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

Abstract

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, a causal role of these events in ischemia-induced neuronal death is unclear. Unexpectedly, we found that the Bcl-2/Bcl-xL inhibitor ABT-737, which enhances death of tumor cells, protects rats against neuronal death in a clinically relevant model of brain ischemia. Bcl-xL is prominently expressed in adult neurons and can be cleaved by caspases to generate a pro-death fragment ΔN-Bcl-xL. We found that ABT-737 administered before or after ischemia inhibited ΔN-Bcl-xL-induced mitochondrial channel activity and neuronal death. To establish a causal role for ΔN-Bcl-xL, we generated knockin mice expressing caspase-resistant Bcl-xL. The knockin mice exhibit strikingly reduced mitochondrial channel activity and reduced vulnerability to ischemia-induced neuronal death. These findings point to truncated Bcl-xL as a potentially important therapeutic target in ischemic brain injury.