Scientific Base

It is now widely accepted that not all brain cells die immediately after stroke. Surrounding a core of severe and rapid tissue injury, brain cell death spreads more slowly in a heterogeneous region called the penumbra. Therapeutic strategies have thus focused on the development of agents that could slow the progression of neuronal death in the penumbra. Multiple mechanisms intervene in neuronal loss including an excessive accumulation of glutamate that acts via glutamate receptors to cause cell death, a process called “excitotoxicity”. Several observations suggest that excitotoxic damage includes a significant component mediated by an apoptotic type of signalization pathway.

There is now abundant evidence that families of serine/threonine kinases, the cyclin-dependent kinases (CDKs), are key elements in the apoptotic pathway. Within this cascade of events, CDK5 exerts a central role as a key regulator of neuronal death and survival and has been associated to several neurodegenerative diseases including cerebral ischemia. Despite accumulating evidences that CDK5 may be an essential target for therapeutic treatment of neurological diseases, only few attempts to regulate CDK5 activity in vivo have been reported so far. Moreover, up-regulation of cell cycle proteins (Cyclin D1, CDK4, and CDK2) is also associated with the proliferation and the activation of glial cells after cerebral ischemia. Activated microglia induced by cerebral ischemia displays a detrimental effect on injured neurons, by promoting the release of pro-inflammatory molecules that contribute to neurotoxicity.

The notion that CDKs could represent potential therapeutic targets for the treatment of stroke has often been proposed. There is growing evidence that CDK inhibitors are protective for neurons and oligodendrocytes, and that they inhibit cell cycle and consequently inhibit microglial cells proliferation, which may play a deleterious effect in ischemic lesion.