Expression of cyclin-dependent kinase 5 mRNA and protein in the human brain following acute ischemic stroke
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Nicholas Mitsios1, Roberta Pennucci, Jerzy Krupinski
1School of Biology, Chemistry and Health Science, Manchester Metropolitan University, Manchester, UK.
Abstract:
Neuronal cell death after brain ischemia may be regulated by activation of cyclin-dependent kinase 5 (Cdk5). In this study, expression of Cdk5 and its activator p35/p25 was examined in human post-mortem stroke tissue and in human cerebral cortical fetal neurons and human brain microvascular endothelial cells exposed to oxygen-glucose deficiency and reperfusion. The majority of patients demonstrated increased expression of Cdk5 and p-Cdk5 in stroke-affected tissue, with about a third showing increased p35 and p25 cleaved fragment as determined by Western blotting. An increase in Cdk5-, p-Cdk5- and p35-positive neurons and microvessels occurred in stroke-affected regions of patients. Staining of neurons became irregular and clumped in the cytoplasm, and nuclear translocation occurred, with colocalization of p35 and Cdk5. Association of Cdk5 with nuclear damage was demonstrated by coexpression of nuclear Cdk5 in TUNEL-positive neurons and microvessels in peri-infarcted regions. In vitro studies showed up-regulation and/or nuclear translocation of Cdk5, p-Cdk5 and p35 in neurons and endothelial cells subjected to oxygen-glucose deficiency, and strong staining was associated with propidium iodide positive nuclei, an indicator of cellular damage. These results provide new evidence for a role of Cdk5 in the events associated with response to ischemic injury in humans.
Insights
Cyclin-dependent kinase 5 (Cdk5) activation is linked to neuronal cell death following brain ischemia. This study found increased Cdk5 expression in human stroke tissue, suggesting its role in ischemic injury response.
Area of Science:
- Neuroscience
- Molecular Biology
- Pathology
Background:
- Brain ischemia can lead to neuronal cell death.
- Cyclin-dependent kinase 5 (Cdk5) is implicated in regulating this process.
- Cdk5's role in human ischemic stroke requires further investigation.
Purpose of the Study:
- To examine the expression and localization of Cdk5 and its activators (p35/p25) in human post-mortem stroke tissue.
- To investigate the role of Cdk5 in cellular damage in neurons and microvessels under oxygen-glucose deprivation and reperfusion conditions in vitro.
Main Methods:
- Western blotting and immunohistochemistry on human post-mortem stroke tissue.
- In vitro studies using human cerebral cortical fetal neurons and brain microvascular endothelial cells subjected to oxygen-glucose deprivation and reperfusion.
- TUNEL assay and propidium iodide staining to assess cellular damage.
Main Results:
- Increased expression of Cdk5, p-Cdk5, and p35/p25 was observed in stroke-affected human brain tissue.
- Cdk5, p-Cdk5, and p35 showed increased presence in neurons and microvessels within stroke regions.
- In vitro studies demonstrated Cdk5 up-regulation and nuclear translocation in response to oxygen-glucose deprivation, correlating with cellular damage.
Conclusions:
- The study provides evidence for the involvement of Cdk5 in the cellular response to ischemic injury in the human brain.
- Cdk5 activation and nuclear translocation are associated with neuronal and microvessel damage following ischemia.
- Cdk5 may represent a therapeutic target for mitigating ischemic brain damage.
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01:15Ischemic Stroke ll: Pathophysiology
01:15Ischemic Stroke l: Introduction