(Stroke. 1997;28:1073-1081.)
© 1997 American Heart Association, Inc.
Articles |
Global Ischemia Activates Nuclear Factor-
B in Forebrain Neurons of Rats
From Eli Lilly and Company, CNS Division, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Ind.
Correspondence to Dr James A. Clemens, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285.
Background and Purpose After global ischemia,
brain levels of hydrogen peroxide, oxygen radicals, and the
cytokines tumor necrosis factor-
(TNF-) and
interleukin-1ß (IL-1ß) are increased. Oxygen radicals, TNF-, and
IL-1ß are known to activate nuclear factor-B (NF-B) in
vitro. The present study was performed to determine whether NF-B
was activated in vivo by global ischemia in hippocampal
CA1 neurons.
Methods Adult male rats were subjected to 30 minutes of
four-vessel occlusion and killed 72 hours later. Levels of NF-B p50
and p65 subunits in hippocampus were determined by immunocytochemistry,
Western blot, and gel-shift analysis. Specific labeling of DNA
strand breaks was demonstrated by means of an Apoptag apoptosis
detection kit.
Results Labeling of DNA strand breaks was present at 72
hours. Chromatin compaction and segregation, a characteristic of
apoptosis, was observed in sections stained with hematoxylin
and eosin. NF-B p50 and p65 immunoreactivity localized only to
nuclei of CA1 neurons at 72 hours after reperfusion. Induction of the
activated p50 and p65 subunits was confirmed by Western blot
and electromobility shift analysis. The results demonstrate
that NF-B is activated selectively in hippocampal CA1
neurons at 72 hours after four-vessel occlusion, which is at the
approximate time of CA1 neuronal cell death.
Conclusions Transient forebrain ischemia resulted
in a marked activation of nuclear NF-B in the highly vulnerable CA1
sector. Intense nuclear localization of NF-B was associated only
with dying neurons; regions of the hippocampus that were not vulnerable
to four-vessel occlusion did not exhibit nuclear NF-B localization.
The elevation of NF-B in degenerating CA1 neurons may be associated
mechanistically with apoptotic or necrotic cell death.
Key Words: apoptosis • cerebral ischemia, global • hippocampus
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