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Decreased Neuronal Death in Na+/H+Exchanger Isoform 1-Null Mice afterIn VitroandIn VivoIschemia
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| Zeitschriftentitel: | The Journal of Neuroscience |
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| Personen und Körperschaften: | , , , , |
| In: | The Journal of Neuroscience, 25, 2005, 49, S. 11256-11268 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
Society for Neuroscience
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| Schlagwörter: |
| Zusammenfassung: | <jats:p>Na<jats:sup>+</jats:sup>/H<jats:sup>+</jats:sup>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<jats:sup>+</jats:sup>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% (<jats:italic>p</jats:italic>< 0.05). In NHE1<jats:sup>+/+</jats:sup>neurons, OGD caused a twofold increase in [Na<jats:sup>+</jats:sup>]<jats:sub>i</jats:sub>, 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<jats:sup>+</jats:sup><jats:sub>i</jats:sub>rise but reduced the second phase of Na<jats:sup>+</jats:sup><jats:sub>i</jats:sub>rise by ∼40–50%. In addition, 60 min REOX evoked a 1.5-fold increase in [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub>in NHE1<jats:sup>+/+</jats:sup>neurons, which was abolished by inhibition of either NHE1 or reverse-mode operation of Na<jats:sup>+</jats:sup>/Ca<jats:sup>2+</jats:sup>exchange. OGD/REOX-mediated mitochondrial Ca<jats:sup>2+</jats:sup>accumulation and cytochrome<jats:italic>c</jats:italic>release were attenuated by inhibition of NHE1 activity. In an<jats:italic>in vivo</jats:italic>focal ischemic model, 2 h of left middle cerebral artery occlusion followed by 24 h of reperfusion induced 84.8 ± 8.0 mm<jats:sup>3</jats:sup>infarction in NHE1<jats:sup>+/+</jats:sup>mice. NHE1<jats:sup>+/+</jats:sup>mice treated with HOE 642 or NHE1 heterozygous mice exhibited a ∼33% decrease in infarct size (<jats:italic>p</jats:italic>< 0.05). These results imply that NHE1 activity disrupts Na<jats:sup>+</jats:sup>and Ca<jats:sup>2+</jats:sup>homeostasis and contributes to ischemic neuronal damage.</jats:p> |
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| Umfang: | 11256-11268 |
| ISSN: |
0270-6474
1529-2401 |
| DOI: | 10.1523/jneurosci.3271-05.2005 |