N-terminally cleaved Bcl-xL mediates ischemia-induced neuronal death

Inhibition of Bcl-2 and Bcl-x L by ABT-737 is known to enhance tumor cell death. Here the authors find that it is actually protective against neuronal death in an animal model of ischemia via blockade of Bcl-x L –induced mitochondrial channel activity. These findings point to Bcl-x L as a potential therapeutic target. 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 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 L is prominently expressed in adult neurons and can be cleaved by caspases to generate a pro-death fragment, ΔN-Bcl-x L . We found that ABT-737 administered before or after ischemia inhibited ΔN-Bcl-x L –induced mitochondrial channel activity and neuronal death. To establish a causal role for ΔN-Bcl-x L , we generated knock-in mice expressing a caspase-resistant form of Bcl-x 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 L could be a potentially important therapeutic target in ischemic brain injury.