Low-dose cardiotonic steroids increase sodium–potassium ATPase activity that protects hippocampal slice cultures from experimental ischemia

The sodium–potassium ATPase (Na/K ATPase) is a major ionic transporter in the brain and is responsible for the maintenance of the Na+ and K+ gradients across the cell membrane. Cardiotonic steroids such as ouabain, digoxin and marinobufagenin are well-characterized inhibitors of the Na/K ATPase. Recently, cardiotonic steroids have been shown to have additional effects at concentrations below their IC50 for pumping. The cardiotonic steroids ouabain, digoxin, and marinobufagenin all show an inverted U-shaped dose–response curve with inhibition of pumping at concentrations near their IC50, while increasing Na/K ATPase activity at doses below their IC50. This stimulatory effect of cardiotonic steroids was observed in vitro in hippocampal slice cultures as well as in the hippocampus in vivo. Increased Na/K ATPase activity has been shown to protect slice culture neurons from hypoxia–hypoglycemia. Ouabain protected slice culture neurons from experimental ischemia at concentrations that increased Na/K ATPase. This protective effect was observed when ouabain was dosed 30 min before, or 2 h following experimental ischemia. Ouabain no longer protected against experimental ischemia if the increase of Na/K ATPase was blocked. These data suggest that the protective effect of ouabain was due to increased Na/K ATPase activity. The demonstration of a neuroprotective effect of cardiotonic steroids could potentially assist in the treatment of stroke since digoxin, one of the cardiotonic steroids examined in this study, has approval by the Food and Drug Administration and can be safely administered at the concentrations that increase Na/K ATPase activity.