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It's only fair to tell you that the role of apoptosis in the setting of brain ischemia is
not exactly clear. In fact, there's a certain amount of controversy about it. It's best to discuss what we know about the situation
separately for focal and global brain ischemia.
Focal Ischemia:
Morphological and biochemical evidence seems to suggest apoptotic death in the
penumbra, with necrosis in the core.
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FOCAL ISCHEMIC NEURONAL DEATH
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PRO-APOPTOSIS
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ANTI-APOPTOSIS
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DNA
laddering is observed in the penumbra within a few hours.
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Necrotic
phenotypes predominate in the core.
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Transcription
of caspase 3 is observed in vulnerable neurons.
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Caspase
inhibitors convert "apoptotic" phenotypes to "necrotic"
phenotypes.
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Activated
caspase 3 is seen by 1-3 h of reperfusion.
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Caspase
3 inhibitors decrease caspase cleavage products, reduce tissue damage and
improve outcome in rodent stroke models.
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Global Ischemia: the
data is conflicting at best, with characteristics of both apoptosis and
necrosis.
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GLOBAL ISCHEMIC NEURONAL DEATH
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PRO-APOPTOSIS
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ANTI-APOPTOSIS
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TUNEL
staining (indicative of DNAse cleavage) observed in both animals and
humans.
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Apoptotic
bodies not observed by most investigators.
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Caspase
inhibitors protect against neuronal death.
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Morphology
typical of necrosis in primate neurons, even in the face of caspase
activation.
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Activated
caspase 3 seen as early as 1 hr of reperfusion.
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Little
evidence of nuclear clumping or chromatin condensation at the light level
(mixed results from EM).
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Caspase
3 mRNA appears early in SVNs.
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PARP
breaks down between 24 and 72 hours.
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BAX
and BclXs expressed in vulnerable CA1 neurons.
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Cytochrome
c
translocation noted in SVNs!
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