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2-Vessel Occlusion/Hypotension: A Rat Model of Global Brain Ischemia
Published on: June 22, 2013
Cell-cycle regulators are involved in transient cerebral ischemia induced neuronal apoptosis in female rats
Yi Wen1, Shaohua Yang, Ran Liu
1Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX 76107-2699, USA.
Abstract:
Recent evidence indicates that cell-cycle regulating proteins are involved in apoptotic process in post-mitotic neurons. In this study, we examined cell-cycle regulators for G1/S cell-cycle progression after a transient focal cerebral ischemia induced by middle cerebral artery (MCA) occlusion. In the cerebral frontoparietal cortex, we observed a marked induction of Cyclin D1 (a coactivator of Cdks), and proliferating cell nuclear antigen (PCNA), together with upregulated Cdk kinase activities. This process is accompanied with multiple phosphorylation of retinoblastoma (Rb) protein at Cdk phosphorylation sites in neurons from the ischemic cortex. We further examined DNA synthesis by the incorporation of BrdU, a nucleotide analog that incorporates into newly synthesized DNA. Within 24-h of reperfusion after 60-min occlusion, substantial BrdU-positive neurons were observed in the ischemic cortex. Inhibition of Cdk4 activity during this ischemia/reperfusion is highly neuroprotective. These results suggest that ischemia/reperfusion cerebral damage induces signalings at the G1/S cell-cycle transition, and may constitute a critical step in the neuronal apoptotic pathway in ischemia/reperfusion induced neuronal damage.
Insights
Ischemia/reperfusion injury triggers cell-cycle progression in neurons, leading to DNA synthesis and cell death. Inhibiting cell-cycle progression offers neuroprotection against stroke damage.
Area of Science:
- Neuroscience
- Cell Biology
- Pathology
Background:
- Cell-cycle regulators are implicated in neuronal apoptosis.
- Post-mitotic neurons typically do not undergo cell-cycle progression.
Purpose of the Study:
- To investigate cell-cycle progression in neurons following focal cerebral ischemia.
- To determine the role of cell-cycle regulators in ischemia/reperfusion-induced neuronal damage.
Main Methods:
- Middle cerebral artery occlusion (MCAO) model in rodents to induce focal cerebral ischemia.
- Analysis of cell-cycle proteins (Cyclin D1, PCNA), Cdk activity, and retinoblastoma (Rb) protein phosphorylation.
- BrdU incorporation assay to assess DNA synthesis in neurons.
- Pharmacological inhibition of Cdk4 activity.
Main Results:
- Focal cerebral ischemia induced G1/S cell-cycle progression markers (Cyclin D1, PCNA) and Cdk activity in cortical neurons.
- Increased retinoblastoma protein phosphorylation was observed in neurons within the ischemic cortex.
- Significant BrdU incorporation, indicating DNA synthesis, occurred in neurons within 24 hours of reperfusion.
- Inhibition of Cdk4 activity demonstrated significant neuroprotection.
Conclusions:
- Ischemia/reperfusion injury in the brain activates G1/S cell-cycle transition signaling in neurons.
- Neuronal cell-cycle re-entry is a critical event in the apoptotic pathway following ischemic stroke.
- Targeting cell-cycle progression, specifically Cdk4, offers a potential therapeutic strategy for neuroprotection.
