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The Journal of Neuroscience, February 15, 2002, 22(4):1350-1362

Ionic Mechanism of Ouabain-Induced Concurrent Apoptosis and Necrosis in Individual Cultured Cortical Neurons

Ai Ying Xiao, Ling Wei, Shuli Xia, Steven Rothman, and Shan Ping Yu

Department of Neurology and Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, Missouri 63110

Energy deficiency and dysfunction of the Na⁺, K⁺-ATPase are common consequences of many pathological insults. The nature and mechanism of cell injury induced by impaired Na⁺, K⁺-ATPase, however, are not well defined. We used cultured cortical neurons to examine the hypothesis that blocking the Na⁺, K⁺-ATPase induces apoptosis by depleting cellular K⁺ and, concurrently, induces necrotic injury in the same cells by increasing intracellular Ca²⁺ and Na⁺.

The Na⁺, K⁺-ATPase inhibitor ouabain induced concentration-dependent neuronal death. Ouabain triggered transient neuronal cell swelling followed by cell shrinkage, accompanied by intracellular Ca²⁺ and Na⁺ increase, K⁺ decrease, cytochrome c release, caspase-3 activation, and DNA laddering. Electron microscopy revealed the coexistence of ultrastructural features of both apoptosis and necrosis in individual cells. The caspase inhibitor Z-Val-Ala-Asp(OMe)-fluoromethyl ketone (Z-VAD-FMK) blocked >50% of ouabain-induced neuronal death. Potassium channel blockers or high K⁺ medium, but not Ca²⁺ channel blockade, prevented cytochrome c release, caspase activation, and DNA damage. Blocking of K⁺, Ca²⁺, or Na⁺ channels or high K⁺ medium each attenuated the ouabain-induced cell death; combined inhibition of K⁺ channels and Ca²⁺ or Na⁺ channels resulted in additional protection. Moreover, coapplication of Z-VAD-FMK and nifedipine produced virtually complete neuroprotection.

These results suggest that the neuronal death associated with Na⁺, K⁺-pump failure consists of concurrent apoptotic and necrotic components, mediated by intracellular depletion of K⁺ and accumulation of Ca²⁺ and Na⁺, respectively. The ouabain-induced hybrid death may represent a distinct form of cell death related to the brain injury of inadequate energy supply and disrupted ion homeostasis.

Key words: Na⁺, K⁺-ATPase; apoptosis; necrosis; hybrid death; potassium channel; calcium; caspase; cytochrome c; DNA fragmentation; ouabain; strophanthidin

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Copyright © 2002 Society for Neuroscience  0270-6474/02/2241350-13$05.00/0

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