Abstract
Recent studies demonstrated that chloride efflux via anion channels is involved in progression of apoptosis in various cell types. We have recently shown that the volume-sensitive outwardly rectifying (VSOR) chloride channel serves as the apoptotic chloride efflux pathway in human epithelial cells (PNAS 101, 6770, 2004). In the present study, we tested the neuroprotective effect of VSOR channel blockers on delayed neuronal cell death induced by transient forebrain ischemia. Whole-cell recordings revealed that cultured hippocampal neurons respond to osmotic swelling with activation of outwardly rectifying chloride current, which is sensitive to DIDS (500 μM) and genistein (100 μM), but not to daidzein (100 μM). Protective effects of these blockers on delayed neuronal cell death were examined in mice subjected to transient common carotid artery occlusion (12 min) by histological assessments. Pre-administration of DIDS (0.48, 12, 60 mg/kg) and genistein (0.24, 6.0, 30 mg/kg) via jugular vein followed by intraperitoneal administrations (once per day) after reperfusion reduced the number of damaged neurons in the CA1 region of hippocampus and cytochrome c release therefrom. These results suggest that VSOR chloride channels are involved in induction of delayed cell death in hippocampal neurons after transient forebrain ischemia and that blockers of this channel may provide a therapeutic target for the treatment of stroke. [Jpn J Physiol 55 Suppl:S149 (2005)]
