N-terminally cleaved Bcl-x sub(L) mediates ischemia-induced neuronal death

• Published in: Nature neuroscience Vol. 15; no. 4; pp. 574 - 580
• Main Authors: Ofengeim, Dimitry, Chen, Ying-bei, Miyawaki, Takahiro, Li, Hongmei, Sacchetti, Silvio, Flannery, Richard J, Alavian, Kambiz N, Pontarelli, Fabrizio, Roelofs, Brian A, Hickman, John A, Hardwick, J Marie, Zukin, R Suzanne, Jonas, Elizabeth A
• Format: Journal Article
• Language: English
• Published: 01.03.2012
• ISSN: 1097-6256
• DOI: 10.1038/nn.3054

Transient global ischemia in rats induces delayed death of hippocampal CA1 neurons. Early events include caspase activation, cleavage of anti-death Bcl-2 family proteins and large mitochondrial channel activity. However, whether these events have a causal role in ischemia-induced neuronal death is unclear. We found that the Bcl-2 and Bcl-x sub(L) inhibitor ABT-737, which enhances death of tumor cells, protected rats against neuronal death in a clinically relevant model of brain ischemia. Bcl-x sub(L) is prominently expressed in adult neurons and can be cleaved by caspases to generate a pro-death fragment, Delta N-Bcl-x sub(L). We found that ABT-737 administered before or after ischemia inhibited Delta N-Bcl-x sub(L)-induced mitochondrial channel activity and neuronal death. To establish a causal role for Delta N-Bcl-x sub(L), we generated knock-in mice expressing a caspase-resistant form of Bcl-x sub(L). The knock-in mice exhibited markedly reduced mitochondrial channel activity and reduced vulnerability to ischemia-induced neuronal death. These findings suggest that truncated Bcl-x sub(L) could be a potentially important therapeutic target in ischemic brain injury.