Doi | 10.1523/JNEUROSCI.3271-05.2005 |
| Citation | Luo J, et al. (2005) Decreased neuronal death in Na+/H+ exchanger isoform 1-null mice after in vitro and in vivo ischemia. J Neurosci 25(49):11256-68 |
| abstractText | 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 approximately 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 approximately 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 approximately 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. |
