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2-Vessel Occlusion/Hypotension: A Rat Model of Global Brain Ischemia
Published on: June 22, 2013
Modulation of ERK and JNK activity by transient forebrain ischemia in rats
Deborah A Shackelford1, Richard Y Yeh
1Department of Neurosciences, University of California at San Diego, La Jolla, CA 92093-0624, USA. dshackelford@ucsd.edu
Abstract:
The mitogen-activated protein (MAP) kinase families of ERK and JNK participate in numerous intracellular signaling pathways and are abundantly expressed in the CNS. Activation of ERK and JNK during reperfusion of ischemic tissue is implicated in promoting cell death, insofar as inhibition of either pathway reduces neuronal cell death. However, ERK or JNK activation provides protection in other neuronal injury models. In this study, we monitored the concurrent modulation of ERK and JNK activity in the hippocampus, neocortex, and striatum during ischemia and immediately upon reperfusion in a rat model of transient global ischemia. All three regions incur a similar reduction in blood flow during occlusion but show different extents and temporal patterns of injury following reperfusion. ERK and JNK were active in the normal rat forebrain, and phosphorylation was reduced by ischemia. Upon reperfusion, ERK was rapidly activated in the hippocampus, neocortex, and striatum, whereas JNK phosphorylation increased in the hippocampus and striatum but not in the neocortex. The response of JNK vs. ERK more closely reflects the susceptibility of these regions. JNK1 was the predominant phosphorylated isoform. A minor pool of phosphorylated JNK3 increased above the control level after reperfusion in hippocampal but not in neocortical particulate fractions. In addition, a novel 32-35-kDa c-Jun kinase activity was detected in the hippocampus, neocortex, and striatum. The results show that ERK and JNK activities are rapidly, but not identically, modulated by ischemia and reperfusion and indicate that the MAP kinase pathways contribute to regulating the response to acute CNS injury.
Insights
Mitogen-activated protein (MAP) kinase pathways, ERK and JNK, are modulated by ischemia and reperfusion in the rat brain. Their differential activation in brain regions suggests a role in acute central nervous system injury.
Area of Science:
- Neuroscience
- Cell Signaling
- Molecular Biology
Background:
- Mitogen-activated protein (MAP) kinase families, including ERK and JNK, are crucial for intracellular signaling and are highly expressed in the central nervous system (CNS).
- Activation of ERK and JNK during reperfusion following ischemia is linked to neuronal cell death, though these pathways can also be protective in other neuronal injury models.
Purpose of the Study:
- To investigate the concurrent modulation of ERK and JNK activity in the hippocampus, neocortex, and striatum during transient global ischemia and immediate reperfusion in a rat model.
- To correlate the regional activation patterns of ERK and JNK with the varying susceptibility of these brain areas to ischemic injury.
Main Methods:
- Transient global ischemia was induced in rats, and blood flow reduction was monitored.
- ERK and JNK activity (phosphorylation levels) were assessed in the hippocampus, neocortex, and striatum during ischemia and reperfusion.
- Specific JNK isoforms (JNK1, JNK3) and novel kinase activities were analyzed.
Main Results:
- Ischemia reduced baseline ERK and JNK phosphorylation. Upon reperfusion, ERK was rapidly activated across all three regions.
- JNK phosphorylation increased in the hippocampus and striatum but not the neocortex, mirroring regional injury patterns.
- JNK1 was the predominant isoform, with increased JNK3 observed in the hippocampus post-reperfusion. A novel 32-35-kDa c-Jun kinase activity was detected in all regions.
Conclusions:
- ERK and JNK activities are rapidly and differentially modulated by ischemia and reperfusion in the rat brain.
- The distinct regional responses of ERK and JNK suggest their involvement in regulating the brain's response to acute CNS injury.
- MAP kinase pathways play a significant role in the complex cascade of events following ischemic insult.
