Abstract
Cell cycle proteins are mainly expressed by dividing cells. However, it is well established that these molecules play additional non-canonical activities in several cell death contexts. Increasing evidence shows expression of cell cycle regulating proteins in post-mitotic cells, including mature neurons, following neuronal insult. Several cyclin-dependent kinases (Cdks) have already been shown to mediate ischemic neuronal death but Cdk1, a major cell cycle G2/M regulator, has not been investigated in this context. We therefore examined the role of Cdk1 in neuronal cell death following cerebral ischemia, using both in vitro and in vivo genetic and pharmacological approaches. Exposure of primary cortical neurons cultures to 4 h of oxygen–glucose deprivation (OGD) resulted in neuronal cell death and induced Cdk1 expression. Neurons from Cdk1-cKO mice showed partial resistance to OGD-induced neuronal cell death. Addition of R-roscovitine to the culture medium conferred neuroprotection against OGD-induced neuronal death. Transient 1-h occlusion of the cerebral artery (MCAO) also leads to Cdk1 expression and activation. Cdk1-cKO mice displayed partial resistance to transient 1-h MCAO. Moreover, systemic delivery of R-roscovitine was neuroprotective following transient 1-h MCAO. This study demonstrates that promising neuroprotective therapies can be considered through inhibition of the cell cycle machinery and particularly through pharmacological inhibition of Cdk1.
Highlights
Despite several neuroprotective clinical trials, protecting the brain against ischemic injury, the second leading cause of death affecting one in every six people worldwide, remains an unsolved and challenging question
We demonstrate that cyclin-dependent kinases (Cdks)[1] is re-expressed in neurons deprived of oxygen and glucose (oxygen–glucose deprivation (OGD) model) and that the lack of Cdk[1] in cortical neuronal cultures drastically increases neuronal survival/death ratio following OGD
No difference of cell survival was observed at 4 h between conditions (Fig. 1b), incubation in OGD medium for 24 h led to increase in neuronal death, as compare with control
Summary
Despite several neuroprotective clinical trials, protecting the brain against ischemic injury, the second leading cause of death affecting one in every six people worldwide, remains an unsolved and challenging question. Understanding the molecular mechanisms underlying stroke pathophysiology is critical to develop more effective therapies. Neurons undergo irreversible damage in the ischemic necrotic core within minutes or few hours. Surrounding the ischemic core, the moderately perfused peri-infarct area undergoes delayed neuronal death within hours or days, via excitotoxicity[2] or other mechanisms. This delayed neuronal loss represents a therapeutic time window for neuroprotective strategies. This has not yet been translated into clinical trials. The lack of understanding regarding the intrinsic signaling pathways involved in neuronal apoptotic death may be a critical
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