What causes oxidative stress after brain ischemia?
Recall that during ischemia, brain
tissue is unable to continue aerobic metabolism due to the loss of
oxygen and substrate, and ATP levels fall rapidly. This leads directly
to depolarization of the neuronal plasma membrane, a surge in
intracellular Ca++, and massive release of glutamate, which, among other things, further increases intracellular Ca++.
Both depolarization itself and the surge in intracellular Ca++
result in the activation of phospholipases, which immediately begin to
munch on the
membranes. That's bad enough, but one of the by-products of this process is the release
of free fatty acids (FFAs), particularly arachidonate.
This arachidonic acid hangs out
during ischemia and on into reperfusion, when oxygen gets added back
into the mix. As you may recall, arachidonate is a substrate of the
enzyme cyclooxygenase, which catalyzes the addition of two molecules of
oxygen to a FFA, yielding prostaglandin PGG. PGG in turn is rapidly
peroxidized to PGH, and in the process the species superoxide (.O2-) is released.
The story so far: Generation of superoxide during brain reperfusion.
Ischemia leads to a surge in intracellular calcium, which in turn
activates phospholipases, which generate FFAs. During reperfusion,
oxidation of FFAs leads to production of the radical species superoxide.
It's important to note
superoxide is produced all the time in normal cells, and it gets soaked
up by mitochondria and antioxidant enzymes and converted to water. In
brain ischemia, however, an overwhelming amount of lipolysis and
superoxide generation overwhelms these systems, which are under stress