Na+/HCO3- Co-transporters Inhibitor S0859 Attenuates Global Cerebral Ischemia-reperfusion Injury of the CA1 Neurons in the Gerbil's Hippocampus.

BACKGROUND: Metabolic acidosis plays a key role in transient global cerebral ischemiareperfusion (I/R) induced delayed neuronal death (DND) of the hippocampal CA1 region of gerbils. Na+ coupled HCO3 - transporters (NBCs) mediated Na+/HCO3- - co-transportation can be activated by the pH gradient of intracellular and extracellular environments induced by acidosis. However, whether NBCs are activated and involved in I/R-induced neuronal injury is unknown. OBJECTIVE: In this work, we studied neuronal apoptosis, astrocyte activation, and hippocampusdependent memory task using a well-established transient global cerebral I/R model of gerbils and investigated whether the specific NBCs inhibitor S0859 could reverse this injury. METHODS: To explore the role of S0859 in I/R-induced DND, we established a transient global cerebral I/R model of Mongolian gerbils and studied neuronal apoptosis by using Nissl stain and TUNEL assay. The excitability and NBCs current were analyzed by whole-cell patch-clamp, while the cognitive function was evaluated by Barnes maze. RESULTS: We found that I/R increased the NBCs current, inhibited the excitability of CA1 neurons, and led to apoptosis in CA1 neurons. Selective NBCs inhibitor S0859 protected CA1 neurons from I/R induced neuronal cell death, astrocyte accumulation, and spatial memory impairment. CONCLUSION: These findings indicate that NBCs mediate transient global cerebral I/R induced DND of CA1 neurons, and NBCs inhibitors could be a promising target to protect neuronal functions after I/R.

Sodium bicarbonate transporter NBCe1 regulates proliferation and viability of human prostate cancer cells LNCaP and PC3.

Studies on cultured cancer cells or cell lines have revealed multiple acid extrusion mechanisms and their involvement in cancer cell growth and progression. In the present study, the role of the sodium bicarbonate transporters (NBCs) in prostate cancer cell proliferation and viability was examined. qPCR revealed heterogeneous expression of five NBC isoforms in human prostate cancer cell lines LNCaP, PC3, 22RV1, C4-2, DU145, and the prostate cell line RWPE-1. In fluorescence pH measurement of LNCaP cells, which predominantly express NBCe1, Na+ and HCO3--mediated acid extrusion was identified by bath ion replacement and sensitivity to the NBC inhibitor S0859. NBCe1 knockdown using siRNA oligonucleotides decreased the number of viable cells, and pharmacological inhibition with S0859 (50 µM) resulted in a similar decrease. NBCe1 knockdown and inhibition also increased cell death, but this effect was small and slow. In PC3 cells, which express all NBC isoforms, NBCe1 knockdown decreased viable cell number and increased cell death. The effects of NBCe1 knockdown were comparable to those by S0859, indicating that NBCe1 among NBCs primarily contributes to PC3 cell proliferation and viability. S0859 inhibition also decreased the formation of cell spheres in 3D cultures. Immunohistochemistry of human prostate cancer tissue microarrays revealed NBCe1 localization to the glandular epithelial cells in prostate tissue and robust expression in acinar and duct adenocarcinoma. In conclusion, our study demonstrates that NBCe1 regulates acid extrusion in prostate cancer cells and inhibiting or abolishing this transporter decreases cancer cell proliferation.

The electrogenic cardiac sodium bicarbonate co-transporter (NBCe1) contributes to the reperfusion injury.

BACKGROUND: Although the participation of the electrogenic sodium/bicarbonate cotransporter (NBCe1) in the recovery from an intracellular acid load is recognized, its role in ischemia-reperfusion is still unclear. METHODS AND RESULTS: Our objective was to assess the role of NBCe1 in reperfusion injury. We use selective functional antibodies against extracellular loop 3 (a-L3) and loop 4 (a-L4) of NBCe1. a-L3 inhibits and a-L4 stimulates NBCe1 activity. Isolated rat hearts were submitted to 40 min of coronary occlusion and 1 h of reperfusion. a-L3, a-L4 or S0859--selective Na(+)-HCO3(-) co-transport inhibitor--were administered during the initial 10 min of reperfusion. The infarct size (IS) was measured by triphenyltetrazolium chloride staining technique. Postischemic systolic and diastolic functions were also assessed. a-L3 and S0859 treatments decreased significantly (P < .05) the IS (16 ± 3% for a-L3 vs. 32 ± 5% in hearts treated with control nonimmune serum and 19 ± 3% for S0859 vs. 39 ± 2% in untreated hearts). Myocardial function during reperfusion improved after a-L3 treatment, but it was not modified by S0859. The infusion of a-L4 did not modify neither the IS nor myocardial function. CONCLUSIONS: The NBCe1 hyperactivity during reperfusion leads to Na(+) and Ca(2+) loading, conducing to Ca(2+) overload and myocardial damage. Consistently, we have shown herein that the selective NBCe1 blockade with a-L3 exerted cardioprotection. This beneficial action strongly suggests that NBCe1 could be a potential target for the treatment of coronary disease.