Activation of the extracellular signal-regulated protein kinase cascade in the hippocampal CA1 region in a rat model of global cerebral ischemic preconditioning
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Abstract
A short period of sublethal preconditioning ischemia (3 min) followed by two days
of reperfusion provides almost complete protection against ischemic cell death induced
by a second (9 min) lethal ischemic episode. Here, we have investigated the extracellular
signal-regulated protein kinase kinase and extracellular signal-regulated protein
kinase, two kinases known to activate gene transcription and to be of importance for
cell survival, after sublethal preconditioning ischemia in the rat hippocampal CA1
region. The activation levels of these two kinases were also studied after a second
ischemic episode both in preconditioned and nonconditioned brains. An increased phosphorylation
of the extracellular signal-regulated protein kinase kinase was found in neuronal
cell bodies, particularly in the nucleus, 30 min, 4 h and two days of reperfusion
after preconditioning ischemia. Two days after preconditioning ischemia both extracellular
signal-regulated protein kinase kinase and extracellular signal-regulated protein
kinase were markedly phosphorylated. During the early reperfusion period (30 min)
after the second ischemic insult the phosphorylation levels of these two kinases were
increased in both nonconditioned and preconditioned brains. In the late reperfusion
time (one day), the phosphorylation levels of the extracellular signal-regulated protein
kinase kinase and extracellular signal-regulated protein kinase were decreased in
preconditioned brains, but remained elevated in nonconditioned brains. We conclude
that phosphorylation of the extracellular signal-regulated protein kinase kinase and
extracellular signal-regulated protein kinase after sublethal ischemia correlates
with the neuroprotection induced by preconditioning, possibly by transcriptional activation
of neuroprotective genes. Also, preconditioning enhances normalization of the disturbed
cell signaling through the extracellular signal-regulated protein kinase cascade induced
by lethal ischemia.