Genetic and pharmacological inhibition of Cdk1 provides neuroprotection towards ischemic neuronal death

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.

Cellular and Molecular Mechanisms of R/S-Roscovitine and CDKs Related Inhibition under Both Focal and Global Cerebral Ischemia: A Focus on Neurovascular Unit and Immune Cells

“…Both ( R )- and ( S )-roscovitine showed a protective effect on global and focal cerebral ischemia models [ 58 , 59 , 60 , 61 ] ( Figure 2 ). We will describe the effects of ( R )- and ( S )-roscovitine on neurological score, infarct size, and cerebral edema.…”

“…In a 2 h tMCAo rat model, ( R )-roscovitine, injected intravenously (IV) 15 min before MCAo, decreased neurological score (mNSS) 22 h after reperfusion compared to vehicle [ 62 ]. ( R )-roscovitine showed a neuroprotective effect on a 1h mice tMCAo model [ 61 ]. Intraperitoneal injection (IP) of ( R )-roscovitine 15 min before surgery and 1- and 3-h post-surgery decreased neurological score 24 h post-MCAo compared to the vehicle-treated group.…”

“…Specific inhibition of either CDK1 or CDK5 showed a beneficial effect on neurological score following ischemic stroke. In a tMCAo mice model, Marlier et al [ 61 ] observed that CDK1-cKO mice had a lower neurological score compared to WT. Interestingly, neurological score was significantly lower in ( R )-roscovitine-treated mice compared to CDK1-cKO.…”

The Role of CDKs and CDKIs in Murine Development

“…Functional roles for CDKs in brain development have so far been restricted to just a handful. While it is essential for embryonic development and assumedly in brain development, Cdk1 does not appear to have a postmitotic role in neurons, with a cKO in such cells resulting in normal development [ 25 ]. Further testing of a Cdk1 role in different regions of the brain remains unfeasible outside of postmitotic cells.…”

Geroprotective properties of neuroprotective and neurotrophic peptides

“…При повреждении ДНК СDK1 инактивируется белком EIF2AK2 для остановки цикла деления клетки и активации механизмов репарации ДНК [31]. Ингибирование CDK1 тормозит апоптоз нейронов, вызванный ишемией вследствие дефицита глюкозы и кислорода в эксперименте [32]. Ограничение избыточного потребления глюкозы приводит к кратковременной остановке клеточного цикла посредством ингибирования CDK1, что продлевает жизнь клеток [33].…”