| First Author | Ofengeim D | Year | 2012 |
| Journal | Nat Neurosci | Volume | 15 |
| Issue | 4 | Pages | 574-80 |
| PubMed ID | 22366758 | Mgi Jnum | J:191168 |
| Mgi Id | MGI:5461128 | Doi | 10.1038/nn.3054 |
| Citation | Ofengeim D, et al. (2012) N-terminally cleaved Bcl-xL mediates ischemia-induced neuronal death. Nat Neurosci 15(4):574-80 |
| abstractText | 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, DeltaN-Bcl-x(L). We found that ABT-737 administered before or after ischemia inhibited DeltaN-Bcl-x(L)-induced mitochondrial channel activity and neuronal death. To establish a causal role for DeltaN-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. |
