Abstract

Brain ischemia causes more extensive injury in hyperglycemic than normoglycemic subjects, and injury is to astroglia as well as neurons. In the present work, it was found that in cortical astrocytes from rat or mice, reoxygenation after hypoxia increases connexin hemichannel activity and decreases cell-cell communication via gap junctions as indicated by increased dye uptake and reduced dye coupling, respectively. These effects were potentiated by high glucose during the hypoxia time period in a concentration-dependent manner (and by zero glucose) and were not observed in connexin 43-/- astrocytes. In sensitive cells, the responses were transient or persistent after short and long periods of hypoxia, respectively. The persistent responses were associated with a progressive reduction in cell viability that was prevented by La3+ or by peptides that block connexin 43 (Cx43) hemichannels or by inhibition of p38 MAP kinase prior to hypoxia/reoxygenation. Treatments that block pannexin hemichannels were not protective. Block of Cx43 hemichannels did not affect the reduction in gap junction mediated dye coupling observed during reoxygenation. Cx43 hemichannels may be a therapeutic target to reduce cell death following stroke, particularly in hyperglycemic conditions.