Survival- and death-promoting events after transient cerebral ischemia: Phosphorylation of Akt, release of cytochrome c, and activation of caspase-like proteases
Yb. Ouyang et al., Survival- and death-promoting events after transient cerebral ischemia: Phosphorylation of Akt, release of cytochrome c, and activation of caspase-like proteases, J CEREBR B, 19(10), 1999, pp. 1126-1135
Release of cytochrome c (cyt c) into cytoplasm initiates caspase-mediated a
poptosis, whereas activation of Akt kinase by phosphorylation at serine-473
prevents apoptosis in several cell systems. To investigate cell death and
cell survival pathways, the authors studied release of cyt c, activation of
caspase, and changes in Akt phosphorylation in rat brains subjected to 15
minutes of ischemia followed by varying periods of reperfusion, The authors
found by electron microscopic study that a portion of mitochondria was swo
llen and structurally altered, whereas the cell membrane and nuclei were in
tact in hippocampal CA1 neurons after 36 hours of reperfusion. In some neur
ons, the pattern of immunostaining for cyt c changed from a punctuate patte
rn, likely representing mitochondria, to a more diffuse cytoplasmic localiz
ation at 36 and 48 hours of reperfusion as examined by laser-scanning confo
cal microscopic study. Western blot analysis showed that cyt c was increase
d in the cytosolic fraction in the hippocampus after 36 and 48 hours of rep
erfusion. Consistently, caspase-3-like activity was increased in these hipp
ocampal samples. As demonstrated by Western blot using phosphospecific Nit
antibody, phosphorylation of Akt at serine-473 in the hippocampal region wa
s highly increased during the first 24 hours but not at 48 hours of reperfu
sion. The authors conclude that transient cerebral ischemia activates both
cell death and cell survival pathways after ischemia. The activation of Nit
during the first 24 hours conceivably may be one of the factors responsibl
e for the delay in neuronal death after global ischemia.