Decreased neuronal death in Na+/H+ exchanger isoform 1-null mice after in vitro and in vivo ischemia.

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 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.

• Authors: Jing Luo, Hai Chen, Douglas B Kintner, Gary E Shull, Dandan Sun
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 25 Issue 49 Pg. 11256-68 (Dec 07 2005) ISSN: 1529-2401 [Electronic] United States
• PMID: 16339021 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cation Transport Proteins
• Membrane Proteins
• Slc9a1 protein, mouse
• Sodium-Hydrogen Exchanger 1
• Sodium-Hydrogen Exchangers

Topics

• Animals
• Brain Ischemia (genetics, metabolism, pathology)
• Cation Transport Proteins (biosynthesis, genetics, physiology)
• Cell Death (genetics, physiology)
• Cell Hypoxia (genetics, physiology)
• Cells, Cultured
• Enzyme Activation (genetics)
• Female
• Male
• Membrane Proteins (biosynthesis, genetics, physiology)
• Mice
• Mice, Knockout
• Neurons (enzymology, pathology)
• Pregnancy
• Sodium-Hydrogen Exchanger 1
• Sodium-Hydrogen Exchangers (biosynthesis, genetics, physiology)