Ouabain improves functional recovery following traumatic brain injury.

Abstract

The cardiac steroid ouabain binds to Na(+), K(+)-ATPase and inhibits its activity. Administration of the compound to animals and humans causes an increase in the force of contraction of heart muscle and stabilizes heart rate. In addition, this steroid promotes the growth of cardiac, vascular, and neuronal cells both in vitro and in vivo. We studied the effects of ouabain on mouse recovery following closed head injury (CHI), a model for traumatic brain injury. We show that chronic (three times a week), but not acute, intraperitoneal administration of a low dose (1 μg/kg) of ouabain significantly improves mouse recovery and functional outcome. The improvement in mouse performance was accompanied by a decrease in lesion size, estimated 43 d following the trauma. In addition, mice that underwent CHI and were treated with ouabain showed an increase in the number of proliferating cells in the subventricular zone and in the area surrounding the site of injury. Determination of the identity of the proliferating cells in the area surrounding the trauma showed that whereas there was no change in the proliferation of endothelial cells or astrocytes, neuronal cell proliferation almost doubled in the ouabain-treated mice in comparison with that of the vehicle animals. These results point to a neuroprotective effects of low doses of ouabain and imply its involvement in brain recovery and neuronal regeneration. This suggests that ouabain and maybe other cardiac steroids may be used for the treatment of traumatic brain injury.