TY - JOUR
T1 - Ischemic preconditioning blocks BAD translocation, Bcl-xL cleavage, and large channel activity in mitochondria of postischemic hippocampal neurons
AU - Miyawaki, Takahiro
AU - Mashiko, Toshihiro
AU - Ofengeim, Dimitry
AU - Flannery, Richard J.
AU - Noh, Kyung Min
AU - Fujisawa, Sho
AU - Bonanni, Laura
AU - Bennett, Michael V.L.
AU - Zukin, R. Suzanne
AU - Jonas, Elizabeth A.
PY - 2008/3/25
Y1 - 2008/3/25
N2 - Transient forebrain or global ischemia induces delayed neuronal death in vulnerable CA1 pyramidal cells with many features of apoptosis. A brief period of ischemia, i.e., ischemic preconditioning, affords robust protection of CA1 neurons against a subsequent more prolonged ischemic challenge. Here we show that preconditioning acts via PI3K/Akt signaling to block the ischemia-induced cascade involving mitochondrial translocation of Bad, assembly of Bad with Bcl-xL, cleavage of Bcl-xL to form its prodeath fragment, ΔN-Bcl-xL, activation of large-conductance channels in the mitochondrial outer membrane, mitochondrial release of cytochrome c and Smac/DIABLO (second mitochondria-derived activator of caspases/direct IAP-binding protein with low pI), caspase activation, and neuronal death. These findings show how preconditioning acts to prevent the release of cytochrome c and Smac/DIABLO from mitochondria and to preserve the integrity of the mitochondrial membrane. The specific PI3K inhibitor LY294002 administered in vivo 1 h before or immediately after ischemia or up to 120 h later significantly reverses preconditioning-induced protection, indicating a requirement for sustained PI3K signaling in ischemic tolerance. These findings implicate PI3K/Akt signaling in maintenance of the integrity of the mitochondrial outer membrane.
AB - Transient forebrain or global ischemia induces delayed neuronal death in vulnerable CA1 pyramidal cells with many features of apoptosis. A brief period of ischemia, i.e., ischemic preconditioning, affords robust protection of CA1 neurons against a subsequent more prolonged ischemic challenge. Here we show that preconditioning acts via PI3K/Akt signaling to block the ischemia-induced cascade involving mitochondrial translocation of Bad, assembly of Bad with Bcl-xL, cleavage of Bcl-xL to form its prodeath fragment, ΔN-Bcl-xL, activation of large-conductance channels in the mitochondrial outer membrane, mitochondrial release of cytochrome c and Smac/DIABLO (second mitochondria-derived activator of caspases/direct IAP-binding protein with low pI), caspase activation, and neuronal death. These findings show how preconditioning acts to prevent the release of cytochrome c and Smac/DIABLO from mitochondria and to preserve the integrity of the mitochondrial membrane. The specific PI3K inhibitor LY294002 administered in vivo 1 h before or immediately after ischemia or up to 120 h later significantly reverses preconditioning-induced protection, indicating a requirement for sustained PI3K signaling in ischemic tolerance. These findings implicate PI3K/Akt signaling in maintenance of the integrity of the mitochondrial outer membrane.
KW - Akt
KW - Ischemic tolerance
KW - PI3K
KW - Postischemic neurodegeneration
UR - http://www.scopus.com/inward/record.url?scp=42449095582&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=42449095582&partnerID=8YFLogxK
U2 - 10.1073/pnas.0800628105
DO - 10.1073/pnas.0800628105
M3 - Article
C2 - 18347331
AN - SCOPUS:42449095582
SN - 0027-8424
VL - 105
SP - 4892
EP - 4897
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 12
ER -