Nuclear translocation and calpain-dependent reduction of Bcl-2 after neonatal cerebral hypoxia-ischemia.
Apoptosis-related mechanisms are important in the pathophysiology of hypoxic-ischemic injury in the neonatal brain. Caspases are the major executioners of apoptosis, but there are a number of upstream players that influence the cell death pathways. The Bcl-2 family proteins are important modulators of mitochondrial permeability, working either to promote or prevent apoptosis. In this study we focused on the anti-apoptotic Bcl-2 protein after neonatal cerebral hypoxia-ischemia (HI) in 8-day-old rats. Bcl-2 translocated to nuclei and accumulated there over the first 24h of reperfusion after HI, as judged by immunohistochemistry and immuno-electron microscopy. We also found that the total level of Bcl-2 decreased after HI in vivo and after ionophore challenge in cultured human neuroblastoma (IMR-32) cells in vitro. Furthermore, the Bcl-2 reduction was calpain-dependent, because it could be prevented by the calpain inhibitor CX295 both in vivo and in vitro, suggesting cross-talk between excitotoxic and apoptotic mechanisms.
Center for Brain Repair and Rehabilitation, University of Gothenburg, Gothenburg, Sweden.
Changlian
C
Zhu
Ulrika
U
Hallin
Yasuhiko
Y
Ozaki
Rita
R
Grandér
Kliment
K
Gatzinsky
Ben A
BA
Bahr
Jan-Olof
JO
Karlsson
Futoshi
F
Shibasaki
Henrik
H
Hagberg
Klas
K
Blomgren
D021581:Active Transport, Cell Nucleus; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D002154:Calpain / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D016253:Microscopy, Immunoelectron; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D002154:Calpain